Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:21]([O:23]C)=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[K+]>O1CCOCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(C2=C(C(=O)OC)CCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1nc2ccccc2n1Cc1ccc(C2=C(C(=O)O)CCC2)cc1
Yield: 67.6 %

Procedure:
A mixture of methyl 2-[4-[(2-propyl-1H-benzimidazol-1-yl)methyl]phenyl]-1-cyclopentene-1-carboxylate (1.60 g, 4.27 mmol), 1N KOH (8.5 mL), and dioxane (8.5 mL) was heated under reflux for 1 h. The mixture was concentrated, diluted with water (10 mL), and extracted with ether (discarded). The aqueous phase was neutralized with 1N HCl (8.5 mL) and the white precipitate was collected by filtration. Trituration with EtOH gave 1.04 g (68%) of product, mp 224°-226° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@H:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1

Procedure:
223 g of N-carbobenzoxy-L-phenylalanyl-L-proline tert.-butyl ester is hydrogenated in analogous manner to step (b), using 2100 ml absolute tetrahydrofuran as solvent instead of ethanol, to give the heading compound as a colourless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[N:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[N:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1cncc(N2C[C@@H](C)O[C@@H](C)C2)n1
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)cnc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (272 mg, 1.529 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[6-(2-methyl-3-furanyl)-2-pyrazinyl]morpholine (418 mg, 1.529 mmol) in chloroform (13 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS shows desired product can be seen and no starting material left, so reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (50 mL), brine (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜5 mL) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound (210 mg, 0.566 mmol, 37.0% yield). LC/MS [M+H]+=352/354.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:11][C:10]([CH2:12][CH2:19][N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)s1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(F)cc2)s1
Temperature: 110 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
To an acetic acid (20.0 mL) solution of 5-(4-fluoro-phenoxy)-thiophene-2-carbaldehyde (2.60 g, 11.7 mmol) described in Manufacturing Example 91-1-2 were added nitromethane (3.57 g, 58.5 mmol) and ammonium acetate (1.80 g, 23.4 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 110° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (3.00 g). To a dimethyl sulfoxide (30.0 mL) solution of this crude product (3.00 g) and acetic acid (3.00 mL) was added sodium borohydride (684 g, 18.1 mol) at room temperature while cooling appropriately, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (1.38 g, 45.7%).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)C1)C2.C1(CCO)CCCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH2:35][CH:44]2[CH2:38][CH2:37][CH2:43][CH2:41][CH2:40][CH2:39]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCCC1CCCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cycloheptylethanol, the title compound was obtained as a colorless solid (0.11 g, 26%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 4.16 (t, J=6.2 Hz, 2H), 2.87 (s, 6H), 1.76-1.35 (m, 13H), 1.29-1.17 (m, 2H); MS (ES−) m/z 419.1, 421.1 (M−1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH4+].[OH-:10].[OH-].[Na+]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: [OH-]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
Cell mass grown according to example C is suspended in 16 liters of a 240 g/l solution containing fumaric acid (neutralized with NH4OH and NaOH in the molar ratio of 2 to 1). The concentration of the cell mass in the fumaric acid solution amounts to 6 g/l (calculated as dry mass). After 24 hours of incubation, 234 g of L-malic acid per liter of fermentation liquid is produced.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1)([CH3:34])([CH3:33])[CH3:32].CC(C)([O-])C.[Na+].C(C1C=C(C(C)C)C=C(C(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)(C)C>O1CCOCC1>[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[N:17]=[C:18]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[O:19][C:20]=4[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=3)[CH2:3][CH2:2]2)=[CH:39][CH:38]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 105 °C
Yield: 12.3 %

