Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:20]([N:24]([CH3:33])[N:25]=CC1C=CC=CC=1)=[N:21][C:22]#[N:23].Cl>CC(C)=O>[CH3:33][N:24]1[C:20]([NH:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:15]=[CH:16][CH:17]=[C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:21][C:22]([NH2:23])=[N:25]1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1
Yield: 14.6 %

Procedure:
A mixture of 3-[3-[1-pyrrolidinylmethyl]phenoxy]propanamine (0.97 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid methyl ester (0.97 g) was heated at 70° for 8 hr under a reduced pressure of 20 mm of mercury. Acetone was added and the solution was treated with hydrochloric acid at room temperature for one hour, washed with ether, basified with sodium carbonate and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave a thick oil which crystallised from ethyl acetate/light petroleum (b.p. 60-80") to give the title compound as a white solid (0.2 g). TLC; silica/methanol/0.88 ammonia 80:1) Rf 0.5, m.p. 95°-95.5°.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].Cl.[C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[CH:33]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:33]=[C:32]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1ccncc1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccncc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 17 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 4-ethynyl pyridine hydrochloride (Aldrich) in the same manner as Example 15. ESI MS m/z 535 [C27H30N6O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[CH2:33][OH:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH2:33][OH:34])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: OC[C@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 55.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.6 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:12].[CH3:15][N:16](C)C=O.C(OCC)C>O.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:12]
Reactant: COc1ccc(Br)cc1C(C)(C)C=O
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C#N)cc1C(C)(C)C=O
Reaction time: 3 h

Procedure:
2-(2-Methoxy-5-bromophenyl)-2-methyl-1-propanal (9.5 g), prepared as in Example 5(d), cuprous cyanide (4.0 g) and dimethylformamide (20 ml) were heated under reflux with stirring for 3 hours. A solution of ferric chloride (7.3 g) in water (25 ml) and hydrochloric acid (3.5 ml conc) was added to the cooled reaction mixture which was then heated at 60°-70° C. for 5 minutes. Isolation of the product through diethyl ether yielded, after recrystallisation from ethanol, 3 g of pure product, mp 115°-117° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-(trifluoromethyl)phenol.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Br[CH2:11][CH2:12][OH:13]>[OH-].[Na+]>[I:1][C:2]1[C:7]([O:8][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCCO)c(I)n1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was dissolved in an aqueous solution of sodium hydroxide (1M, 30 mL). 2-bromoethanol (3.91 mL, 55.2 mmol) was added dropwise and then the solution was heated to 100° C. for 3 hours. The resulting mixture was extracted with chloroform (2×200 mL) and the combined organic phases then back extracted with aqueous sodium hydroxide solution (1M, 50 mL). The organic phase was dried over magnesium sulfate and the volatiles removed in vacuo to afford the desired product (5.26 g) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH2:9][N:10]2[C:13]([NH:15]C2C=CC=CC=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[CH2:24](N=C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C(#N)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])([CH3:23])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)CCN(C(=O)Nc2ccccc2)c2cc(C#N)ccc21
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1(C)CCN(C(=O)NCc2ccccc2)c2cc(C#N)ccc21
Yield: 87.8 %

Procedure:
A solution of the title J compound from Example 1 (0.20 g, 1.07 mmole), benzyl isocyanate (0.14 g, 1.07 mmole) and 4-dimethylaminopyridine (50 mg) in acetonitrile (4.5 mL) was heated under argon at reflux for one hour. The solvent was recovered under vacuum and the crude product was chromatographed on silica eluting with hexane/ethyl acetate (7:3) to afford 0.30 g of the title compound as a white solid; m.p. 114°-115° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[N:26][C:25]([Br:28])=[CH:24][N:23]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:21]([C:22]3[CH:27]=[N:26][C:25]([Br:28])=[CH:24][N:23]=3)[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:17])([CH3:16])[CH3:18]
Reactant: CCOC(=O)C1(CCNc2cnc(Br)cn2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cnc(Br)cn1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 4-[2-(5-bromo-pyrazin-2-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.825 g, 1.81 mmols) in THF (10 mL) was added a 1 M solution of potassium t-butoxide in THF (2.0 mL), and allowed to stir at room temperature. After 1 hour LCMS was taken and reaction was not complete. After 5 hours, an additional 1 mL of potassium t-butoxide was added. The reaction mixture was allowed to stir for 16 hours. The three reaction mixtures were diluted with ethyl acetate (20 mL), quenched with water (5 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford crude product. Purification over silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.186 g (25%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14][CH2:15]Br.CC([O-])(C)C.[K+]>>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1cccc2ncccc12
Reactant: BrCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: BrCCCOc1cccc2ncccc12
Yield: 35.5 %

