Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:28][CH2:29][CH2:30][CH3:31].C(OCC)(=O)C>CN(C)C=O>[CH2:28]([N:14]([C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCI
Reactant: COc1ccc(-c2csc(NCCc3ccc(C#N)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCc1ccc(C#N)cc1)c1nc(-c2ccc(OC)cc2)cs1
Temperature: 25 °C

Procedure:
600 mg 4-{2-[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-ethyl}-benzonitrile were dissolved in 30 ml dimethylformamide. 85.9 mg sodium hydride (24% in mineral oil) were added and the reaction mixture stirred at room temperature for thirty minutes. Then 245 μl 1-Iodobutane were added and the reaction mixture stirred at room temperature for two hours. Then 100 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml water and then dried over MgSO4. The solvents were removed in vacuo and the residue purified by RP-HPLC to obtain 279 mg 4-(2-{Butyl-[4-(4-methoxy-phenyl)-thiazol-2-yl]-amino}-ethyl)-benzonitrile.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:30][O-:31].[Na+]>CN(C)C=O.[Cu]I>[F:28][C:25]([F:26])([F:27])[CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:8]3=[N:9][C:10]=2[C:2]([O:31][CH3:30])=[CH:3][CH:4]=1)[OH:29]
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(OC)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 1-[9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.425 mmol), sodium methoxide (28% methanol solution, 3 mL), copper(I) iodide (121 mg, 0.635 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (96.6 mg, 0.229 mmol, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11](OCC2C=CC=CC=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][C@H:9]1[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(OCc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=O)NC[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
(R)-2-Benzyl-4-benzyloxy-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (795 mg, 1.94 mmol) was dissolved in methanol (21 ml) and stirred for 16 h at 70° C. under a hydrogen pressure of 8 bar. After cooling insoluble material was removed by filtration and the filtrate concentrated, to afford the title compound (486 mg, 82%). White foam, MS (ISP)=305.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([CH3:18])[C:11]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]>CO>[Cl:9][C:10]1[CH:15]=[C:14]([CH:13]=[C:12]([CH3:18])[C:11]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([NH:2][OH:3])=[NH:17]
Reactant: Cc1cc(C#N)cc(Cl)c1NS(C)(=O)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Temperature: 65 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Hydroxylamine hydrochloride (60 mg, 858 μmol) and NaHCO3 (72 mg, 858 μmol) is added to a solution of N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg, 429 μmol) in methanol (10 mL). The mixture is stirred at 65° C. for 18 h. The solvent is removed in vacuo and the residue is dissolved in a small volume of water (2 mL) and extracted three times with EA (15 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give the title compound (118 mg) as a white solid; LC-MS**: tR=0.19 min, [M+1]+=277.94; 1H NMR (CDCl3): δ2.57 (s, 3H), 3.13 (s, 3H), 6.21 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]3[CH:25]=[CH:26][N:27]=[C:16]23)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]3[N:17]([CH:25]=[CH:26][N:27]=3)[C:18]=12
Reactant: Cc1ccnc2c1n1ccnc1n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc2c1n1ccnc1n2-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 9-[4-(benzyloxy)phenyl]-5-methyl-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridine (1.35 g), 10% palladium on carbon (containing water (50%), 0.675 g), THF (50 ml) and methanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from hexane/THF to give the title compound (0.950 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH:27][CH:28]=[O:29])[CH:6](O)[C:7](=[CH2:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH3:2].C=CCCC=C.S(Br)(Br)=O.[P:41]([O:50]C(C)C)([O:46][CH:47]([CH3:49])[CH3:48])[O:42][CH:43]([CH3:45])[CH3:44].C(OC(=O)C(NC=O)C=C(CBr)CCCCCCNC(OCC1C=CC=CC=1)=O)C.C(Br)(C)C.C(=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH:27][CH:28]=[O:29])[CH:6]=[C:7]([CH2:25][P:41]([O:46][CH:47]([CH3:49])[CH3:48])([O:42][CH:43]([CH3:45])[CH3:44])=[O:50])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH3:2]