Procedure:
To a mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (227 mg, 0.55 mmol), 4-bromobenzoic acid tert-butyl ester (170 mg, 0.66 mmol), sodium tert-butoxide (106 mg, 1.1 mmol) and (2′,4′,6′-triisopropyl-1,1′-biphenyl-2-yl)dicyclohexylphosphine (X-PHOS, 38 mg) in dioxane (5 mL) bubbled with argon was added tris(dibenzylideneacetone)dipalladium Pd2(dba)3 (23 mg). The mixture was heated at 105° C. for 2 hrs. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was dried and concentrated. The residue was crystallized from ethyl acetate to give a pale yellow solid as 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid tert-butyl ester (40 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=N[CH2:25][CH2:26][CH2:27][N:28](C)C.C(N(CC)CC)C>ClCCl>[CH:27]1([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])[CH:11]=2)[CH2:25][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NC2CC2)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further minutes. Cyclopropyilamine (0.027 g, 0.38 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford N-cyclopropyl-3-(5-dimethylcarbamoyl-pent-1-ynyl)benzamide (25) (0.10 g, 0.34 mmol, 91% yield).
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=[CH:3]1.[C:12]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:16][CH:15]=1)#[CH:13]>>[OH:8][C:7]1[N:2]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:32][CH:33]=2)[CH:3]=[N:4][C:5]2=[N:11][CH:10]=[CH:9][C:6]=12
Reactant: Oc1c2ccnc-2ncn1I
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC

Procedure:
By allowing 3-iodo-4-hydroxypyrrolo[2,3-d]pyrimidine to react with dimethyl N-(4-ethynylbenzoyl)-L-glutamate in the manner described in Example 2, there is obtained dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which is purified by chromatography over silica, m.p. 160 ° C. (dec.). 1NMR (d6 -DMSO)δ1.98-2.15 (m, 2H), 2.45 (t, J=7.5 Hz, 2H) 3.57 (s, 3H), 3.64 (s, 3H), 4.40-4.45 (m, 1H), 7.51 ((d, J=2.5 Hz, 1H), 7.55 (d, J=8.2 Hz, 2 H), 7.87 (s, 1H), 7.90 (d, J=8.2 Hz, 1 H), 11.97 ((d, J=3.7 Hz, 1 H), 12.31 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH:32]1([CH2:38][NH2:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:32]1([CH2:38][NH:39][C:16](=[O:18])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:20][CH2:19][C:5]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NCC1CCCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NCC2CCCCC2)CCN(C)C1
Reaction time: 16 h

Procedure:
3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid was mixed with EDCI and cyclohexylmethanamine in dichloromethane and the reaction mixture was stirred for 16 h to obtain N-(cyclohexylmethyl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C1C=CC=CC=1.Cl.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: COC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC1(c2ccc(OC(C)=O)cc2)Sc2ccccc2N(C)C1=O
Reaction time: 3 h
Yield: 52.7 %

Procedure:
3,4-Dihydro-2-(4-hydroxyphenyl)-2-methoxy-4-methyl-3-oxo-2H-1,4-benzothiazine (0.2 g, compound No. 5) is dissolved in a mixture of acetic anhydride (2 ml) and pyridine (5 ml). The mixture is standed for 3 hours at room temperature, and then poured into a mixture of benzene and dilute hydrochloric acid. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 0.1 g (52.7%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13]Cl)[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[I-].[Na+]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:7]([O:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1COCCN1
Reactant: COc1cc(C#N)c(N)cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Product: COc1cc(C#N)c(N)cc1OCCCN1CCOCC1

Procedure:
A mixture of 2-amino-4-chloropropoxy-5-methoxy-benzonitrile (1.000 g, 4.12 mmol), morpholine (1.0 mL) and catalytic amount of sodium iodide were added into a round bottom flask. The solution was stirred and heated under reflux for 2 h. After reaction, extracted the solution with dichloromethane and water, and then combined the organic phases. After evaporating most of the solvent, equivalent amount of hydrochloric acid ether was added into the solution, and filtered to yield 1.100 g of white solid product with a recovery rate of 91%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 102.9 %

