Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(N)CN
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A solution of 10 mL (95.4 mMol) 1,2-diamino-2-methylpropane and 20 mL (144 mMol) triethylamine in 300 mL dichloromethane was cooled to 0° C. To this solution was added a solution of 26 gm (93.3 mMol) (triphenyl)methyl chloride in 50 mL dichloromethane. The resulting mixture was stirred at room temperature for about 18 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate containing from 0–10% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 16.0 gm (52%) of the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=O)[CH:28]=[CH:29][CH:30]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:32]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)c1

Procedure:
Starting from 400 mg (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 610 mg (3.81 mmol) of 3-methoxyphenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 160 mg (28%) of the diastereomer which elutes more rapidly, M.p.: 92° C., and 145 mg (25%) of the diastereomer which elutes more slowly, M.p.: 54° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 85 g, 492 mmol) in DMF (365 mL) was added DIPEA (129 mL, 738 mmol) and piperidine (58.4 mL, 591 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was poured onto water (4 L) and the resulting precipitate was collected by filtration to give the title compound as a white solid (85.12 g) in a 78% yield.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.Cl[CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([O:3][CH2:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(C)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)CC(C)C)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
An oily suspension (50% by weight; 1.8 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (9.3 g) in anhydrous dimethylformamide (120 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. 1-Chloro-4-methyl-2-pentanone (8.1 g) is then added dropwise while the temperature is maintained at 0° C., and stirring is continued for a further 1 hour at 0° C. and then for 4 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of ice (150 g) and water (350 cc), neutralized with 1N hydrochloric acid solution and extracted with dichloromethane (3×250 cc). The organic phases are combined, washed with water (4×75 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is taken up with ethyl acetate (25 cc) and the insoluble product is separated by filtration, washed successively with ethyl acetate (10 cc) and diisopropyl ether (10 cc) and then discarded. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is purified by chromatography on silica (120 g) contained in a column 3 cm in diameter [eluant: dichloromethane/methanol (98.5:1.5 by volume)]. Elution is first performed with 170 cc of solvent: the corresponding eluate is discarded; elution is then performed with 800 cc of solvent and the corresponding eluate concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization of the residue in ethyl acetate, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(4-methyl-2-oxopentyloxy)-1isoindolinone (3 g), m.p. 120° C., is obtained. 1-Chloro-4-methyl-2-pentanone may be prepared by the method described by ASINGER F., et al., Ann. Chem., 1964, 672, 156.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: CNO
Reactant: N#C/N=C1\CC(c2ccncc2)Oc2ccc(Br)cc21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccncc3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
