Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:13][C@H:10]1[CH2:11][CH2:12][C@@H:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])=[O:3]
Reactant: C[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@@H](C)CC1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (19.3 mL) was slowly added dropwise to a solution of cis-4-methylcyclohexanol (14.2 g) and triethylamine (34.5 mL) in methylene chloride (250 mL) with stirring at 0° C. The mixture was heated to room temperature, stirred for 3 hours, and then separated into aqueous and organic layers by the addition of water, followed by extraction with methylene chloride. The organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product of cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) was used without further purification in the next reaction. Cesium carbonate (60.1 g) and cis-4-methylcyclohexyl methanesulfonate (approximately 24 g) were added to a solution of ethyl 1H-imidazol-4-ylacetate (9.48 g) in N,N-dimethylformamide (120 mL). The mixture was stirred at 110° C. for 9 hours and then separated into aqueous and organic layers by the addition of water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (1.77 g).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:23]3[C:22]4[C:26](=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=4)[NH:25][C:24]3=[O:29])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A stirred solution of 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (67 mg, 0.267 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with ethanol (1 ml×3) and purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[N:29]=[C:28]([C:9]2[CH:10]=[C:11]([N:15]3[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:12]=[CH:13][CH:14]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CC1(C)OB(c2cccc(N3CCC(=O)CC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Product: O=C1CCN(c2cccc(-c3ccnc(Cl)n3)c2)CC1

Procedure:
1-(3-(2-Chloropyrimidin-4-yl)phenyl)piperidin-4-one was prepared from 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-one and 2,4-dichloropyrimidine according to procedure B.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].C[O-].[Na+].[CH2:15]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:4]2[CH:5]3[C:8]([CH3:10])([CH3:9])[C:1]([CH3:11])([CH2:7][CH2:6]3)[C:2]2=[O:3])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1

Procedure:
A solution of 100 millimols (15.2 g) of camphor in 250 ml of toluene is heated for 1 hour at the boil with 100 mmols (5.4 g) of sodium methylate. After cooling, 100 mmols (17.8 g) of p-butoxybenzaldehyde are introduced and the mixture is heated at the reflux temperature for 4 hours. The reaction mixture is cooled and 50 ml of water are then added; the toluene phase is separated off, washed with water, dried over sodium sulphate and concentrated to dryness. The solid residue is crystallised from aqueous isopropanol. After drying, 12 g of a white powder, which melts at 62°, are collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][CH2:33][CH3:34])(=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:42]
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), adipic acid monoethyl ester (0.25 g, 1.44 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified by chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.275 g), melting point: 88° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11](Br)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc(Br)c2ncccc2c1
Product: CCc1cc(-c2ccc(Cl)c(Cl)c2)c2ncccc2c1

Procedure:
6-ethyl-8-bromoquinoline and 3,4 dichlorobenzene boronic acid can be combined to form 6-ethyl-8-(3,4-dichlorophenyl)quinoline,
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1[O:34][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>P([O-])([O-])([O-])=O.C(#N)C1C=CC=CC=1>[C:13]([NH2:20])(=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
TG1/pNHJ10H and TG1/pNEJ20L were inoculated into 10 ml of 2×YT medium containing 50 μg/ml of ampicillin and incubated at 30° C. overnight (12 hours). 1 ml of the resultant culture was added to 100 ml of 2×YT medium (50 μg/ml of ampicillin, 0.1 g of CoCl2.6H2O/l). The mixture was incubated at 30° C. for 4 hours. IPTG was added to the mixture to a final concentration of 1 mM. The mixture was incubated at 30° C. for 10 hours. After harvesting the cells, the cells were suspended in 5 ml of 0.1M phosphate buffer (pH 7.5). The suspensions were disrupted by sonification for 5 min and centrifuged at 12,000×g for 30 min. The resulting supernatants were used for the enzyme assay. The enzyme assay was carried out in a reaction mixture (12 ml) containing 50 mM potassium phosphate buffer (pH 7.5), 6 mM benzonitrile and an appropriate amount of the enzyme. The reaction was carried out at 20° C. for 30 min and stopped by the addition of 0.2 ml 1M HCl. The amount of benzamide formed in the reaction mixture was determined by HPLC. As a control, the mixture obtained by the same procedure as described above but from E. coli TG1 was used. The levels of nitrile hydratase activity in cell-free extracts of E. coli containing pNHJ10H and pNHJ20L were 1.75×10-3 and 6.99×10-3 units/mg, respectively, when cultured in 2×YT medium in the presence of CoCl2 and IPTG. Benzamide was found in the reaction mixture of TG1/pNHJ10H and pNHJ20L, whereas no benzamide was found in the reaction mixture of TG1. A number of references are cited herein, the disclosures of which are incorporated in their entirities, by reference herein.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CON(C)[C:23]([CH:25]1[CH2:28][CH2:27][CH2:26]1)=[O:24]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:23]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)C1CCC1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)C3CCC3)cc21