Procedure:
To a mixed solution of a commercially available product of 4-bromo-3-fluorophenol (15.0 g, 78.5 mmol) and DMF (30 mL) were added potassium carbonate (21.7 g, 157 mmol) and benzyl bromide (10.2 mL, 86.4 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 20 minutes and then at 70° C. for 40 minutes. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (22.7 g, yield: quantitative).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=O.[CH3:8][NH:9][C:10]([NH2:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:8][N:9]1[C:1](=[O:7])[CH2:2][C:3](=[O:5])[NH:12][C:10]1=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(N)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)NC1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
To a solution of malonic acid (80 g, 0.79 mol) and methylurea (50 g, 0.68 mol) in 180 ml of acetic acid at 70° C., acetic anhydride (130 ml, 1.37 mol) is added slowly. After the completion of the addition, the reaction mixture is stirred at 90° C. for 3 hours, and then cooled to room temperature. The solvent is removed under reduced pressure, and the residue is treated with 350 mL of ethanol to precipitate out yellowish solid. The solid is recrystallized from ethanol to give 63.1 g product as crystalline solids (Yield: 65.8%). m.p.=131.2-133.1° C. [Lit.1: m.p.=130-131.5° C.].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:12]([C:9]([N:19]([CH3:21])[CH3:20])([CH2:10][CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:3][CH:4]=1)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Temperature: 25 °C

Procedure:
608.7 g (2.03 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one (Example 1, B), 354.2 g (4.06 mol) of morpholine, 562 g (4.06 mol) of K2CO3 and 2000 ml of dimethylsulfoxide are heated at 160° for 12 hours, with stirring. After this time, a sample no longer shows any starting ketone in a thin-layer chromatogram. The reaction solution is cooled to room temperature, poured onto ice and extracted with methylene chloride. The organic phase is dried over MgSO4, filtered and evaporated. The oily residue crystallizes from ethanol. The product melts at 111°-119°.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14][CH2:13]2>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:18]([N+:7]([O-:8])=[O:6])[CH:19]=1
Reactant: O=[N+]=O
Reactant: Clc1ccc2c(c1)CCCC2
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)cc2c1CCCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50.3 %

Procedure:
To a suspension of 85% nitronium tetrafluoroborate (6.19 g, 39.6 mmol) in dichloromethane (60 mL) was added dropwise a solution of 6-chlorotetralin (6.0 g, 36 mmol) in dichloromethane (60 mL) over 15 min at 0° C. The mixture was stirred for 40 min at 0° C. and quenched by addition of ice-water (100 mL). The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 30:1~4:1 hexane/toluene to give 3.83 g of the title compound (54%): 1H NMR (CDCl3) δ7.65 (d, 1H, J=2.3 Hz), 7.30 (d, 1H, J=8.9 Hz), 2.90 (m, 4H), 1.76 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[CH3:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(Br)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2 g, 9.3 mmol) was dissolved in 100 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (4.5 mL, 55 mmol) followed by the dropwise addition of oxalyl chloride (2.4 mL, 27 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (0.95 g, 4.0 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 1.3 mL pyridine followed by 4-bromo-2-methylaniline (0.75 g, 4.0 mmol). The reaction was allowed to warm to ambient temperature, stirred overnight then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (1.09 g, 70%) APCI (AP−): 381.0, 383.0 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:40])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:39])(=[O:14])=[O:15])=[CH:9][C:8]=1[O:40][C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.072 g, 0.131 mmol), pyridine (63.4 μL, 0.784 mmol) and benzoyl chloride (30.5 μL, 0.262 mmol) to give a quantitative yield of the title compound. 1H NMR (DMSO-d6) δ 1.33 (s, 9 H), 1.57 (s, 3 H), 2.17 (s, 6 H), 2.31 (s, 3 H), 7.17 (s, 2 H), 7.36-7.48 (m, 3 H), 7.62-7.68 (m, 3 H), 7.78-7.82 (m, 1 H), 7.96 (t, 1 H), 8.10-8.24 (m, 4 H), 8.49 (s, 1 H).