Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(CC)C.CN(C)[CH:19]=[O:20].Cl>O1CCCC1.C(OCC)(=O)C>[NH:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH:19]=[O:20])=[N:11][N:10]=[N:9]1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of 5-phenyl-1H-tetrazole (500 mg, 3.42 mmol) in 10 mL of dry tetrahydrofuran was added dropwise s-butyllithium (1.04 mol/L, 6.6 mL, 6.9 mmol) under nitrogen at −78° C. After the reaction mixture was stirred at the same temperature for 30 min, N,N-dimethylformamide (2 mL, 30 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 10 min, 1M HCl (10 mL) was added. The solution was allowed to warm up to room temperature, diluted with ethyl acetate, and extracted. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by recrystallization (hexane 2.5 mL, ethyl acetate 2.5 mL) to obtain the title compound (390 mg, 99%).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:20]=1[CH2:21]Br>C(O)C.O1CCCC1>[C:2]([NH:5][C:6]([CH2:21][C:20]1[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(OC)cccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
Sodium metal (1.15 g) was dissolved in absolute ethanol (500 mL), and to the resulting solution was added diethyl 2-acetylaminomalonate (9.1 g). After 15 min at room temperature, a solution of 2-methoxy-6-nitrobenzyl bromide (J. Med. Chem. 1977, 20, 190–196) (8.6 g) in tetrahydrofuran (25 mL) was added over 2 min. After 16 h stirring at room temperature the mixture was evaporated. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated and washed sequentially with water and brine before drying over anhydrous sodium sulfate. Evaporation was followed by silica gel chromatography eluting initially with dichloromethane, followed by ethyl acetate, to obtain diethyl 2-acetylamino-2-(2-methoxy-6-nitrobenzyl)malonate (10.8 g).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](O)CC[C@@]21C
Yield: 91.2 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5.15-dien-17-one and 30 ml of 2N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-a) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[CH:9]=1)[CH3:22])[CH3:21]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(Br)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 91.7 %

Procedure:
Cesium carbonate (57.8 g, 177.4 mmol) was added to a solution of 3-bromophenol (10.23 g, 59.1 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (7.7 mL, 59.1 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether and extracted twice with 1N HCl and three times with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (25% ether in hexanes) to provide the titled compound (14.8 g, 97%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.13-7.07 (m, 3H), 7.02-7.13 (m, 1H), 6.79 (dt, 1H, J=7.63 Hz, 2.35 Hz), 4.70 (q, 1H, J=6.75 Hz), 4.23 (q, 2H, J=3.52 Hz), 1.60 (d, 3H, J=7.04 Hz), 1.24 (t, 3H, J=7.04 Hz). Rf=0.36 in 25% ether in hexanes.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>C(#N)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1
Reactant: COCCCBr
Reactant: Cc1cc(CCN)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COCCCNCCc1ccc(C#N)c(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A mixture of 500 mg 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate and 756 mg potassium carbonate were stirred in 10 ml acetonitrile at 80° C. for fifteen minutes. Then 279 mg 1-bromo-3-methoxypropane, dissolved in 5 ml acetonitrile, were added dropwise at 80° C. The reaction mixture was stirred under micro wave irradiation at 120° C. for one hour. The cooled reaction mixture was filtered through a pad of celite to remove the salt. Then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 268 mg 4-[2-(3-Methoxy-propylamino)-ethyl]-2-methyl-benzonitrile as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)=[O:6])([CH3:4])[CH3:3].[F-].[Cs+].C[Si]([C:20]#[N:21])(C)C>C1COCC1>[C:20]([CH:8]([C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: CC1(/C=N/S(=O)C(C)(C)C)COC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(C#N)NS(=O)C(C)(C)C)COC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To a solution of (NE)-2-methyl-N-[(3-methyloxetan-3-yl)methylene]propane-2-sulfinamide (CAN 1450658-44-2, 1.3 g, 6.39 mmole) in dry THF (35 ml) under argon atmosphere was added cesium fluoride (1.17 g, 7.67 mmol) followed by trimethylsilyl cyanide (761 mg, 1.03 ml, 7.67 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo followed by dilution with ethylacetate. The organic phase was extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.21 g, 82%). MS (ESI, m/z): 231.6 (M+H+).
Reaction SMILES: O.NN.[OH-].[K+].[CH3:6][O:7][C:8]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:14][C:13](=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>C(O)CO>[CH3:6][O:7][C:8]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c1Sc1ccccc1CC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1cccc2c1Sc1ccccc1CC2
Temperature: 175 °C