To a solution of methylhydroxylamine HCl salt (76.9 mg, 0.92 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25 w % in MeOH, 0.19 mL, 0.828 mmol), followed by (E)-N-(6-bromo-2-(pyridin-4-yl)chroman-4-ylidene)cyanamide (300 mg, 0.92 mmol), After stirring for 10 min, the solvent was removed in vacuo. The residue was dissolved in DCM (20 mL). The mixture was filtered, and the solvent was removed in vacuo to give a reside, which was purified by preparative TLC to give 6-bromo-2′-methyl-2-(pyridin-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (80 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine (the product of Example 1D, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The separated organic layer was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.01 (m, 1H), 1.13 (m, 1H), 1.25 (d, J=6 Hz, 3H), 1.36 (m, 1H), 1.54 (m, 1H), 1.89 (m, 3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.65 (m, 1H), 2.79 (m, 1H), 3.27 (dd, J=12 Hz, J=6 Hz, 1H), 3.40 (m, 1H), 7.22 (d, J=9 Hz, 2H), 7.59 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23].Cl.C([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])C.C(N(CC)CC)C.O.N>C(#N)C>[C:28]([CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH2:20][CH:21]=[CH2:22])[C:12]([OH:19])=[C:13]([CH2:16][CH:17]=[CH2:18])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:23])[CH3:31])([OH:32])=[O:27]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCBr
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: N
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCCN(C)CC(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(4-Bromobutyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone (1.9 g) was dissolved in 50 ml of acetonitrile, then 2 g of N-methylglycine ethyl ester hydrochloride and 5 ml of triethylamine were added thereto, and stirred at 80° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, the extract was washed with an aqueous solution saturated with sodium bicarbonate, next with water, then concentrated under reduced pressure. Thus obtained oily residual product was subjected to purification by means of a silica gel column chromatography, then dissolved in 10 ml of methanol and 10 ml of 1N-sodium hydroxide aqueous solution, and stirred at 70° C. for 1 hour. After the reaction mixture was cooled, the mixture was acidified by adding hydrochloric acid, further the acidified reaction mixture was made basic by adding 25% ammonia water. This reaction mixture was concentrated under reduced pressure to dryness, thus obtained solid residual product was subjected to extraction by means of Soxhlet's extractor with chloroform as the solvent. The chloroform extract was concentrated under reduced pressure to dryness, and recrystallized from acetone, there was obtained 1-[4-(N-carboxymethyl-N-methyl-amino)butyl ]-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([OH:24])=O)[C:19]=2[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45])(=[O:38])=[O:37])([O-:29])=[O:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([N:42]3[CH2:43][CH2:44][N:39]([S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N+:27]([O-:29])=[O:28])(=[O:38])=[O:37])[C:40](=[O:45])[CH2:41]3)=[O:24])[C:19]=2[N:20]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]1)OCc1ccccc1
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
To a solution of [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid (1.48 g, 4.5 mmol), 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.45 g, 4.5 mmol), and PyBOP (2.81 g, 5.4 mmol) in DMF (13 mL) was added N,N-diisopropylethylamine (1.96 mL, 13 mmol) at room temperature. After stirring for additional 40 min, the reaction mixture was diluted with water (80 mL) to precipitate solid. The solid was filtered off, washed with ethyl alcohol and triturated with acetonitrile and THF to give pure product (1.56 g, 58%). 1H NMR (DMSO-d6) δ 11.47 (s, 1H), 11.38 (s, 1H), 8.40˜7.96 (m, 4H), 7.82 (s, 0.6H), 7.78 (s, 0.4H), 7.45˜7.35 (m, 5H), 5.25 (s, 2H), 5.13 (s, 1.2H), 5.04 (s, 0.8H), 4.51 (s, 0.8H), 4.26 (s, 1.2H), 4.10˜4.02 (m, 2.4H), 3.93˜3.83 (m, 1.6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][N:12]3[CH:15]=[CH:16][CH:17]=[C:11]3[CH2:10]2)[CH2:3][CH2:2]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>N1C=CC=CC=1>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH2:17][CH:11]3[CH2:10]2)[CH2:3][CH2:2]1)=[O:25]
Reactant: C1=Cn2cccc2CN1CCC1CCNCC1
Reactant: O=C(Cl)c1ccccn1
Solvent: c1ccncc1
Product: O=C(c1ccccn1)N1CCC(CCN2CCN3CCCC3C2)CC1

