Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH:5]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([I:18])[C:12]3=[C:11](C)[N:10]=2)[O:4]1.[OH-].[NH4+:21]>>[NH2:21][C:11]1[N:10]=[C:9]([CH:5]2[O:4][CH:3]([CH2:2][OH:1])[CH:7]([OH:8])[CH2:6]2)[N:14]=[C:13]2[NH:15][N:16]=[C:17]([I:18])[C:12]=12
Reactant: [NH4+]
Reactant: Cc1nc(C2CC(O)C(CO)O2)nc2[nH]nc(I)c12
Agent: [OH-]
Product: Nc1nc(C2CC(O)C(CO)O2)nc2[nH]nc(I)c12

Procedure:
Compound 8 (6.8 g, 17.35 mmol) was stirred in 200 mL of concentrated ammonium hydroxide (sealed container) at room temperature for 36 h. The mixture was evaporated and the residue was precipitated from acetonitrile-ether. The solid was filtered and dried: 5.36 g (82%) yield. NMR and spectral data on this compound is identical to
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=O)[C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[N:13][CH:12]=2)=[C:4]([NH:22][CH3:23])[CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[C:17]([F:20])([F:19])[F:18])[N:22]([CH3:23])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Cl)c(F)cc1NC(=O)c1cnccc1C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(-c2cnccc2C(F)(F)F)nc2cc(F)c(Cl)cc21
Temperature: 140 °C

Procedure:
To the solution of compound N-(4-chloro-5-fluoro-2-(methylamino) phenyl)-4-(tri-fluoromethyl) nicotinamide (0.1 g, 0.0028 mol) in DMA (5 ml) was added DBU (0.05 g, 0.0037 mol). Reaction mixture was heated at 140° C. for 24 h. Reaction mass was quenched with ice water and layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic extracts were washed with brine dried over Na2SO4 and concentrated to get crude product which was purified by column chromatography to provide 6-chloro-5-fluoro-1-methyl-2-[4-(trifluoromethyl)pyridin-3-yl]-1H-benzimidazole 335; as a white colored solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.11-9.09 (d, J=5.2 Hz, 1H), 9.03 (s, 1H), 8.07-8.04 (m, 2H), 7.82-7.79 (d, J=10 Hz, 1H), 3.65 (s, 3H). MS (M+1): 330.12, Purity 99.52%.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:15][SiH:16]([Cl:18])[Cl:17]>[Pt].C1(C)C=CC=CC=1>[Cl:15][Si:16]([Cl:18])([Cl:17])[CH2:3][CH2:2][CH2:1][C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: C=CCc1ccc(-c2ccc(C)s2)s1
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(CCC[Si](Cl)(Cl)Cl)s2)s1

Procedure:
The hydrosilylation reaction of Example 1 was repeated using 5.0 g of 5-allyl-5′-methyl-2,2′-bithiophene in place of 2-allylthiophene, 2.5 g of anhydrous toluene, 6.0 g of trichlorosilane, and 50 mg of Platinum Catalyst. 5-(3-Trichlorosilylpropyl)-5′-methyl-2,2′-bithiophene was obtained as a colorless liquid: 1H NMR (CDCl3) δ 6.92 (d, 1H, J=3.6 Hz); 6.91 (d, 1H, J=2.7 Hz); 6.70 (d, 2H, J=3.6 Hz); 6.65 (m, 1H); 2.91 (t, 2H, J=7.2 Hz); 2.48 (d, 3H, J=1.2 Hz); 1.97 (m, 2H); 1.47 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].N1CCCC1.[ClH:43].Cl.Cl.N1C=C(CN2C3C=CC([C:63]4[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1>>[ClH:43].[ClH:43].[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH2:36][CH2:64][N:65]3[CH2:63][CH2:68][CH2:67][CH2:66]3)(=[O:34])=[O:35])[CH2:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: C1CCNC1
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)CCN1CCCC1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 46 %

Procedure:
Example 327 was prepared in 46% yield as a light yellow solid from Compound A of Example 250 and pyrrolidine as described for Compound B of Example 250.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(O)CC4)c3)n2)n1
Yield: 57.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-hydroxypiperidine [CAS-no. 5382-16-1] (0.207 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 57%) as a white solid. MS (ISP) 554.3 [(M+H)+]; mp 195° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 2-ethoxy-2-methylpropanoate (1.6 g, 10.95 mmol) in MeOH (14 mL) was treated drop-wise with a solution of KOH (1.228 g, 21.89 mmol) in water (7 mL) and stirred at RT overnight. The mixture was treated with water, washed with Et2O (2×) and the aqueous layer was acidified to pH 2 with 2M HCl. The mixture was extracted with EtOAc (4×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford 2-ethoxy-2-methylpropanoic acid (1.1 g, 76%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 12.42 (s, 1H), 3.34 (q, J=7.0 Hz, 2H), 1.28 (s, 6H), 1.06 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 70 °C
Yield: 88.4 %