Procedure:
Following the same procedure as in Example 1-(a), reaction and treatment were carried out using 1.0 g of 5-hydroxyquinoline, 2.1 g of 1,3-dibromopropane and 0.78 g of t-BuOK as a base, in order to obtain 0.65 g of 5-(3-bromopropoxy)quinoline.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C:20](=[O:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]1)[CH2:11][CH2:10]3)#[N:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C:20](=[O:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@@H:14]2[O:31][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 17β-cyano-5α-androst-2-en-11-one (2.8g.) and 85% m-chloroperbenzoic acid (2.0g.) in chloroform (50 ml.) was stirred for 1.5 hour at room temperature and then diluted with chloroform (75 ml.). This solution was washed with aqueous 10% sodium bicarbonate and water prior to drying. Filtration and evaporation afforded a solid (3.18g.) which was recrystallised from ether/petrol to afford the pure title compound; m.p. 206°-208°; [α]D + 93°, (c 0.7).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([NH:24][C:23]1[CH:22]=[C:21]([F:20])[C:27]([F:28])=[C:26]([F:29])[CH:25]=1)=[O:18]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2cc(F)c(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 25.9 %

Procedure:
The product is prepared according to the procedure described in example 68, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 214 mg of 3,4,5-trifluoroaniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 72 mg of 2-(1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)-N-(3,4,5-trifluorophenyl)acetamide are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([F:15])=[CH:9][CH:8]=3.[OH-].[K+].Cl[CH2:19][C:20]1([CH3:23])[CH2:22][O:21]1>CN(C)C=O>[F:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:19][C:20]3([CH3:23])[CH2:22][O:21]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: Fc1ccc2[nH]c3ccc(F)cc3c2c1
Reactant: CC1(CCl)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(Cn2c3ccc(F)cc3c3cc(F)ccc32)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a stirred solution of 3,6-difluoro-9H-carbazole (2.0 g, 9.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added 85% potassium hydroxide (0.780 g, 11.8 mmol) and the mixture was stirred for 1 hr. 2-(Chloromethyl)-2-methyloxirane (2.098 g, 19.7 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (1.7 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.68 (dd, 2H, J=8.4, 2.4 Hz), 7.41 (dd, 2H, J=9.0, 4.2 Hz), 7.23 (td, 2H, J=9.0, 2.4 Hz), 4.62 and 4.22 (AB, 2H, J=15.6 Hz), 2.71 & 2.66 (AB, 2H, J=4.5 Hz), 1.33 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)(C)(C)C.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[O:13][C@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1

Procedure:
To [(1S,3S)-3-(5-fluoro-2-nitro-phenoxy)-cyclopentyl]-carbamic acid tert-butyl ester, cpd. XXXVII.1 (2.13 g) in DCM (150 ml) was added at 0° C. TFA (10 ml) and stirred at rt overnight. The reaction mixture was concentrated at rt and triturated with diisopropyl ether to give the desired compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Temperature: 78 °C
Yield: 65 %

Procedure:
5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.959 g, 2.37 mmol) and ethyl formate (0.60 mL, 7.43 mmol) were dissolved in anhydrous ethanol (10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.8 mL, 7.50 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.666 g, 1.54 mmol, 65%).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([NH:9]C(=O)OC(C)(C)C)[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([N:4]2[CH:8]=[C:7]([NH2:9])[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cn(C2CC2)cn1
Agent: Cl
Solvent: CO
Product: Nc1cn(C2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 237D (0.60 gm, 2.3 mmole) in a 5.0 N solution of HCl in methanol was left stirring at room temperature for 1 hr. This was applied onto a Phenomenex Strata-X-C 33 um cation mixed-mode polymer, flushed with methanol, and the product was eluted with a 2 N solution of ammonia in methanol. Removal of the solvents left 237E, (0.20 gm; 59% yield). 1H NMR (500 MHz, CDCl3) δ 0.87 (m, 4 H) 3.21 (s, 1 H) 6.27 (s, 1 H) 7.16 (br s, 1 H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[O:1][CH2:2][CH2:3]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCOc2cccnc21
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCCCNC1CCOc2cccnc21
Yield: 71.8 %

