Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:5].C1([C@@]2(N3C4N=CN=C(N)C=4N=C3)O[C@H](CO)[C@@H](O)[C@H]2O)CCCCC1.[Mg+2].[Cl-].[Cl-]>C(N1C(=O)C2N=C(C3CCC4C(=CC=CC=4)C3)NC=2N(CCC)C1=O)CC>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CCCn1c(=O)c2nc(C3CCc4ccccc4C3)[nH]c2n(CCC)c1=O
Agent: Nc1ncnc2c1ncn2[C@]1(C2CCCCC2)O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cl-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
Incubation tubes, in triplicate, receive 100 μl of [3H]NECA (94 nM in the assay), 100 μl of 1 μM cyclohexyl-adenosine (CHA), 100 μl of 100 mM MgCl2, 100 μl of 1 IU/ml adenosine deaminase, 100 μl of test compounds at various concentrations over the range of 10-10M to 10-4M diluted with assay buffer (50 mM Tris-HCl, pH 7.7) and 0.2 μl of membrane suspension (5 mg wet weight), in a final volume of 1 ml of 50 mM Tris-HCl, pH 7.7. Incubations are carried out at 25° C. for 60 minutes. Each tube is filtered through GF/B glass fiber filters using a vacuum. The filters are rinsed two times with 5 ml of the ice-cold buffer. The membranes on the filters are transferred to scintillation vials to which 8 ml of Omnifluor with 5% Protosol is added. The filters are counted by liquid scintillation spectrometry.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>>[C:35]([O:34][C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:21][CH:22]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 73.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 0.845 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) and 1.22 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 1.31 g of the title compound were obtained as a gum. This compound was allowed to stand at room temperature, which caused it to crystallize. It was then recrystallized from a mixture of diisopropyl ether and hexane, to give pure title compound, melting at 90°-91° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([Cl:21])(=[O:20])=[O:19].O>ClC(Cl)C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][CH2:16][C:15]1[C:10]([Cl:9])=[C:11]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Cl)c(CCl)c1Cl
Temperature: 120 °C
Yield: 11.6 %

Procedure:
10 g (0.075 mol) of N-chlorosuccinimide and 30 mg of benzoyl peroxide are added to a solution of 6.5 g (0.025 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 30 ml of 1,1,2,2-tetrachloroethane at room temperature and under a nitrogen atmosphere. The reaction mixture is heated at 120° C. for 3 hours, cooled to room temperature, poured into water and then extracted with dichloromethane. The organic phase is washed with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. It is then dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from hexane gives 0.85 g of the expected product in the form of white crystals (yield=11.5%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(#N)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:10]2[N:7]=[C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)[S:8][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: NC(=S)c1ccc[nH]1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
Pyrrole-2-carbothioamide (cf. J. Org. Chem., 38, 667, 1973) (1.51 g, 12 mmole) and α-bromo-4,4'-dimethoxydeoxybenzoin (cf. Aust. J. Chem., 8, 385. 1955) (4.02 g, 12 mmole) are dissolved in acetonitrile (120 ml). The mixture is stirred at 60° C. for 50 minutes. After the reaction, the reaction mixture is distilled under reduced pressure to remove the solvent. To the resulting residue are added chloroform and aqueous solution of sodium carbonate, and the mixture is shaken. The chloroform layer is taken, and the aqueous layer is further extracted with chloroform. The chloroform layers are combined, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is recrystallized from ligroin to give 4,5-bis(4-methoxyphenyl)-2-(pyrrol-2-yl)-thiazole (3.74 g, yield: 86%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([C:1]1[CH:7]=[C:8]([NH2:9])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:18]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: NNc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(F)cc2)n1

Procedure:
The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.): 4.17 g (32.3 mMol) of pivaloylacetonitrile are added to a solution of 4.20 g (32.3 mMol) 4-fluoro-phenylhydrazine in 150 ml of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound as a yellow solid: 1HNMR (CDCl3) δ ppm 7.59 (d, 2H), 7.10 (d, 2H), 5.58 (s, 1H), 3.62 (brs, H2N), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3Cl)[CH:12]=2)[N:6]=1)=[O:4].[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:12]=2)[N:6]=1)=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COC(=O)c1cccc(-c2cc3nccc(Cl)c3s2)n1
Product: COC(=O)c1cccc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)n1

Procedure:
The title compound was prepared from 6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridine-2-carboxylic acid methyl ester and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.43 (d, 1H), 8.22 (s, 1H), 8.18 (d, 1H), 8.11 (t, 1H), 8.02 (d, 1H), 7.26 (m, 2H), 6.92 (d, 1H), 6.59 (d, 1H), 6.10 (s, 1H), 3.89 (s, 3H), 2.36 (s, 3H); RP18-HPLC RT: 5.34 minutes; API MS: 415 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([F:24])[CH:16]=1>>[F:24][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
Production Example 14 was repeated except that 4-(trifluoromethyl)phenylboronic acid and 4-bromo-2-fluorobenzenecarboxylic acid were used, to provide the title compound as white solid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8]2)=[CH:3][CH:2]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1.CN(C1C=CN=CC=1)C.N12CCCN=C1CCCCC2>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH2:10][C:9]([O:12][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCC(=O)N2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)=N2)cc1
Temperature: 30 °C
Yield: 98.2 %

