Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[CH:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C(OC([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[C:21]1[CH2:29][N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[C:31]1=[O:36])=O)(C)(C)C>>[O:36]=[C:31]1[C@@H:32]([NH:35][S:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:11])=[O:10])[CH2:33][CH2:34][N:30]1[CH2:29][C:21]1[NH:20][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Product: O=C1[C@@H](NS(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1cc2cnccc2[nH]1

Procedure:
The title compound is prepared as described in EXAMPLE 56. Part A using 2-(5-chlorothiophen-2-yl)-ethenesulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])[CH3:2].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: [Br-]
Reactant: CCc1cccc(C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(C)c1O
Temperature: 0 °C
Yield: 182.7 %

Procedure:
Then, 16 g of 2-ethyl-6-methylphenol was dissolved in 200 ml of chloroform, which was stirred at 0° C., and 56.6 g of tetrabutylammonium tribromide was added in small portions to this solution. After stirring at room temperature for 1 hour, the solvent was distilled out under reduced pressure. The residue was dissolved in 300 ml of diethyl ether, successively washed with 10% hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 23 g of 4-bromo-2- ethyl-6-methylphenol (92% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.C1C(=O)N([I:27])C(=O)C1>>[I:27][C:6]1[C:7]([NH2:9])=[N:8][C:3]([S:2][CH3:1])=[N:4][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=1
Reactant: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C1CCC(=O)N1I
Product: CSc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (7.0 mmol) 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine and 1.6 g (7.0 mmol) NIS. Yield after precipitation: 1.9 g (66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[CH3:20]>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:13][C:12]=1[CH3:20]
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Product: Cc1cc(C(=O)Cc2cccc(F)c2)ccc1Br

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 169 using 3-fluorobenzyl bromide and 4-bromo-3-methylbenzoyl chloride (Cignarella; G.; Curzu, M. M.; Grella, G.; Loriga, M.; Anania, V.; Desole, M. S.; J. Farmaco. Ed. Sci., 1983, 38, 187-198.).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=4)=[C:20]([Cl:31])[CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1)[NH:17][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:42]3[CH2:43][CH2:44][CH:39]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][CH2:41]3)=[C:6]([O:32][CH3:33])[CH:7]=2)[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCN1CCC(N2CCCC2)CC1
Yield: 82.1 %

Procedure:
A mixture of 200 mg (0.40 mmol) of 7-(2-chloroethoxy)-4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino]-6-methoxy-3-quinolinecarbonitrile and 1.5 g (10 mmol) of 4-pyrrolidin-1-yl-piperidine are heated in N,N-dimethylformamide at 85° C. for 5 hours and at 40° C. for 60 hours. The reaction mixture is poured slowly into saturated aqueous sodium bicarbonate to yield a solid which is subsequently filtered off. The crude solid is washed with water, then recrystallized from anhydrous ethyl ether to give 203 mg of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino}-6-methoxy-7-{2-[4-(1-pyrrolidinyl)-1-piperidinyl]ethoxy}-3-quinolinecarbonitrile as an off-white solid, mp 127-130° C.
Reaction SMILES: P(Br)(Br)[Br:2].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][CH2:12]O)([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[Br:2][CH2:12][CH2:11][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phosphorus tribromide (0.94 ml) was added dropwise to a solution of 3-nitrophenethyl alcohol (5 g) in anhydrous diethyl ether (30 ml) at 0°. The mixture was stirred at room temperature for 2 hours and then treated with a solution of potassium carbonate and then water. The organic layer was dried and concentrated in vacuo to give the title compound as an oil (4.51 g).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>O1CCCC1>[CH2:24]([O:26][N:27]=[C:14]([CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:15])[CH3:25]
Reactant: CCON
Reactant: CCC(C)Oc1ccc(CCC(C)=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCON=C(C)CCc1ccc(OC(C)CC)cc1

