Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(CC2[C:16]([OH:17])=[C:15](C(O)=O)[C:14]3[C:9](=[C:10]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=CC=1.C(C1C=CC=C2C=1NC(=[O:40])C2=O)C.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C.ClC1C=CC(CC2C(O)=C(C(O)=O)C3C(=C(CC)C=CC=3)N=2)=CC=1>>[C:21]1([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[NH:8][C:16](=[O:17])[C:15]3=[O:40])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cccc2c1NC(=O)C2=O
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Agent: CCc1cccc2c(C(=O)O)c(O)c(Cc3ccc(Cl)cc3)nc12
Product: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Yield: 25 %

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-ethyl-1H-indole-2,3-dione (1.00 g, 5.71 mmol) with intermediate 2 (1.62 g, 7.14 mmol). The crude acid was purified as described above for Compound 3 to give product as a bright yellow powder (Compound 7, 0.488 g, 25% yield): 1H NMR (400 MHz, DMSO-D6) δ 1.21 (t, J=7.5 Hz, 3H) 3.11 (q, J=7.3 Hz, 2H) 4.32 (s, 2H) 7.34 (s, 4H) 7.40 (d, J=7.1 Hz, 1H) 7.46 (t, 1H) 8.32 (d, J=8.1 Hz, 1H); HRMS (ESI+) calcd for C19H17ClNO3 (MH+) 342.0892, found 342.0890.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[N:13]=[CH:12][C:11]3[N:19]([CH3:32])[C:20](=[O:31])[N:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=4[F:30])[C:10]=3[C:9]=2[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB(/[CH:43]=[CH:44]/[C:45]2[CH:49]=[CH:48][S:47][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O=O>[F:30][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:22]=1[N:21]1[C:10]2[C:9]3[CH:8]=[C:7](/[CH:43]=[CH:44]/[C:45]4[CH:49]=[CH:48][S:47][CH:46]=4)[C:16]([O:17][CH3:18])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:19]([CH3:32])[C:20]1=[O:31])[C:28]#[N:29]
Reactant: COc1cc2ncc3c(c2cc1OS(=O)(=O)C(F)(F)F)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reactant: CC1(C)OB(/C=C/c2ccsc2)OC1(C)C
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc2ncc3c(c2cc1/C=C/c1ccsc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
1-(4-Cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl trifluoromethanesulfonate (119 mg, 240 μmol), 4,4,5,5-tetramethyl-2-[(E)-2-thiophen-3-ylvinyl]-1,3,2-dioxaborolane (142 mg, 602 μmol), tripotassium phosphate (107 mg, 504 μmol) and trans-bis(tricyclohexylphosphine)palladium(II) dichloride (18 mg, 24 μmol) were dissolved in oxygen-free N,N-dimethylformamide (5 ml). The mixture was subsequently heated at 130° C. for 45 min (microwave). The reaction mixture was then filtered with suction, the filtrate was diluted with water and stirred at room temperature for 30 min. The precipitate formed was filtered off with suction and rinsed with water. The residue was chromatographed on flash silica gel (solvent gradient ethyl acetate/0-25% by vol. of ethanol), giving 3-fluoro-4-{7-methoxy-3-methyl-2-oxo-8-[(E)-2-thiophen-3-ylvinyl]-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}benzonitrile (90 mg, 181 μmol) as solid. MS: 457.1 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:6]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 103.5 %

Procedure:
A mixture of 4-iodo-pyrazole (582 mg, 3.0 mmole) and cesium carbonate (1.96 g, 6.0 mmole) was stirred with DMF (6 mL) for 5 minutes. Trifluoroethyl triflate (0.52 mL, 870 mg, 3.75 mmole) was added and the reaction was stirred at room temperature for 4.5 hours. The reaction was added to water (60 mL) and extracted with ether (3×25 mL). The combined organic extracts were washed with water (3×20 mL) and with brine; then dried (MgSO4) and evaporated to afford the title compound (857 mg, 89%). 1H-NMR (CDCl3, 500 MHz): δ 4.72 (q, J=8.20, 2H), 7.58 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH2:7][N:8]1[CH2:16][CH2:15][CH:14]2[NH:17][CH:10]([CH2:11][CH2:12][CH2:13]2)[C:9]1=[O:18].[O:24]=[C:25]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=1)[C:26](O)=[O:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH2:7][N:8]1[CH2:16][CH2:15][CH:14]2[N:17]([C:26](=[O:27])[C:25]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)=[O:24])[CH:10]([CH2:11][CH2:12][CH2:13]2)[C:9]1=[O:18]
Reactant: COc1ccc(CCN2CCC3CCCC(N3)C2=O)cc1OC
Reactant: COc1cc(C(=O)C(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CCN2CCC3CCCC(C2=O)N3C(=O)C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (27 mg, 0.09 mmol) in 3 ml DCM was added sequentially 2-oxo-2-(3,4,5-trimethoxyphenyl) acetic acid (23 mg, 0.1 mmol), EDC-HCl (20 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), TEA (10 mg, 0.1 mmol) at room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The reaction mixture was purified with flash chromatography in EtOAc. TLC [EtOAc]: Rf=0.42
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:5]([S:2](=[O:4])(=[O:3])[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CC(C)(C)N
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C(=O)OC
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C(=O)OC