Reactant: C=C(CCCCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OCC
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: C=CCCC=C
Agent: CCOC(=O)C(C=C(CBr)CCCCCCNC(=O)OCc1ccccc1)NC=O
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)Br
Product: CCOC(=O)C(C=C(CCCCCCNC(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To 13.70 g (32.60 mmol) of crude 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in 137 ml of tetrahydrofuran there are added, under argon, 18.5 ml (156.4 mmol) of hexa-1,5-diene and then, dropwise at 10° within a period of 15 minutes, 6.1 ml (78.2 mmol) of thionyl bromide. The mixture is stirred for one hour at 10° and for 2 hours at room temperature and is then poured into 200 ml of ice-cold saturated sodium hydrogen carbonate solution; the organic phase is separated off and re-extracted once with dichloromethane. The organic phases are washed with ice-cold 0.5-normal sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness by evaporation in vacuo at 40°. 64 ml (260 mmol) of triisopropyl phosphite (96%) are added immediately to the resulting crude 10-(N-benzyloxycarbonylamino)-4-bromomethyl-2-formylamino-dec-3-enoic acid ethyl ester (27 g, yellow honey), and the mixture is stirred for 17 hours at 80° under a pressure of approximately 100 mbar, the isopropyl bromide that forms being captured in a cold trap (CO2). The excess triisopropyl phosphite is then distilled off under reduced pressure and the evaporation residue (23 g) is purified by chromatography on a column filled with 650 mg of silica gel (0.04-0.063 mm) with ethyl acetate/methanol (95:5). 8.73 g of 10-(N-benzyloxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylaminodec-3-enoic acid ethyl ester are obtained in the form of a yellowish honey.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([I:17])C(=O)C1>>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[I:17])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cccc(N)n1
Product: CCc1nc(N)ccc1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 10.0 g (83 mmol) 6-ethyl-pyridin-2-ylamine and 18.4 g (83 mmol) NIS. Yield after precipitation from the reaction mixture: 18.0 g (89%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:16]C)[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2].[C-]#N.[Na+].C#N.Cl>CS(C)=O.CCCCCC.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:16])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2]
Reactant: CCc1cc(OC)cc2c1C(=O)CCC2(C)C
Agent: C#N
Agent: Cl
Agent: [C-]#N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(O)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 8-ethyl-4,4-dimethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (Intermediate 176, 1.1 g, 4.73 mmol) and sodium cyanide (1.6 g, 33 mmol) in anhydrous dimethylsulfoxide (20 mL) was heated at 210° C. overnight under argon. The reaction mixture was then cooled to ambient temperature, poured into ice and acidified (Caution! Hydrogen cyanide evolution!) using 10% hydrochloric acid and extracted with ethyl acetate. The combined organic extract was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford a dark orange solid. Flash column chromatography on silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a yellow solid (0.82 g, 82%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19](Cl)=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=1>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CC(=O)Cl)CC2)CC1
Reactant: Fc1cc(Br)cc(F)c1F
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCc3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
Using trans-4-[2-(trans-4-propylcyclohexyl)ethyl]-cyclohexylacetyl chloride and a Grignard reagent prepared from 1-bromo-3,4,5-trifluorobenzene, as starting raw materials, 1-[trans-4-{2-(trans-4-propylcyclohexyl)ethyl}-cyclohexyl]-2-(3,4,5-trifluorophenyl)ethane was obtained in the same manner as in Example 2.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C@@H:7]1[N:12]2[C:13](=[O:26])[C@@H:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:11]2[S:10][CH:9]=[C:8]1[O:27][CH3:28])=[O:6].O.Cl>O1CCCC1.C(Cl)Cl>[O:18]([CH2:17][C:16]([NH:15][C@@H:14]1[C:13](=[O:26])[N:12]2[C@@H:7]([C:5]([OH:6])=[O:4])[C:8]([O:27][CH3:28])=[CH:9][S:10][C@H:11]12)=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reaction time: 0.08 h