Procedure:
Prepared from 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester and cyclobutanecarboxylic acid methoxy-methyl-amide using a procedure analogous to that of Preparation 263. MS: [M+H]+=331.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:22]1[CH:27]=[C:26]2[O:28][S:29]([C:32]3=[CH:33][CH:34]=[CH:35][C:24](=[C:25]23)[CH:23]=1)(=[O:31])=[O:30]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:29]([C:32]3[C:25]4[C:24](=[CH:23][CH:22]=[CH:27][C:26]=4[OH:28])[CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S1(=O)Oc2cccc3cccc1c23
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3cccc(O)c23)CC1
Temperature: 100 °C

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 1,8naphthalene sultone by heating to 100° C. for 30 minutes and subsequently heating to 140° C. for 20 minutes. After cooling, the product obtained is purified over a silica gel column (eluant: ethyl acetate/methanol=9:1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7][C:6]=1[NH2:12])C.C(O)(=O)C.[CH:18](N)=[NH:19]>C(OCCO)C>[Cl:11][C:9]1[CH:8]=[N:7][C:6]2[N:12]=[CH:18][N:19]=[C:4]([OH:3])[C:5]=2[CH:10]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Oc1ncnc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 2-amino-5-chloro-nicotinic acid ethyl ester (1.5 g, 7.38 mMol) and formamidine acetate (3.1 g, 29.51 mMol) in 2-ethoxyethanol (50 mL) was heated at reflux overnight. The solution was cooled to room temperature, and allowed to stand for 2 hours. The resulting precipitate was collected by filtration, rinsed with a small amount of 2-ethoxyethanol followed by diethyl ether (10 mL), and allowed to air dry. The filtrate was concentrated in-vacuo, and the residue was triturated with methylene chloride. The resulting solids were combined with the solids from the earlier filtration, and this material was crystallized from methanol to yield 475 mg of tan needles as product, in three crops. MS (ES+)=182 (M+H)+. Yield=37%.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:21][CH2:20]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: CC1CCNCC1
Product: CC1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 377 mg (3.80 mmol) of 4-methylpiperidine to give 65 mg (54% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][S:24][CH2:23][CH2:22][NH:21]1)=[O:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]([O:37][C@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:37][C@H:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([N:21]1[CH2:22][CH2:23][S:24][CH2:25][C@H:20]1[C:18](=[O:19])[NH:17][CH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[O:40])(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1
Reactant: CC(=O)O[C@@H](C(=O)Cl)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](C(=O)N1CCSC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of (R)-tert-Butyl-4-chloro-2-{(thiomorpholine-3-carboxamido)-methyl}-benzyl-carbamate (0.56 g, 1.40 mmol) in CH2Cl2 (25 mL) was added triethyl amine (0.59 mL, 4.2 mmol) and solution of (2R)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl acetate (0.496 g, 2.8 mmol) in CH2Cl2 (5 mL) dropwise at −10° C. and the resulting mixture was allowed to warm up to room temperature over 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile/water) to obtain the title compound (0.42 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 80 °C

Procedure:
2,3-Dichloropyridine (15.0 g, 101.6 mmol), piperazine(9.78 g, 113.70 mmol), and triethylamine (14.36 g, 141.95 mmol) were dissolved in 300 mL of DMSO and the resulting mixture was heated at about 80° C. for about 24 h. The reaction mixture was then cooled to room temperature and extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, concentrated, and purified using a silica gel column eluted with a gradient elution from ethyl acetate to 2:1 ethyl acetate:methanol to provide N-(3-chloropyridin-2-yl)-piperazine (compound 1) as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:18][C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[C:9](=[O:16])[C:10](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.50 g), 2-thiophenecarboxaldehyde(0.34 g), piperidine(0.43 g) and molecular sieve 4A in toluene was stirred at 80° C. for 7 hrs. The reaction solution was filtered (celite), evaporated and recrystallised (ethanol) to give ethyl 4-methyl-4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo-4H-1,3-oxazin-3-yl)-2-(2-thienylmethylidene)-3-oxo-pentanoate (Compound 206, 0.20 g), NMR 1.23(t,3H) 1.58(s,6H) 1.94(s,3H) 4.29(q,2H) 5.19(s,2H) 7.05(7.20-7.37(6H) 7.48(1H) 8.05(s,1H). By proceeding in a similar manner the following compounds were also obtained:
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:6])[CH3:5].O>C(O)C>[Cl:13][C:11]1[CH:12]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:15])=[O:2])[CH:8]=[C:9]([Cl:14])[CH:10]=1
Reactant: COC(=O)C(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1cc(Cl)cc(Cl)c1
Yield: 98.9 %