Procedure:
Hydrazine hydrate (4 ml) and potassium hydroxide (2.72 g, 48 mmol) was added to 6-methoxy-11H-dibenzo[b,f]thiepin-10-one (4.10 g, 16 mmol) in ethylene glycol (20 ml) and the reaction mixture was heated at 175° C. for 3 hours. The reaction mixture was cooled down to room temperature and water was added (100 ml). The white solution was extracted with ether (3×200 ml), the organics were combined, washed with water (100 ml), brine (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give an oil which solidify upon standing to give a brown solid which was used without any further purification (2.45 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.N#N.Cl[Sn](Cl)(Cl)Cl.ClC[CH:26]([O:29]C(CCl)CCl)CCl.Cl>O.C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:26]=[O:29])[C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:16])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: Clc1cccc2cc3cccc(Cl)c3cc12
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: ClCCl
Product: O=Cc1c2cccc(Cl)c2cc2c(Cl)cccc12
Yield: 21 %

Procedure:
1,8-Dichloroanthracene prepared by the method of H. O. House et. al. (J. Org. Chem. 38 1167 (1973)). A 3 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser, and N2 line was charged with 1,8-dichloroanthracene (17.3 g, 70 mmol) and CH2Cl2 (1500 mL). After further cooling with salt-ice bath to 5°, SnCl4 (Aldrich, 98%, 36.5 g, 0.14 mol, 16.4 mL), was added in one portion to the reaction. No temperature change occurred. The pot temperature was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 16.09 g, 0.14 mol, 12.60 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to reflux (37°). Considerable HCl gas evolution occurred during the warming and the early part of the reaction at 37°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt, 100 g) and filtered again and the volume reduced to 100 mL. The clear yellow solution was passed through a 1000 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted 1,8-dichloroanthracene (11 g, 63%) from the aldehyde and a more polar product. Fractions containing the aldehyde were combined and the PhCH3 removed, to give 5.83 g (21%) of 4,5-dichloro-9-anthracenecarbaldehyde mp 218°-220°, (PhCH3 /CH3OH), (C, H, Cl), (lit. 224°-226°, E. L. Stogryn, J. Med. Chem. 17 563 (1974)).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.C(C([O:22][CH2:23][C:24]([NH2:26])=[S:25])=O)(C)(C)C>CCO>[OH:22][CH2:23][C:24]1[S:25][C:2]([CH3:15])=[C:3]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])[N:26]=1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Solvent: CCO
Product: COC(=O)c1cccc(-c2nc(CO)sc2C)c1
Temperature: 60 °C
Yield: 44.6 %

Procedure:
A solution of methyl 3-(2-bromo-propionyl)-benzoate (2.7 g) and 2-(tert.-butyl-carbonyloxy)thioacetamide (2.1 g) in EtOH (20 mL) was heated at reflux for 8 h. The mixture was partitioned between H2O and AcOEt. The organic layer was dried and evaporated. The residue was dissolved in MeOH (20 ml), NaOMe (0.54 g) was added, and the mixture was heated to 60° C. for 1 h. The mixture was diluted with AcOEt and then washed with 3N HCl and brine. The organic layer was dried and evaporated and the residue was crystallized from AcOEt to give methyl 3-[2-hydroxymethyl-5-methyl-thiazol-4-yl]-benzoate (1.17 g) as white solid.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([O:11][CH:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 29.8 %

