Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.C(#N)C.[H-].[Na+].[C:26](OC=O)(=[O:28])C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:10]2[N:11]([CH3:20])[CH2:12][N:13]([CH3:19])[CH2:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:26]=[O:28])=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: CN1CC([N+](=O)[O-])=C(NCc2ccc(Cl)nc2)N(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CC([N+](=O)[O-])=C(N(C=O)Cc2ccc(Cl)nc2)N(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a mixture of 0.27 g of 4-(6-chloro-3-pyridylmethylamino)-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 13), 5 ml of dry THF and 5 ml of dry acetonitrile was added 0.0239 g of sodium hydride (60%, in oil) in small portions over 1 minute with ice cooling. After the mixture was stirred at room temperature for 30 minutes, a solution of 0.24 g of formic acetic anhydride in 1 ml of THF was added dropwise over a period of 4 minutes with ice cooling and the mixture was then stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (20:1)) to give 0.14 g of 4-[N-(6-chloro-3-pyridylmethyl)-N-formylamino]-1,3-dimethyl-5-nitro-1,2,3,6-tetrahydropyrimidine (Compound No. 30) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][S:25][CH2:26][C:27]([NH:14][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1cccc(-c2ccc(F)cc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccc(F)cc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4′-fluorobiphenyl-3-amine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid to give 5-chloro-2-([((2-[(4′-fluorobiphenyl-3-yl)amino]-2-oxoethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 78%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:18])[CH3:17]>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:18])[CH3:17])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)NCC(C)c1ccc(-c2ccsc2)cc1
Reaction time: 6 h

Procedure:
To a solution of 1.0 mL (0.088 mmol) of a 0.088 M solution of 2-(4-(3-thienyl)phenyl)propylamine in tetrahydrofuran was added 37 mg (0.132 mmol) of piperidinylmethyl polystyrene. To the mixture was added 10.4 mg (0.132 mmol) of acetyl chloride and the mixture was shaken for 6 hours. To this mixture was added 0.15 g (0.3 mmol) of aminomethyl polystyrene and the vessel was shaken for 12 hours. The reaction mixture was filtered through a cotton plug and concentrated to afford the title compound. The NMR spectrum was consistent is with the proposed title structure.
Reaction SMILES: [C:1]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl[CH2:19][C:20]([O-:22])=[O:21].[Na+]>>[C:1]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:19][C:20]([OH:22])=[O:21])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C([O-])CCl
Agent: [Na+]
Product: CCOC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reaction time: 7 h
Yield: 58 %

Procedure:
4-Carbethoxy-4-phenylpiperidine (4.01 g.) was dissolved in 13 ml. absolute alcohol and refluxed together with 2.01 g. sodium chloroacetate. After 7 hours no starting material was present as evidenced by TLC. The precipitated sodium chloride was removed by filtration and washed with 3 ml. ethanol. On cooling of the filtrate white cyrstals appeared. Filtration and drying gave 2.9 g. (58%) of the title compound. m.p. 148°-150°C. Evaporation of the mother liquor gave a glass which did not crystallize from acetone/hexane.
Reaction SMILES: [OH:1][C:2]1([CH2:19][OH:20])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17].[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([O:20][CH2:19][C:2]1([OH:1])[C:6](=[O:7])[O:5][C@H:4]2[C:8]3[C@@:13]([CH3:16])([CH2:14][CH2:15][C:3]12[OH:18])[CH2:12][CH2:11][CH2:10][C:9]=3[CH3:17])(=[O:23])[CH3:22]
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(CO)C3(O)CC[C@@]2(C)CCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1(O)C(=O)O[C@H]2C3=C(C)CCC[C@]3(C)CCC21O
Reaction time: 0.5 h