Procedure:
Following the procedure of Example 1, 4-[4-(1-methylpropoxy)phenyl]-2-butanone (4.41 g, 20.0 mmol) and pyridine (3 ml) in 45 ml of tetrahydrofuran are reacted with ethoxyamine hydrochloride (4.41 g, 45.2 mmol) to give 4-[4-(1methylpropoxy)phenyl]-2-butanone O-ethyloxime, as a mixture of syn and anti stereo isomers. MS m/e 263 (M ).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH2:15])[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1>O1CCCC1.C1C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1)[CH3:11]
Reactant: C=CC(OCC)OCC
Reactant: Brc1cnc2nccnc2c1
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(CCc1cnc2nccnc2c1)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9-BBN (10.2 mL of a 0.5M solution in tetrahydrofuran) at 0° C. was added dropwise 0.77 mL of acrolein diethyl acetal and the mixture allowed to warm slowly to room temperature. After 15 hours, the mixture was diluted with 12 mL dry tetrahydrofuran followed by the sequential addition of potassium phosphate (1.6 g), palladium(1,1'-bis(diphenylphosphino)ferrocenyl) dichloride (160 mg) and 7-bromo-pyrido[2,3-b]pyrazine (924 mg) and then heated to reflux on an oil bath. After 5 hours, the mixture was cooled to 0° C., diluted with 15 mL benzene and the excess reagents quenched by the addition of 2N sodium hydroxide (3.5 mL) and 30% hydrogen peroxide (2.5 mL). The mixture then extracted with ethyl acetate, washed with brine and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:4; then 1:1; then 4:1) to give the title compound (1.2 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].CCN(C(C)C)C(C)C.[CH2:32](Br)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A suspension of (E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (500 mg, 1.55 mmol, Intermediate 1) in DCM (15 ml) was treated with DIPEA (0.33 ml, 1.86 mmol) and phenethyl bromide (0.251 ml, 1.86 mmol), and stirred at RT for 8 days. The mixture was concentrated and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester a yellow solid (280 mg).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 62% of theory, C30H32N6O5 (556.6) Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1) ##EQU63##
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=2[O:6]1>>[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10][Cl:3])=[CH:8][C:7]=2[O:6]1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OCO2
Product: ClCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
153.9 g (1.29 mols) of thionyl chloride are poured onto 65.6 g (0.431 mol) of 3,4-methylenedioxybenzyl alcohol. The mixture is stirred for 90 minutes at ambient temperature (15°-25° C.) and the excess thionyl chloride is then evaporated. The residue is taken up in dimethylformainde (DMF) and the latter is then evaporated. Finally, the residue is taken up in 500 ml of DMF (it is not necessary to isolate the 3,4-methylenedioxybenzyl chloride thus obtained).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: CSc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.56 g, 0.0041×1.2 mol) and sodium hydride (0.17 g, (ca.60% in mineral oil), 0.0041×1.05 mol) in tetrahydrofuran, 2,6- dichloro-4-methylmercaptopyridine (0.80 g, 0. 0041 mol) was added, and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Br:28][C:25]1[CH:24]=[N:23][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=2)=[O:13])=[N:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Br)cn1)c1ccccc1SSc1ccccc1C(=O)Nc1ncc(Br)cn1
Yield: 11.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-amino-5-bromopyrimidine (2.03 g, 11.7 mmol) in 16 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized first from DMF, then from acetonitrile-DMF to yield 0.40 g of the title compound, mp 249°-253° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[I:18]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([I:18])=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 95° for 1.5 hours with 8.88 g (35 mmol) of iodine in 25 ml of N,N-dimethylformamide. The reaction mixture was then poured into 300 ml of water, decolorized with sodium thiosulphate solution and extracted four times with methylene chloride. The organic extracts were washed three times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187°-188°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Clc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Cl)nn2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.0 g) synthesized in Example 4 and 3,6-dichloropyridazine (1.2 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.9 g) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.7 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:25]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[N:16]=[CH:15][N:14]([CH3:25])[C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cnc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
4-[(4-Chlorophenyl)methyl]-6,7-dihydro-3H-imidazo-[1,2-a]purin -9(4H)-one (Procedure 3), 6.02 g. (0.02 mole), is dissolved with warming in a mixture of 100 ml. of water and 15 ml. of ethanol containing 1.0 g. (0.25 mole) of sodium hydroxide. Approximately 3 ml. (approximately a molar equivalent) of methyl iodide was added and the mixture was stirred for about 48 hrs. at room temperature. The precipitated solid was collected, air dried, and recrystallized from isopropanol, m.p. 182.5°-184.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2Cl.[CH3:20][NH:21][CH3:22].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:21]([CH3:22])[CH3:20]
Reactant: CNC
Reactant: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 60 °C