Procedure:
To a stirred solution under nitrogen of 1-p-tolyl-3-pyrazolidinone (52.8 g, 0.30 mole) in 500 ml toluene and 50 ml anhydrous tetrahydrofuran was added sequentially t-butyl-dimethylsilyl chloride (49.5 g, 0.30 mole), triethylamine (33.0 g, 0.30 mole), 4-(N,N-dimethylamino)pyridine (0.1 g) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (0.1 g). The mixture was refluxed for 3 hours, then cooled to 30° C., and filtered. After the solids were washed with ether, the solvents of the combined filtrate were removed under reduced pressure. The resulting solid was dissolved in 500 ml anhydrous ether and filtered to remove salts. Removal of the solvent of the filtrate yielded 85.6 g (98% yield) of 1-p-tolyl-3-(t-butyldimethylsiloxy)-2-pyrazoline.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH2:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:55][C:56]1([CH3:62])[N+:60]([O-:61])=[CH:59][CH2:58][CH2:57]1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:60]4[C:56]([CH3:62])([CH3:55])[CH2:57][CH2:58][C@@H:59]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(=O)c2c1
Reactant: CC1(C)CCC=[N+]1[O-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 57.2 %

Procedure:
To a solution of 0.500 g of 2-Butyl-6-ethenyl-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 25 ml of toluene is added 0.161 g of 5,5-dimethyl-1-pyrroline N-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 2:1 ethyl acetate-hexanes to give 0.332 g of the desired product. FAB MASS SPEC 818 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]
Reactant: O=C1CCCCC1Cl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCCC1Oc1ccccc1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
A mixture of 2-bromophenol (5 g), potassium carbonate (5.99 g) and 2-chlorocyclohexanone (4.22 g) in N,N-dimethylformamide was stirred at 60° C. for 4 hours. The reaction mixture was poured into cold water and the separated oil was extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from n-hexane to give 2-(2-bromophenoxy)cyclohexanone (4.36 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[NH:11][C:12](N)=O)/[CH3:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:22]=[O:23])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: C/C(=N\NC(N)=O)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a stirred solution of (E)-2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxamide (1 g, 5.12 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) at 5° C. was added phosphorous oxychloride (5 mL) dropwise. The resulting solution was stirred at 70° C. for 2 h. The reaction mixture was cooled to 0° C. and quenched by the addition of 15 mL of ice/water mixture. The pH value of the solution was adjusted to 7 with 4N sodium hydroxide solution. The resulting mixture was stirred at 70° C. for an additional 1 h. The reaction mixture was cooled back to room temperature. The precipitate was collected by filtration and dried in a vacuum oven to give 600 mg (62%) of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde as a gray solid. LCMS (method A, ESI): RT=1.23 min, m/z=191.0 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]([CH3:16])[CH2:4][C:5]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:15].CS(Cl)(=O)=O.CC([O-])(C)C.[K+]>O1CCCC1>[CH3:2][CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][CH2:12][O:13][CH3:14])[O:15][CH2:16]1
Reactant: COCOc1cccc(O)c1CC(C)CO
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1cccc2c1CC(C)CO2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a 50 ml round-bottomed flask under argon, 2-(3-hydroxy-2-methylpropyl)-3-{[(methyloxy)methyl]oxy}phenol (Intermediate 115, 377.9 mg) was dissolved in tetrahydrofuran (5 ml) to give a colourless solution. TEA (0.409 ml, 2.93 mmol) was added and the reaction mixture was cooled at 0° C. At that temperature methanesulfonyl chloride (0.124 ml, 1.591 mmol) was added. The reaction mixture was stirred at 0° C. After 45 minutes, additional methanesulfonyl chloride (0.124 ml, 1.591 mmol) was added. After additional 45 minutes, potassium 2-methyl-2-propanolate (422 mg, 3.76 mmol) was added. After 15 minutes from this latter addition, additional potassium 2-methyl-2-propanolate (422 mg, 3.76 mmol) was added. After 15 minutes the reaction was completed. The reaction was then quenched with 10 ml of a saturated aqueous solution of NH4Cl, acidified until pH˜2 with 2M hydrochloric acid and diluted with 25 ml of dichloromethane. Phases were separated through a phase separator cartridge. The organic phase was evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([Li])CCC>O1CCCC1>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CC(=O)O)cc1C
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (4-methoxy-3-methyl-phenyl)-acetic acid (5.04 g, 27.97 mmol) and triethylamine (3.9 mL, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added trimethylacetyl chloride (3.44 mL, 27.97 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, 0° C. for 1 hour, then re-cooled to −78° C. At the same time, to a separate flask charged with a solution of (R)-(+)-4-benzyl-2-oxazolidinone (4.96 g, 27.97 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen at −78° C. was added dropwise a solution of n-butyllithium (14 mL, 28 mmol, 2 M in hexanes). The second reaction mixture was stirred at −78° C. for 20 minutes, then transferred via cannula into the first reaction flask containing the mixed anhydride at −78° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2×250 mL). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give (R)-4-benzyl-3-[2-(4-methoxy-3-methyl-phenyl)-acetyl]-oxazolidin-2-one as a pale yellow oil (8.5 g, 89%).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH3:15])[C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:16]2[CH2:18][CH2:17]2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.N1CCCC1>O.CS(C)=O>[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@H:29]1[CH2:33][CH2:32][N:31]([C:7]2[C:6]([CH3:15])=[C:5]3[C:10]([C:11](=[O:12])[N:2]([NH2:1])[C:3](=[O:19])[N:4]3[CH:16]3[CH2:18][CH2:17]3)=[CH:9][C:8]=2[F:13])[CH2:30]1)[CH3:28])([CH3:21])([CH3:22])[CH3:23]
Reactant: Cc1c(F)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Solvent: C1CCNC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC[C@H]([C@H](C)NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Temperature: 120 °C
Yield: 52.5 %