Procedure:
Compound of example 2 (150 mg, 0.531 mmole) was dissolved in dichloromethane (10 mL). Acetic anhydride (54.25 mg, 0.531 mmole), pyridine (84 mg, 1.062 mmole) and 4-(dimethylamino)-pyridine (DMAP) (2 mg) were added to this solution and reaction mixture was stirred for 30 minutes. Reaction mixture was extracted with dichloromethane (3×100 mL). The dichloromethane layer was washed with water and brine and was dried over sodium sulfate. The solvent was removed and crude product was purified by crystallization using ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[O-:12][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>CC(C)=O.CC(C)=O.O>[C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ccc(C=O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)n1ccc(C(=O)O)c1
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 1-tert-butyl-1H-pyrrole-3-carbaldehyde (0.339 g, 2.24 mmol) in acetone (40 mL) was added, over a 2 h period, a solution of KMnO4 (0.708 g, 4.48 mmol) in Acetone/H2O (1:1, 60 mL). After 3 h, the reaction was poured into a solution of 10% NaHSO3/1N HCl (120 mL) and the solution was extracted with DCM (3×60 mL). The combined extracts were washed with H2O (2×60 mL) and 5% NaHCO3 (3×60 mL). The bicarbonate washes were carefully acidified to pH 3 and extracted with DCM (3×60 mL). The combined organic layers were washed with brine (1×), dried (MgSO4) and concentrated afford 1-tert-butyl-1H-pyrrole-3-carboxylic acid (0.270 g, 72% yield) as a white solid. MS (ESI) m/z: 168.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH2:7]([O:9][P:10](Cl)Cl)[CH3:8]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[P:10]1[O:9][CH2:7][CH3:8]
Reactant: CCOP(Cl)Cl
Reactant: CNCCNC
Product: CCOP1N(C)CCN1C
Yield: 45.9 %

Procedure:
Substantially the same procedure was followed as in Example 1, with 3.00 grams (34 mmol) N,N'-dimethylethylenediamine and 4.55 grams (31 mmol) ethylphosphorodichloridite to produce 2.31 grams of 1,3-dimethyl-2-ethoxy-1,3-diaza-2-phosphacyclopentane, ##STR25## as phosphorus amide catalyst.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][C:14]=2[OH:32])[CH:10]=[CH:11][CH:12]=1)[CH3:2].IC.[C:36]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:15][C:14]=2[O:32][CH3:36])[CH:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2OC)c1
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 35 (0.23 g, 0.508 mmol, 1.0 eq), iodomethane (0.13 mL, 2.1 mmol, 4.1 eq), and K2CO3 (0.56 g, 4.06 mmol, 8.0 eq) in acetone (5 mL) was heated to 70° C. for 24 hours. LC/MS showed complete conversion. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (neutral aluminum gel, 0-3% methanol in dichloromethane). Yield: 63%, 99% pure. M+1=468
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][C:39](=[O:40])[CH2:38][NH:37][C:35]([O:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:36])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCc1ccccc1)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A solution of 2.15 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide and 1.86 g of N-(benzyloxycarbonyl)-glycine in 8 ml of dimethylformamide was cooled to 0° C. and treated with 2.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature, diluted with diethyl ether and washed sequentially with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give 2.96 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-[N-(benzyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)=O.CC(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:34]1[CH:35]=[N:36][CH:28]=[CH:29][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1ccnc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80 mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) via addition funnel, at a rate that kept the internal temp below −59° C. (˜2 h). After final addition, the yellow-green slurry was stirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0 g, 56.69 mmol). The bath was not removed, but the contents were allowed to slowly warm to room temp. After 4 days, the dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL). The aqueous layer was separated and the organics were again extracted with base (1000 mL). The pH of the two aqueous layers was adjusted to ˜2 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered. The resultant yellow cake was washed with water (2×400 mL) and dried under high vacuum at 40° C. (17-19 g). LC/MS [(5.2 min; 359 (M+1)].
Reaction SMILES: C(O[C:4](=[O:26])[CH2:5][CH2:6][C:7]1[C:8](Cl)=[N:9][C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[Br:24])=[N:11][C:12]=1[CH3:13])C.[CH2:27]([CH:29]([NH2:32])[CH2:30][CH3:31])[CH3:28]>CN1CCCC1=O>[Br:24][C:16]1[CH:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:10]1[N:11]=[C:12]([CH3:13])[C:7]2[CH2:6][CH2:5][C:4](=[O:26])[N:32]([CH:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:8]=2[N:9]=1
Reactant: CCOC(=O)CCc1c(C)nc(Nc2ccc(C(C)C)cc2Br)nc1Cl
Reactant: CCC(N)CC
Solvent: CN1CCCC1=O
Product: CCC(CC)N1C(=O)CCc2c(C)nc(Nc3ccc(C(C)C)cc3Br)nc21
Temperature: 130 °C
Yield: 49.4 %