Procedure:
To a solution of 9.0 g (36 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid methyl ester in 40 ml ethanol 40 ml 2 N sodium hydroxide solution was added. After stirring for 4 hrs at RT 150 ml water was added and the solution washed twice with 200 ml Et2O. The aqueous phase was acidified with 25% hydrochloric acid solution and three times extracted with 150 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated to yield 8.3 g (97%) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid as a off-white solid.
Reaction SMILES: C(N[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=O)CC.[C:13](NC1C=C(C=CC=1)N)(=[O:17])CCC.C(NC1C=C(C=CC=1)N)(=O)C1C=CC=CC=1>>[NH2:9][C:8]1[CH:7]=[C:6]([O:17][CH3:13])[CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)Nc1cccc(N)c1
Reactant: CCCC(=O)Nc1cccc(N)c1
Agent: Nc1cccc(NC(=O)c2ccccc2)c1
Product: COc1cccc(N)c1

Procedure:
m-propionylaminoaniline, m-butyrylaminoaniline or m-benzoylaminoaniline;
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[CH3:36][S:37][C:38](=[NH:40])[NH2:39]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:39]=[C:38]([S:37][CH3:36])[N:40]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (200 mg, 0.618 mmol) in DMF (5.154 ml) was added potassium carbonate (256 mg, 1.855 mmol) and 2-methyl-2-thiopseudourea sulfate (129 mg, 0.928 mmol). The reaction was warmed to 120° C. and stirred for 1 hr. The solvent was evaporated and the crude residue partitioned between DCM and water. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude product was purified by flash chromatography with a gradient of 2-10% MeOH in DCM and further purified reverse phase HPLC with a gradient of 10-100% MeCN in H2O to give 7.8 mg of the desired product as a white solid. HRMS (ES+)=351.1391. UV-LC: 100/100% UV purity at 214/254 nm; HPLC: tR=3.38 minute over 7.75 minutes. 1H NMR (400 MHz, MeOD) δ ppm 0.10-0.14 (m, 2H) 0.41-0.47 (m, 2H) 1.03-1.15 (m, 1H) 2.63 (s, 3H) 2.94 (d, J=7.07 Hz, 2H) 7.18 (d, J=5.56 Hz, 1H) 7.83 (d, J=7.07 Hz, 2H) 8.31 (d, J=7.07 Hz, 2H) 8.64 (s, 1H) 8.65 (d, J=5.05 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](=O)[CH3:7])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:16][S:19][C:6]=1[CH3:7])=[O:17])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)nsc1C
Yield: 39.7 %

Procedure:
To a solution of the 2-(amino-phenyl-methylene)-3-oxo-butyric acid ethyl ester (41 g, 170 mmol) in toluene (340 mL) were added P2S5 (117.3 g, 520 mmol) and tetrachloro-1,4-benzoquinone (43.2 g, 170 mmol) at r.t. with stirring. The mixture was then refluxed with stirring for 15 min. After cooling to r. t. the mixture was filtered and the filtrate was concentrated to give a brown oil, which was purified by flash column chromatography on silica gel. Elution with 5-35% EtOAc/hexanes gave the title compound as a reddish oil (16.7 g): MS (m/z) 248.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:18]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])([CH3:1])[CH3:10])=[CH:5][CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(Cc1ccccc1)NC(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CC(C)(C)NC(=O)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 99 %

Procedure:
A flame-dried 250 ml flask was charged with N-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (5.93 g, 24.2 mmol), acetyl chloride (4.00 g, 55.6 mmol), and methylene chloride. The resulting solution was cooled to about 0° C., and aluminum (III) chloride (11.0 g, 82.2 mmol) was added in portions over about thirty minutes. Over the course of the addition, the solution changed from colorless to greenish-brown. After the addition was complete, the solution was heated to reflux for about thirty minutes, and was then cooled to room temperature and poured over 300 ml of ice water. After stirring for about ten minutes, the mixture was diluted with 125 ml of methylene chloride, and the layers were separated. The aqueous layer was extracted with an additional 125 ml of methylene chloride. The combined organic extracts were then washed with water and brine, sequentially, and then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil, (6.9 g, 99% yield) which was ascertained to be about 85% pure by NMR, was carried into the subsequent reaction without further purification. LRMS ([M+1]+)=288.2.