Procedure:
The procedure is as in Example 7, but starting with 5-hydroxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g) in methylene chloride (80 cc), triethylamine (5.05 g), isobutyryl chloride (4.25 g) and 4-dimethylaminopyridine (50 mg). The solid obtained is washed with tetrahydrofuran. 6-(7-Chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl isobutyrate (2.3 g), m.p. 260°-262° C., is thereby obtained.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CCN(C(C)C)C(C)C>CCO>[I:8][C:7]1[C:2]([NH:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: NCC(F)(F)F
Reactant: Clc1ncncc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)CNc1ncncc1I
Temperature: 120 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-5-iodopyrimidine (0.250 g, 1.040 mmol) and 2,2,2-trifluoroethanamine (0.216 g, 2.184 mmol) in EtOH (volume: 2.080 ml) was added Hunig's Base (0.200 ml, 1.144 mmol). The reaction mixture was heated in a microwave for 4 hr at 120° C. and then allowed to cool to room temperature. The solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-90% EtOAc in hexanes over 25 min, tr=12 min) gave the title compound (0.188 g, 0.614 mmol, 59.1% yield) as a yellow residue. ESI MS (M+H)+=303.9.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.O1CCOCC1.[I:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O>[C:27]([CH:21]([NH:20][C:18](=[O:19])[NH:17][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:5])=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:44]([C:41]1[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=1)(=[O:46])=[O:45])([OH:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)O)C(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCC(NC(=O)NC(CCCCNS(=O)(=O)c1ccc(I)cc1)C(=O)O)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a round bottom flask 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (300 mg, 0.62 mmol) is suspended in water (10 mL) and 1,4dioxane (10 mL) and TEA (1.75 mL, 1.25 mmol) was added followed by 4-iodo-benzenesulfonyl chloride and the mixture stirred overnight at 50° C. The reaction mixture was evaporated to dryness, taken up in DCM and chromatographed over silica gel to afford the desired product (375 mg, 80%) as a clear oil. The compound was deprotected using the previously described methods followed by HPLC purification to afford the desired product MIP-1097 as a whiter solid (270 grams, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, 2H), 7.68 (t, 1H), 7.53 (d, 2H), 6.35 (dd, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 2.65 (m, 2H), 2.22 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.35 (m, 2H), 1.25 (m, 2H), (3 CO2H not seen). ESMS m/z: 565 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])[C:13]#[CH:14]>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:23](=[O:24])[NH:22][S:19]([O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[O:15][CH2:12][C:13]#[CH:14])(=[O:21])=[O:20])[N:7]=1
Reactant: C#CCOc1ccccc1OS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: C#CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 30 ml of dichloromethane, and 5.1 g (0.02 mol) of 2-propargyloxyphenoxysulfonyl isocyanate--dissolved in 20 ml of dichloromethane--are added at 0° C. After the reaction mixture has been stirred for 24 hours at room temperature, it is diluted with 50 ml of dichloromethane, washed with 50 ml of 1N hydrochloric acid and 50 ml of water, dried and evaporated. The oily residue crystallizes on trituration with diethyl ether. 7.4 g (91% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-(2-propargyloxyphenoxysulfonyl)urea of melting point 125°-126° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C[C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([OH:24])=O>>[CH2:20]1[CH:19]2[C:18]3([C:22]([NH:11][C:10]4[S:9][C:8]5[CH2:12][CH2:13][C:14]6[C:15]([C:7]=5[C:6]=4[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:7]=[CH:6][CH:4]=6)=[O:24])[CH2:17][CH:25]([CH2:14][CH:13]1[CH2:12]3)[CH2:21]2
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Product: CCOC(=O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1-c1ccccc1CC2

Procedure:
The title compound was prepared as described in Example 12, substituting Example 278A for 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester and 2-hexahydro-2,5-methano-pentalene-3a-carboxylic acid for 2,2,3,3-tetramethylcyclopropanecarboxylic acid. 1H NMR (300 MHz, CD3OD) δ ppm 1.35 (t, J=7.0 Hz, 3H) 1.60-1.73 (m, 4H) 1.77-1.87 (m, 2H) 1.92 (dd, J=10.2, 2.7 Hz, 2H) 2.00-2.10 (m, 2H) 2.68 (t, J=6.8 Hz, 1H) 2.85-2.94 (m, 2H) 2.99-3.08 (m, 2H) 4.36 (q, J=7.1 Hz, 2H) 7.09-7.31 (m, 4H) 11.44 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:35][C@@H:36]1[CH2:41][CH2:40]C[NH:38][CH2:37]1.CCN(C(C)C)C(C)C.[OH-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([N:38]3[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O[C@@H]1CCCNC1
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(N3CCC(O)C3)c3ccccc3n2)CC1
Temperature: 110 °C
Yield: 24.7 %