Procedure:
A solution of 0.5 g (1.9 mmol) of 3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (Example 24e), 0.64 g (3.0 mmol) of ((S)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester, 0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at 110° C. for 24 hours. After thin layer chromatography showed incomplete reaction, an additional 0.43 g (2.0 mmol) of pyrrolidine derivative and 0.81 g (8.0 mmol) of triethylamine are added and the reaction is heated at 120° C. for 18 hours. The reaction mixture is cooled to room temperature, poured into 200 mL of ice and water and extracted with ethyl acetate (2×125 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 1.3 g of crude product. Chromatography on flash grade silica gel (230-400 mesh) eluting with 400 mL of dichloromethane/ethyl acetate (8:2), 600 mL of (6:4) and 1 L of (4:6) provided 0.46 g of the title compound, mp 84-86° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:19]([O:23][C:24](OC([O-])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>[OH-].[Na+]>[C:19]([O:23][C:24](=[O:25])[NH:13][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Yield: 96.8 %

Procedure:
1-benzylpyrrolidin-4-ylamine (10 g, 57 mmol) was dissolved in 3M sodium hydroxide aqueous solution (21 ml) and t-butanol (114 ml) in a 500 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 13.07 g, 59.9 mmol) wad added thereto while stirring. The resulting mixture was reacted at room temperature for 12 hrs, extracted with ethyl acetate twice. The organic layer was separated, washed with 0.1N hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 15.25 g of the title compound as a white solid (yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>>[Cl:18][CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: ClCCBr
Solvent: CCN(CC)CC
Product: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-piperazine (0.05 mol), 1-bromo-2-chloroethane (0.1 mol) and triethylamine (0.05 mol) was stirred for 30 minutes at 100° C. The mixture was cooled, then partitioned between CH2Cl2 and water. The layers were separated. The organic phase was filtered over dicalite. The organic filtrate was dried, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g (35%) of 4-(2-chloroethyl)-1-(3,4-dichlorophenyl)-piperazine (interm. 9).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])=[CH:30][CH:31]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Compound 19 was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath. TFA (5 mL, 65 mmol) was and the mixture stirred in an ice bath for 2 h. The reaction was concentrated at RT and dried under high vacuum to provide the title compound, 18, as a white solid (53 mg, 74%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 2.40 (q, 2H), 6.51 (d, J=16 Hz, 1H), 6.90 (d, J=8 Hz, 2H), 6.96 (d, J=8 Hz, 2H), 7.14-7.18 (m, 3H), 7.16-7.20 (m, 4H), 7.54 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.66-7.71 (m, 3H), 8.03 (d, J=8 Hz, 2H), 12.2 (br s, 1H); MS, m/z, 473 (M−H)−.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[S:33]>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: COc1ccccc1N=C=S
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4OC)CC3)nc21

Procedure:
Pipemidic acid (53 mg, 0.175 mmol) and 2-methoxyphenyl isothiocyanate (20 μL, 0.145 mmol) were used. Purification on silica yielded compound 21 in Table 1, below (36 mg, 53%). 1H NMR (250 MHz, CDCl3) δ 9.33 (s, 1H), 8.68 (s, 1H), 7.84 (d, J=7.30 Hz, 1H), 7.54 (s, 1H), 7.20-7.04 (m, 1H), 7.03-6.85 (m, 2H), 4.44-3.73 (m, 13H), 1.49 (t, J=6.60 Hz, 3H) ppm.