Procedure:
In a manner analogous to the method described in example 29, methyl 4-chlorosulfonyl-2-ethoxy-benzoate was reacted with tert-butylamine to give 4-tert-butylsulfamoyl-2-ethoxy-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.22 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.21 g, 51% yield), mp=118–120° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=−23.7° (c=1, EtOH).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:48])([CH3:47])[CH2:33][C:32](=[O:49])[C:31]1=2.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:29])[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:47])([CH3:48])[CH2:33][C:32](=[O:49])[C:31]1=2
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C(=O)NS(C)(=O)=O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 2 h
Yield: 56.1 %

Procedure:
1,1′-Carbonyldiimidazole (54.6 mg, 0.34 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (130 mg, 0.26 mmol) in DMF (2.6 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, methanesulfonamide (32.1 mg, 0.34 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.050 ml, 0.34 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 71 hours. Thereafter, an aqueous solution of citric acid (249 mg, 1.30 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). Ethanol was added to the fraction thus obtained, and the generated solid was then collected by filtration and dried to obtain the title compound (84.4 mg, yield: 56%).
Reaction SMILES: C([O-])(=O)C.[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][NH2+:12][CH2:11][CH2:10]1)(=[O:7])[CH3:6].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:10][CH2:11]1)([O-:24])=[O:23]
Reactant: CC(=O)NC1CC[NH2+]CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5 %

Procedure:
To a flask was added 4-acetylamino-piperidinium acetate (as prepared in the previous step) (800 mg, 4.00 mmol), DMF (40 mL), 2-fluoro-1-nitrobenzene (422 μL, 4.00 mmol), triethylamine (836 μL, 6.00 mmol) and the mixture stirred at RT for 17 h. The solvents were removed in vacuo and the residue was purified by silica gel preparative TLC eluting with dichloromethane/hexane/acetonitrile (47.5/47.5/5 v:v:v) yielded 55 mg (5%) of the title compound as a crystalline orange solid. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 8.09 (br d, 1H, J=7.2 Hz), 7.45 (m, 1H), 6.88 (m, 1H), 6.67 (m, 1H), 4.38 (m, 1H), 3.86-3.74 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.14 (s, 3H), 1.67-1.52 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH2:15])=[O:14])[C:6](=[O:12])[NH:7]2.O.[NH2:17]N.O>C(O)(=O)C>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][NH2:17])=[O:14])[C:6](=[O:12])[NH:7]2
Reactant: Cc1nccc2[nH]c(=O)c(C(N)=O)cc12
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C(=O)NN)cc12

Procedure:
A mixture containing 34 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxamide and 150 ml of hydrazine hydrate was heated on a steam bath for 18 hours and then stripped to dryness on a steam bath. To the residue was added 100 ml of water and the aqueous mixture was neutralized by adding acetic acid. The fine yellow needles were collected, washed successively with water and methanol, and then dried at 90° C. to produce 32.6 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, m.p.>310° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:12]Br>O1CCOCC1>[Br:12][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)c(F)c1
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)c(F)c1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred solution of 1-(3-fluoro-4-hydroxyphenyl)-1-ethanone (2.0 g, 12.98 mmol) in dioxane (3 ml) was added a solution of bromine (2.09 g, 13.1 mmol) in dioxane (12 ml), and the mixture was stirred for 16 hours. The mixture was concentrated in vacuo to give title compound (3.02 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[O-:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14].[C:20]1([I+]C2C=CC=CC=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:15][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S+:6]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1csc(Sc2cccs2)c1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: c1ccc([S+](c2cccs2)c2cccs2)cc1
Reaction time: 24 h
Yield: 77 %