Procedure:
6-Bromo-4-chloro-2-(3-fluorophenyl)-quinoline (20 g, 59.4 mmoles) was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath and dissolved in 150 mL of N-methylpyrrolidinone. 250 mL of a 40% aq. solution of dimethylamine was added with stirring. The mixture was warmed to 60° C. for 48 hrs. At the end of this time the mixture was cooled, added to 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:28])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([Li])CCC.[O:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:36]1>O1CCCC1>[Si:11]([O:10][CH2:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:35]1([OH:34])[CH2:36][CH2:37][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:40]1)[OH:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[Si](OCC(O)c1ccccc1Br)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2C(O)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.9 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)-2-{[tert-butyl(diphenyl)silyl]oxy}ethanol (step 2, 5.63 g, 12.4 mmol) in tetrahydrofuran (36 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (15.9 mL, 25.3 mmol) at −78° C. for 5 min and the mixture was stirred for 5 h at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidine-1-carboxylate (2.33 g, 13.6 mmol) in tetrahydrofuran (10 mL) at −78° C. and the mixture was stirred for 2 h at the same temperature. This resulting mixture was slowly warmed up to room temperature and stirred for 16 h at the same temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution, and concentrated to give a yellow residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (2/1) to afford 1.76 g (26%) of the title compound as a colorless solid:
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][CH2:6][C:7]#[N:8])(=[O:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:4]1[CH2:5][CH2:6][CH2:7][NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)C(CCC#N)C(C)=O
Agent: [Ni]
Solvent: CCO
Product: CC(=O)C1=C(C)NCCC1

Procedure:
A solution of 4,4-diacetylbutyronitrile (15.3 g, 0.1 mole) in ethyl alcohol (50 ml) over Raney nickel (2 g) was hydrogenated at room temperature and three atmospheres pressure. After hydrogen uptake had ceased, the catalyst was filtered off and the filtrate concentrated under reduced pressure to give 3-acetyl-2-methyl-1,4,5,6-tetrahydropyridine.
Reaction SMILES: FC(F)(F)C(O)=O.NN.[CH3:10][O:11][C:12](=[O:31])[CH2:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:17]=1)[NH2:15].[O-:32][C:33]#[N:34].[Na+]>C1(C)C=CC=CC=1>[NH2:34][C:33]([NH:15][N:14]([CH2:13][C:12]([O:11][CH3:10])=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:17]=1)=[O:32]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1cccc(OCc2ccc(F)cc2)c1
Agent: NN
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cccc(OCc2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.75 ml, 35.8 mmol) was added at 25° to a stirred suspension of the hydrazine (Intermediate 79, 3.7 g, 12.2 mmol) and sodium cyanate (2.71 g, 41.75 mmol) in toluene (70 ml). The mixture was stirred at 25° for 1 h, during which time a white solid precipitated. 8% sodium bicarbonate (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were then washed with water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating in vacuo to a yellow oil. Trituration with hexane/ether/ethyl acetate (1:1:4) gave the title compound (Intermediate 80) as a white crystalline solid (2.9 g; 68%) m.p. 119°-121°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@H:43]([O:46][Si](C(C)C)(C(C)C)C(C)C)[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@H](O)C5)n4c3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of Intermediate 26d (19 mg, 0.024 mmol) in THF (1 mL) at −30° C. was added TBAF (1M in THF, 36 μL, 0.036 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (2 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph column, 35-75% MeCN in H2O, 0.1% HCO2H) gave the title compound as an off-white powder after freeze-drying (10.0 mg, 60%). LCMS (Method 5): Rt 4.00 min, ink 621 [MH+]. 1H NMR (400 MHz, CDCl3): 1.29 (9H, s), 1.89-2.09 (4H, m), 2.13-2.29 (2H, m), 2.34 (3H, s), 3.35 (1H, td, J 9.2, 4.6), 3.45 (1H, d, J 11.1), 3.50 (1H, dd, J 11.1, 4.3), 3.60 (1H, m), 4.51 (1H, m), 5.04 (1H, td, J 8.5, 5.3), 5.15 (1H, t, J 4.1), 5.57 (1H, d, J 8.6), 6.26 (1H, s), 6.67 (1H, br s), 6.89 (1H, dd, J 9.9, 1.7), 7.15 (2H, d, J 7.1), 7.24-7.29 (4H, m), 7.30-7.38 (4H, m).