Procedure:
15 ml of cooled 0.1 N aqueous potassium hydroxide solution are added, whilst stirring, to a solution, cooled in an ice bath, of 382 mg of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester in 30 ml of tetrahydrofurane. After 5 minutes, 100 ml of water and 70 ml of methylene chloride are added and the mixture is acidified by adding 10 ml of 1 N aqueous hydrochloric acid. The methylene chloride phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is crystallised from chloroform/diethyl ether and gives 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of melting point 142° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[ClH:33]>>[ClH:33].[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To N-t-butyloxycarbonyl-glycyl-L-proline benzylester (25.7 g, 68.2 m mole) 4N hydrogen chloride dioxane solution (170 ml) was added and the solid material was dissolved. The mixture was stirred for 1 hour at room temperature. The mixture was evaporated under reduced pressure to obtain a half-solid glycyl-L-proline benzylester hydrochloride (20.2 g, 64.8 m mole, yield: 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]3[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=3)=[O:43])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:43])[C:44]3[CH:45]=[CH:46][C:47]([C:48]4[NH:10][C:9]5[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:27])[C:15]6[CH:20]=[CH:19][C:18]([N:21]7[CH2:26][CH2:25][O:24][CH2:23][CH2:22]7)=[CH:17][CH:16]=6)=[CH:5][C:4]=5[N:1]=4)=[CH:50][CH:51]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4nc5cc(NC(=O)c6ccc(N7CCOCC7)cc6)ccc5[nH]4)cc3)cc2)CC1

Procedure:
Compound 250 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-morpholinobenzamide and 4-(4-(4-methylpiperazinyl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C36H37N7O3: 616.30; found: 616.13.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:22]1[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29]O)[O:23]1.S(Cl)([Cl:33])=O.N1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:22]1[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][Cl:33])[O:23]1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c2ncn([C@@H]3O[C@H](CCl)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a stifling mixture consisting of Compound 18 (1.03 g, 2.42 mmol) and acetonitrile (80 mL) under a nitrogen atmosphere and cooled over an ice-acetone bath was added thionyl chloride (0.53 mL, 7.3 mmol). The reaction mixture continued stirring cold for 15 minutes and was subsequently treated with pyridine (0.469 g, 4.84 mmol) with dropwise addition. An immediate color change was observed, and the mixture was stirred cold for another 45 minutes. The cold bath was removed and the mixture was allowed to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol. The ice bath-cooled mixture under a nitrogen atmosphere was treated with ammonium hydroxide solution to pH 10. The resulting mixture was stirred for 1.5 hours, as it was allowed to warm to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica column (80 g) chromatography. Elution with a gradient (100% dichloromethane to 10% methanol in dichloromethane), combination of fractions containing separated desired product, and concentration under reduced pressure afforded the title intermediate (0.175 g, 16.4% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1 H), 6.81 (t, 1H, J=5.5 Hz), 6.73 (s, 2H), 6.26 (t, 1H, J=5.5 Hz), 5.73 (d, 1H, J=5.5 Hz), 5.47 (d, 1H, J=5.9 Hz), 5.36 (d, 1H, J=5.1 Hz), 4.75 (broad m, 1 H), 4.20 (m, 1H), 4.01 (m, 1H), 3.90 (dd, 1H, 11.4, 5.2 Hz), 3.79 (m, 1H), 3.23 (m, 2H), 3.08 (m, 2H), 2.06 (s, 2H), 1.34 (s, 9H); LC/MS (ESI+) m/z 444.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CC1C=CC(S(O[CH2:30][CH2:31][CH:32]2[CH2:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[N:46]4[C:42]([S:43][C:44]([CH2:47][O:48][CH3:49])=[N:45]4)=[N:41][C:40]=3[Cl:50])[CH2:33]2)(=O)=O)=CC=1.O>C1COCC1>[Cl:50][C:40]1[N:41]=[C:42]2[N:46]([C:39]=1[CH2:38][N:34]1[CH2:33][CH:32]([CH2:31][CH2:30][F:1])[CH2:36][C:35]1=[O:37])[N:45]=[C:44]([CH2:47][O:48][CH3:49])[S:43]2
Reactant: [F-]