Procedure:
Reaction of 2,3-Dihydro-pyrano[3,2-b]pyridin-4-one (277 mg, 1.85 mmol) with (4-Amino-butyl)-carbamic acid tert-butyl ester (269 mg, 1.43 mmol) using general procedure B for reductive amination with NaBH(OAc)3 (605 mg, 2.86 mmol), followed by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 97:2:1 followed by 95:4:1) afforded [4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acid tert-butyl ester (330 mg, 72%) as a pale yellow oil.
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To 400 ml ethanol is added 21.5 g of 4-hydroxy-4'nitrobiphenyl, and the mixture heated to reflux. A solution of 7.1 g KOH in 30 ml of water is added dropwise at reflux temperatures. After complete addition, 18 g of 5-bromo-1-pentene is added and the reaction medium is heated at reflux temperature for about 15 hours. Ethanol is removed under vacuum from the cooled mixture, and the solid residue is slurried with water in a blender, filtered, washed with water, and air dried. The product then is recrystallized from 90/10 hexane/toluene, mp 74°-76° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:28])[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[NH2:26])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:28])[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:27])[NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(N)=O)CC1
Reactant: Clc1ccnc2ccccc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2ccnc3ccccc23)CC1

Procedure:
This was prepared from 4-chloroquinoline (0.49 g) and amide (a) (0.73 g) according to the procedure of Example (1l) affording a white solid (0.66 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][CH2:24][CH3:25])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1
Reactant: CCOCCn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(Cl)cc1
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-(2-ethoxy-ethyl)-9H-purine.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[CH3:22][C:23]1[C:24]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)=[C:25]([C:36](O)=[O:37])[N:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:27]=1.[CH2:46]([N:48]([CH2:57][CH3:58])[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:47]>C(Cl)Cl>[CH2:57]([N:48]([CH2:46][CH3:47])[CH2:49][CH2:50][N:51]1[CH2:52][CH2:53][N:54]([C:36]([C:25]2[N:26]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:27]=[C:23]([CH3:22])[C:24]=2[C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)=[O:37])[CH2:55][CH2:56]1)[CH3:58]
Reactant: CCN(CC)CCN1CCNCC1
Reactant: Cc1ccc(Cn2cc(C)c(-c3ccc(C)cc3)c2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCN(CC)CCN1CCN(C(=O)c2c(-c3ccc(C)cc3)c(C)cn2Cc2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
EDCI (166 mg, 0.87 mmol) and HOAt (11 mg, 0.08 mmol) were added at 0° C. to a reaction mixture of 4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid (252 mg, 0.79 mmol) and 1-(2-diethylaminoethyl)-piperazine (146 mg, 0.79 mmol) in DCM (5 mL) and the reaction mixture was stirred for 30 min at 0° C. and overnight at RT. After removal of the solvent, purification proceeded by means of column chromatography and the desired product [4-(2-diethylamino-ethyl)-piperazin-1-yl]-[4-methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrol-2-yl]-methanone (148 mg, 38% of theoretical) was obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][O:16][CH3:17])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([O:16][CH3:17])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: CONc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Yield: 20.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.24 g (6.00 mmol)) in DMF (8.0 ml), N-(2,4-dinitrophenyl)-O-methylhydroxylamine (0.85 g (3.99 mmol)) was added under ice-cooling with stirring. After 15 minutes' stirring under ice-cooling, p-toluenesulfonyl chloride (1.15 g (6.03 mmol)) was added. Then, the temperature of the reaction mixture was brought to room temperature and stirred at the same temperature for 18 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.30 g (21%) of the title compound as orange crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[C:12](=[O:14])=[O:13]>C1COCC1.CCCCCC>[CH3:1][N:2]1[C:6]([C:12]([OH:14])=[O:13])=[N:5][CH:4]=[N:3]1
Reactant: Cn1cncn1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
1-Methyl-1H-1,2,4-triazole (1.19 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6M solution of butyllithium in hexane (9.4 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml) and the solvent was decanted off. To the residue was added ethyl acetate (20 ml) and water (20 ml). The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1 day (50° C.) to give the title compound (1.61 g) as a white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH:15]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1)=[O:6].O>CO>[O:6]1[C:5]([C:7]2[CH:27]=[CH:26][C:10]3[N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]5[CH:25]=[CH:24][N:23]=[CH:22][N:21]=5)[CH:15]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Solvent: CO
Solvent: O
Product: c1cc(-c2ccncn2)cc(-n2cnc3cc(-c4ccno4)ccc32)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 5-(3dimethylamino-1-oxo-2-propen-1-yl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (307 mg) and NH2OH,HCl (135 mg, 2.5 equivalents) in methanol (14 ml) was stirred at 80° C. for 2 hours. After cooling the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographied (CH2Cl2 -methanol 40:1 (v/v)) to give 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (226 mg, 80%).