Procedure:
Di-(2-thienyl)sulfide (2.1 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ethyl ether was added and the mixture vigorously stirred overnight to achieve solidification. Filtration and washing with ethyl ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 3.4 g (78%) of the title compound, di(2-thienyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: C(S[S:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:26](O)=[O:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[O:27]=[C:26]1[CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH2:23][CH2:22][S:21]1
Reactant: O=C(O)CCC(CCCSSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1CCCSC1=O
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-[3-(tritylthio)mercaptopropyl]pentanedioic acid (150 g, 0.33 mol) in dichloromthane (500 mL) was added dropwise trifluoroacetic acid (110 mL) over 30 minutes. After being stirred for an additional 30 minutes, a solution of triethylsilane (45 mL, 0.33 mol) in dichloromethane (50 mL) was added and the mixture was stirred at 45° C. for 1 hour. The volatiles were removed in vacuo and the residue was triturated with hexanes (500 mL×2). The oily residue was dissolved in toluene (500 mL) containing 10-camphorsulfonic acid (14 g) and refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1/4). Subsequent recrystallization from EtOAc/hexanes afforded 23.3 g of 3-(2-oxotetrahydro-2H-thiopyran-3-yl)propanoic acid as a white solid (37% yield): 1H NMR (CD3OD) δ 1.65–1.78 (m, 2 H), 2.05–2.18 (m, 4 H), 2.35–2.48 (m, 2 H), 2.65–2.74 (m, 1 H), 3.13–3.29 (m, 2 H); 13C NMR (CD3OD) δ 23.3, 27.4, 29.3, 31.2, 32.3, 50.0, 177.0, 206.4. Analysis calculated for C8H12O3S: C, 51.04; H, 6.43; S, 17.03. Found: C, 51.08; H, 6.38; S, 17.16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:14])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3×250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97% yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:60]=[CH:59][C:58](B(O)O)=[CH:57][CH:56]=1>>[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:57][CH:56]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccc(Cl)cc4)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 4-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.99 (br s, 2H), 8.97 (d, J=0.6 Hz, 1H), 8.28 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.83 (dd, J=8.3, 1.7 Hz, 1H), 7.63-7.58 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[C:11]1([CH2:17][CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(CCNCCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
3,3-Diethoxypropan-1-amine (0.20 g) dissolved in ethanol (10 mL) was treated with 2-phenylacetaldehyde (0.163 g) and acetic acid (0.02 mL). The resulting mixture was stirred at room temperature for 15 minutes and treated with sodium cyanoborohydride (0.051 g). After 14 hours the mixture was concentrated, taken up in ethyl acetate (30 mL) washed with saturated sodium bicarbonate (20 mL), brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a crude sample of the sub-titled compound (0.33 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>CCO.[Pd].[C]>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 11-6 (4.0 g, 13.9 mmol) and 10% Pd/carbon (4.0 g) in EtOH (100 mL) was stirred under a balloon of hydrogen for 4 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate /methanol) to give 11-7 as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[CH2:11]([N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][N+:16]#[C-:17])[CH3:12]>CO>[CH2:11]([N:13]([CH2:19][CH3:20])[C:14]([C@H:15]1[C@H:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[O:8][CH:17]=[N:16]1)=[O:18])[CH3:12]
Reactant: O=Cc1ccncc1
Reactant: [C-]#[N+]CC(=O)N(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=O)[C@@H]1N=CO[C@H]1c1ccncc1

Procedure:
SLA 07194A was prepared in accordance with method D using pyridine-4-carbaldehyde (1.14 mL, 9.52 mmol), KOH (0.54 g, 9.60 mmol) in methanol (5 mL) and N,N-diethyl-2-isocyanoacetamide SLA 07184A (1.21 g, 8.65 mmol). After work-up and column chromatography on florisil (ethyl acetate) trans-N,N-diethyl-4,5-dihydro-5-(pyridin-4-yl)oxazole-4-carboxamide SLA 07194A was obtained as a brown oil (0.25 g, 12% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=[O:46])[N:30]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]([CH3:37])=[N:32]2>CN(C=O)C>[O:45]=[C:39]1[CH:38]([N:30]2[C:29](=[O:46])[C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[CH2:26][NH:25][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:32]=[C:31]2[CH3:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a stirred solution of (4-fluoro-phenyl)-acetic acid (0.23 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-fluoro-phenyl)-acetamide as a white solid (480 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.83 min (99.2%); mp, decomposed at 290° C.; 1HNMR (DMSO-d6)2.12-2.19 (m, 1H, CHH), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, ArCH2), 4.68-4.83 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.09-7.72 (m, 7H, Ar), 8.36 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.28, 30.58, 41.36, 41.70, 56.48, 114.89 (d, JC-F=21 Hz), 117.69, 124.72, 125.58, 130.86 (d, JC-F=7 Hz), 132.45 (d, JC-F=3 Hz), 133.82, 140.68, 148.44, 154.80, 160.91, 161.00 (d, JC-F=242 Hz), 169.50, 170.15, 172.59. LCMS MH=437; Anal Calcd For C23H21N4O4F: C, 63.30; H, 4.85; N, 12.84; F, 4.35. Found: C, 63.25; H, 4.66; N, 12.73; F, 4.21.