Procedure:
In the manner of Example 2, 2-(4-piperidylethyl)pyrrolo[1,2-a]pyrazine and 2-pyridine carbonyl chloride will react in pyridine solution to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([NH:20][NH2:21])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[C:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(=O)[CH3:28].CS(C)=O>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([NH:20][N:21]=[C:27]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)[CH3:28])=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: NNC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
A mixture of 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carbohydrazide (100 mg, 0.25 mmole), 4-acetyl benzoic acid (50 mg, 0.3 mmole), DMSO (5 mL), and one drop of glacial acetic acid was stirred at room temperature for 12 hours. Ethyl acetate (50 ml) was added to the flask. The mixture was extracted with water and brine. The product crystallized from the organic phase was filtered, affording 97 mg (73%) of the title compound. 1H NMR (DMSO-d6) δ9.0 (s, 2H), 8.5 (d, 1H), 8.25 (s, 1H), 8.0-7.9 (m, 4H), 7.6-7.5 (m, 3H), 7.4-7.3 (m, 2H), 6.6 (s, 1H), 5.9 (s, 2H), 2.4 (s, 3H),MS (APCI; (M+H)+) m/z 531.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C>C(#N)C>[N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:9][CH2:10][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCN(CCN2CCNCC2)CC1

Procedure:
The N-protected 2-hydroxyethylpiperazine (3.0 g), triethylamine (1.42 g) and methylene chloride (30 ml) is cooled to 0° in an ice bath under nitrogen. A mixture of methanesulfonyl chloride (1.64 g) in methylene chloride (30 ml) is added dropwise over 10 min. The cooling bath is removed and the mixture allowed to warm to 20°-25° for 30 min. The mixture is then washed with water (60 ml), dried over sodium sulfate and the solvent removed to give crude mesylate. 4-[2,6-Bis(1-pyrrolidinyl)4-pyrimidinyl]piperazine (4.23 g), potassium carbonate (1.93 g) and acetonitrile (150 ml) are added to the crude mesylate. The mixture is heated at reflux for 18 hr. The acetonitrile is removed under reduced pressure and the residue distributed between chloroform (200 ml) and water (200 ml). The phases are separated, the organic phase is washed with saline, dried over sodium sulfate and the solvent removed under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (200 g) with ethyl acetate/methanol/ammonium hydroxide (9.5/0.4/0.1). The appropriate fractions are pooled and concentrated to give the N-protected form of the title compound as a solid, mp 148°-149°.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=[O:14])[C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][Cl:21]>CN(C=O)C.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:1]=[CH:2][CH:3]=[C:4]2[C:13]1=[O:14].[Br:17][CH2:18][CH2:19][CH2:20][N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:1]=[CH:2][CH:3]=[C:4]2[C:13]1=[O:14]
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccccc2n2cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2cccn2c2ccccc2n1CCCBr
Product: O=c1c2cccn2c2ccccc2n1CCCCl
Temperature: 80 °C

Procedure:
Pyrrolo[1,2-a]quinoxalin-4(5H)-one (500 mg; 2.71 mmol) was dissolved in anhydrous DMF (10 mL) in a 25 mL round bottomed flask. NaH (68.6 mg; 2.71 mmol; 95%) was carefully added to the flask under a blanket of nitrogen. The reaction mixture was allowed to react for 2 h at room temperature after which 1-bromo-3-chloropropane (511.99 mg, 3.25 mg) was added and the mixture was heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O, brine, dried over sodium sulfate, then filtered and concentrated. The crude mixture was purified by flash chromatography to yield the desired 5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one and 5-(3-bromopropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one in approximately a 60:40 ratio. The mixture was used in the next step without further purification. [M+1]+=261 Chloride; [M+1]+=305 Bromide. 1H NMR (CDCl3): δ 2.18-2.42 (2H); 3.49-3.62 (1H); 3.63-3.81 (1H); 4.38-4.50 (2H); 6.61-6.71 (1H); 7.13-7.514 (4H); 7.65-7.80 (2H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[S:29][C:30]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=4[N:32]=3)=[CH:26][CH:27]=2)=[O:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC(C)=O)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 4-acetoxy-3-nitrobenzoic acid (0.44 g, 1.95 mmol) and thionyl chloride (5 ml) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section above using the acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.50 g, 1.95 mmol) in dry THF (25 ml) containing diisopropylethylamine (0.302 g, 2.34 mmol) to give the title compound (0.728 g, 86%) as a tan-coloured solid after work-up.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7]/[N:8]=[CH:9]/[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:21]=[C:22](/[C:25]2[CH:30]=[CH:29]C(Cl)=[CH:27][CH:26]=2)\[C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.Cl[CH2:40][Cl:41]>>[C:1]([O:5][C:6]([CH:7]1[CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=2)[C:22]([C:25]2[CH:26]=[CH:27][C:40]([Cl:41])=[CH:29][CH:30]=2)([C:23]#[N:24])[CH:9]([CH:10]([CH3:12])[CH3:11])[NH:8]1)=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: ClCCl
Reactant: CC(C)/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 45 %

Procedure:
In a manner similar to the method described in Example 1c, [2-methyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 49a (1 g, 5.4 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.85 g, 3.1 mmol) prepared in Example 1b, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isopropyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.64 g, 45%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:28])[CH3:27])[C:20]=2[S:29][CH2:30]C)[CH:11]=1>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:27])[CH3:28])[C:20]=2[S:29][CH3:30])[CH:11]=1
Reactant: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 17 h

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10%-sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.