Reactant: COCc1nn2c(CN3CC(CCOS(=O)(=O)c4ccc(C)cc4)CC3=O)c(Cl)nc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn2c(CN3CC(CCF)CC3=O)c(Cl)nc2s1
Yield: 22 %

Procedure:
A 1M solution of tetrabutylammonium fluoride in THF solution (4 ml) is added to 2-(1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-5-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate a39 (308 mg, 0.617 mmol, 1 eq). The resulting solution is irradiated in a microwave apparatus (Biotage) at 100° C. for 1 h. Water (10 ml) is added to the reaction mixture, and the crude compound is extracted by ethyl acetate (4×10 ml). The cumulated organic layer are washed successively by a saturated NH4Cl aqueous solution (2×10 ml), water (2×10 ml), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by flash chromatography over silicagel (eluent: CH2Cl2/MeOH 99:1) to afford 47 mg of pure 1-{[6-chloro-2-(methoxymethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2-fluoroethyl)pyrrolidin-2-one 28.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([CH3:29])[C:25]2=[O:30])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C.O1CCCC1>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([CH3:29])[C:25]2=[O:30])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCN(C)C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Yield: 79.1 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (1.72 g) in methanol (40 ml) was added 28% sodium methoxide in methanol solution (0.83 ml) and the mixture was stirred under ice-cooling for 30 minutes. Acetic acid (0.25 ml) was added to the reaction mixture at the same temperature. The mixture was evaporated in vacuo to give a residue. The residue was dissolved in a mixture of ethyl acetate (80 ml) and tetrahydrofuran (30 ml) and the solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.23 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:4]=[CH:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:13])[C:11]=2[CH:12]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][NH:23][C:24]([NH:13][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:12]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:4]=[CH:5]3)=[O:25])=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2cnc(C(F)(F)F)cc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnc(C(F)(F)F)cc12

Procedure:
Prepared from 3-(trifluoromethyl)isoquinolin-5-amine (Description 64) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1.Cl[CH2:35][C:36]#[N:37].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]#[N:37])[CH2:29][CH2:30]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (0.19 g), 2-chloroacetonitrile (0.038 ml), potassium iodide (0.020 g), potassium carbonate (0.139 g) and DMF (2.5 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The crude product was purified by column chromatography on silica using a 93:7 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g) as a solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 2.6 (m, 2H), 3.05 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.65 (m, 2H), 3.9 (s, 2H), 4.05 (s, 3H), 4.35 (m, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: [M−H]− 509 and 511; Elemental Analysis: Found C, 58.41; H, 5.62; N, 15.93. C25H27ClN6O4 0.2H2O requires C, 58.35; H, 5.37; N, 16.33%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])C.[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:17][O:19][C:20](=[O:23])[CH2:21][NH:22][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CO
Product: COC(=O)CNC(C)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Titanium isopropoxide (4.4 g, 4.6 mL, and 15.5 mmol) was added to a stirred solution of 4-acetyl-biphenyl (1 g, 5.1 mmol) and glycine ethyl ester hydrochloride (2.2 g, 16.0 mmol) in MeOH (20 mL) and stirring continued at room temperature overnight. NaBH4 (800 mg, 20 mmol) was added in portion wise and the resulting mixture was stirred at room temperature for 10 hrs. The above mixture was quenched with 2N aqueous NH3 solution, filtered the solid precipitated. The filtrate was extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (using neutral alumina and 20% EtOAc in hexane as eluent) to afford 297 mg (21.67% yield) of (1-biphenyl-4-yl-ethylamino)-acetic acid methyl ester. 1H NMR (CDCl3): δ 7.64 (t, 4H), 7.5-7.3 (m, 5H), 3.9-3.8 (q, 2H), 3.7 (s, 3H), 3.4 (d, 2H), 1.5 (d, 3H).