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (150 mg, 0.315 mmol) in DMSO (3.0 mL) was added (R)-3-hydroxypiperidine (68 mg, 0.5 mmol) and DIEA (65 mg, 0.5 mL). The mixture was heated at 110° C. for 18 hours. The crude reaction mixture was treated with lithium hydroxide (3.0 mL 0.25 M) for 4 hours. The reaction was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-hydroxypyrrolidin-1-yl)quinoline (41.0 mg); NMR (DMSO-d6) 1.2 (t, 3), 2.00-2.20 (m, 4), 2.45 (m, 2), 3.30-3.75 (m, 8), 4.05 (q, 2), 4.60 (s, 1), 5.11 (m, 1), 7.39 (s, 1), 7.65 (m, 1), 7.95 (m, 1), 8.28 (m, 1), 8.58 (br s, 1), 9.75 (m, 1) ppm.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:17])[N:13]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCC(CC)c1cc(C)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2cc(C)nc12
Temperature: 100 °C

Procedure:
4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-ylamine (850 mg, 4.74 mmol), chloroacetone (0.415 ml, 5.22 mL) and 20 mL of ethanol are heated in the microwave at 110° C. for 35 minutes. Sodium bicarbonate (1.2 g, 14.2 mmol) is added, and the reaction mixture is heated in an oil bath at 100° C. overnight. The solvent is evaporate and the residue is taken up in ethyl acetate and washed three times with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated to a brown oil. The crude product is purified via silica gel chromatography using a hexane:ethyl acetate gradient. The title compound is an oil weighing 3.69 g (17.0 mmol, 84%). 1H-NMR (DMSO-d6), δ 7.34 (s, 1H); 6.84 (s, 1H); 2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712 (t, J=7.49 Hz, 6H) ppm. MS/ES+=219 (100%, M+2).
Reaction SMILES: C([O:3][C:4]1[C:5]2[N:6]([CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=2)C.C(O)C.[OH-].[Na+].Cl>O>[Cl:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[Cl:15])[N:6]1[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=[C:5]1[C:4](=[O:3])[NH:13]2
Reactant: CCOC(=O)c1cn2c(n1)c(OCC)nc1cc(Cl)c(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(n1)c(=O)[nH]c1cc(Cl)c(Cl)cc12
Yield: 101.8 %

Procedure:
A mixture of 0.14 g of the product of Step B, 10 ml of ethanol, 20 ml of water and 3 ml of 1 N sodium hydroxide solution was refluxed overnight and the resulting clear solution was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 0.12 g of 4,5-dihydro-7,8-dichloro-4-oxoimidazo-[1,2-a]-quinoxaline-2-carboxylic acid in the form of a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20](I)[CH2:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Product: CCCCSC(=N)Nc1cccc(CNC(=O)OC(C)(C)C)c1
Yield: 92 %

Procedure:
Using the compound obtained in Example 24 as a starting material and also using n-butyl iodide as a reagent, reaction was performed as in Example 29 to give 220 mg of the titled compound (yield, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:45]=[CH:44][C:32]([O:33][C:34]([F:43])([F:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[C:38]([O:37][C:35](=[O:36])[C:34]([F:43])([F:42])[O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:9][CH:8]=2)[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[O:12])=[CH:45][CH:44]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)C(F)(F)Oc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of methyl-4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate (0.150 g, 0.551 mmol) (Example 1, Step 2) in degassed THF at −20° C. was added potassium tert-butoxide (0.606 ml), followed by a solution of tert-butyl 2-[4-(bromomethyl)phenoxy]-2,2-difluoroacetate (H. Fretz, Tetrahedron 54, 4849, 1998) (0.203 g, 0.604 mmol) in THF (0.5 ml). The reaction was allowed to warm slowly to room temperature, and was then quenched with saturated ammonium acetate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using toluene/ethyl acetate 5% giving 0.176 g of the title compound.