Procedure:
A solution of 3-[2-(2-bromo-4-isopropyl-phenylamino)-4-chloro-6-methyl-pyrimidin-5-yl]-propionic acid ethyl ester (XII; 0.22 g, 0.50 mmol) in N-methylpyrrolidinone (2.5 mL) was treated with 1-ethyl-propylamine (0.22 g, 2.5 mmol) and heated to 130° C. in a sealed tube for 130 hours. The cooled reaction mixture was poured onto water (50 mL) and extracted with diethyl ether (3×50 mL). The combined extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The brown solid was chromatographed over silica gel, eluting with 20% ethyl acetate in hexane, to provide 113 as a white solid (0.11 g, 43%; mp 124-126° C.; ESIMS m/z (M+H) 445).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16].[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:26][CH:27]=1)[C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16]
Reactant: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Reactant: ClCc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 198 mg of 5-fluoro-3-methyl-1H-indole-2-propanoic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 155 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 307 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise under nitrogen at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluted HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, taken up with acetone, filtered and dried, yields 35 mg of the title compound (m.p. 222° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][C:23]=1[CH:28]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:28][C:23]4[NH:24][C:25]([CH3:27])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 37 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (50 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 50 mg (37%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.07 (br s, 1H, NH), 9.18 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.35 (s, 1H), 7.30-7.40 (m, 2H), 6.05 (s, 1H), 3.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.16 (s, 3H, CH3). MS 398 [M++1].
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[CH:21]=[C:20]([CH2:22][Br:23])[CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1C(C)=O)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)=O)c1ccccc1

Procedure:
To a solution of 1.25 g (4.19 mmol) of the product of Step A dissolved in 15 mL of CCl4 was added 0.821 g (4.61 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 3.5 hours, then cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.431 g (27%) yield of the title compound.
Reaction SMILES: CC1C=CC(S(O[C@@H:12]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13][CH:14]([C:21]#[N:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C=O)C.CCOC(C)=O>[C:15]1([C@:14]2([C:21]#[N:22])[CH2:13][C@H:12]2[CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: -42 °C
Yield: 94.7 %

Procedure:
To (1R)-3-cyano-3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl 4-methylbenzenesulfonate (7.4 g, 17.0 mmol), accessed via the method of preparation 2, in 70 mL DMF at −42° C. was added 1M lithium bis(trimethylsilyl)amide in hexanes (25.5 mL, 25.5 mmol, 1.5 eq) dropwise and stirred with continued cooling at −42° C. for 1 h. The reaction mixture was diluted with EtOAc, washed successively with water (4×) and brine, dried over MgSO4, filtered and concentrated to give the title compound (4.25 g, 16.1 mmol, 95%) as a yellow oil which was shown to be a 94:6 mix of the title compound to the product of Preparation 3B. 1H NMR (300 MHz, CDCl3) δ 7.42-7.29 (m, 10H), 4.64 (m, 2H), 3.91-3.86 (m, 1H), 3.74-3.68 (m,1H), 2.00-1.90 (m, 1H), 1.68-1.56 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1

Procedure:
Prepared from 4-fluorobenzaldehyde and the product of Example 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:32][CH2:33][N:34](CC)[CH3:35]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][N:34]([CH2:33][CH2:32][C:31]1[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:29]([O:28][CH3:27])[CH:30]=1)[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C)CCc1ccc(OC)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(OCCO)c(OCc2ccccc2)c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2OCc2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-(2-Benzyloxy-4-nitrophenoxy)ethanol (400 mg, 1.383 mmol) was dissolved in pyridine (5 ml); after cooling at 0° C., methanesulfonyl chloride (0.22 ml, 2.76 mmol) was slowly added dropwise, followed by stirring at room temperature for 2 h. The solvent was evaporated under vacuum and the residue was diluted with a saturated aqueous solution of sodium bicarbonate (10 ml), followed by extraction with chloroform (100 ml). The extracted organic layer was dried with sodium sulfate and the solvent was evaporated; the resulting residue was dissolved in 15 ml of a 1:2 solvent system of ethanol and acetonitrile and, thereafter, 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.765 ml, 4.148 mmol) was added, followed by stirring at the reflux temperature for 8 h. The reaction solution was cooled to room temperature and thereafter the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 1:1 solvent system of n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 1-(2-benzyloxy-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (600 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.249 g, 1.03 mmol) and triethylamine (0.151 mL, 1.14 mmol) and 4-chlorobenzoyl chloride (0.241 g, 1.14 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from ethyl acetate to yield 0.17 g (43%) of the title compound as a white solid mp 174°-175° C. HRMS m/e calculated for C22H22ClN3O: 379.1448. Observed m/e: 379.1465. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 69.38; H, 5.80; N, 10.96.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH:25]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26]1.O>CN1C(=O)CCC1>[CH:25]1([CH2:29][NH:30][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCC1CCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCC3CCC3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.5 g, 1.314 mmol) and (cyclobutylmethyl)amine (0.24 g) in NMP (5 ml) was stirred at ambient temperature for 18 h. Water (50 ml) was then added, and the resulting precipitate was collected by filtration and dried, giving the title compound as a cream solid (0.434 g).