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (1.0 g, 3.3 mmol), tert-butyl bromoacetate (1.4 g, 7.2 mmol) and potassium carbonate (1 g, 7.2 mmol) in acetonitrile was heated at 70° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (elution gradient: 10% acetone/hexane) to give 5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (1.2 g) as a solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:17](=[O:27])[C:16]2=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:33][C:34]1[N:35]=[CH:36][N:37]=[C:38]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:17](=[O:27])[C:16]3=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:39]=1[C:40]#[N:41]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1c(N)ncnc1N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
In a reactor vessel (S)-2-(1-amino-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (42 mg, 0.1 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (16 mg, 0.1 mmol) were dissolved in 1-butanol (840 μl) under argon atmosphere. N,N-Diisopropylethylamine (76 μl, 0.87 mmol) was added and the reaction mixture was heated at 120° C. overnight. Further N,N-diisopropylethylamine (76 μl, 0.87 mmol) was added afterwards and the reaction mixture was stirred at 120° C. overnight. The crude was evaporated and purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (64% yield) of the title compound as a yellow solid. Purity 97%.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17](N)[C:18](NC)=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C:31]([NH2:33])=[O:32].[CH4:34]>O.Cl>[C:24]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:30]([CH3:34])[C:31](=[O:32])[NH:33][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: Cn1c(=O)[nH]c2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 190 °C

Procedure:
A mixture of 4.64 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine and 1.2 parts of urea is stirred and heated for 1.50 hours at 190° C. The reaction mixture is cooled and dissolved in a mixture of 150 parts of water and 6 parts of a hydrochloric acid solution 10 N. The solution is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution 5 N. The product is extracted three times with dichloromethane. The combined extracts are dried, filtered and evaporated. The solid residue is stirred in 20 parts of ethanol. The product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is treated with 20 parts of ethanol. The product is filtered off, washed with a small amount of ethanol and dried, yielding 1.7 parts of 5-[ 4-(diphenylmethyl)-1-piperazinylmethyl]-1,3-dihydro-1-methyl-2H-benzimidazol-2-one; mp. 246° C.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.C1C[O:20]CC1>>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([C:1]([OH:20])([CH3:3])[CH3:2])[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cccnc1Cl
Reactant: C1CCOC1
Agent: [Li+]
Product: CC(C)(O)c1ccnc(Cl)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of lithium diisopropylamide (2 M in heptane/THF/ethylbenzene, stabilised with 0.5% w/w LiBr; 1.9 ml, 3.8 mmol) and THF (3 ml) was cooled to −78° C. and a solution of 2-chloro-3-fluoropyridine (500 mg, 3.8 mmol) in THF (3 ml) was added dropwise over 1 min. After 2 h, acetone (pre-dried twice over activated 4 Å molecular sieves) was added dropwise and the mixture allowed to warm to ambient temperature, then quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (50 ml). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (silica; 10-20% EtOAc/isohexane) to afford 2-(2-chloro-3-fluoropyridin-4-yl)propan-2-ol (687 mg, 95%): δH (360 MHz, CDCl3) 1.66 (6H, s), 7.53 (1H, m), 8.16 (1H, m); m/z (ES+) 190 (100%, [MH]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>O1CCCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (2 g, 14.2 mmol), tert-butyl 2-aminoethylcarbamate (2.7 g, 17.0 mmol) and triethylamine (1.7 g, 2.4 mmol) in tetrahydrofuran was refluxed for 7 h. After cooling to rt 100 mL of water was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed and the product was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)=[O:4].Cl.[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(OC(C)C)(C)C>>[C:12]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)[CH:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: N#Cc1cccc(NC(=O)CCl)c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Product: N#Cc1cccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-cyano-phenyl)-acetamide (Example 166a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 101-103° C. (diisopropylether)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:25])[C:17]([C:22](Cl)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:25])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and o-toluoyl chloride in a similar manner as described above to give a gray solid (19% yield). 1H-NMR (DMSO-d6): δ 11.01 (s, 1H), 8.70 (d, 1H), 7.59 (m, 1H), 7.47 (d, 1H), 7.33 (m, 2H), 7.26 (m, 2H), 7.17 (dd, 1H), 5.34 (m, 1H), 2.65 (m, 2H), 2.42 (s, 3H), 2.07 (m, 2H), 1.87 (m, 2H); MS m/z 383 (M−1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][C:21](=[O:29])[CH:22]([O:26][CH2:27][CH3:28])[C:23]([OH:25])=O)=[CH:17][CH:16]=1)#[N:14].[C:32](=[N:40]O)([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21](=[O:29])[CH:22]([O:26][CH2:27][CH3:28])[C:23]2[O:25][N:40]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:39]=2)=[CH:30][CH:31]=1)#[N:14]
Reactant: CCOC(C(=O)O)C(=O)NCc1ccc(C#N)cc1
Reactant: NC(=NO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1nc(-c2ccccc2)no1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of 1,1′-carbonyldiimidazole (272 mg) in THF (10 ml) was added a solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid (400 mg) in THF (10 ml). The mixture was stirred for 30 min before addition of a solution of benzamidoxime (228 mg) in THF (20 ml). After stirring 18 h the solvent was evaporated. The crude product was dissolved in EtOAc and extracted with HCl 0.1 N, NaHCO3 and brine. After drying (MgSO4) the solvent was evaporated. The resulting white powder was redissolved in DMF (15 ml) and this solution was heated 5 min in a sealed tube at 140° C. using microwave radiation. DMF was removed, the residue was diluted with EtOAc and washed twice with water. The aqueous phases were extracted with more EtOAc. The combined organic phases were dried over MgSO4 and the solvent was evaporated. Flash chromatography (MeCl2/Et2O, from 100:0 to 95:5) yielded (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-acetamide, 305 mg (55%); lightly yellow oil. MS 363.1 (100, [M+H]+), 380 (53, [M+NH4]+).
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.C([Mg]Br)CC.[C:11]([C:15]1[CH2:19][CH2:18][C:17](=O)[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>C(OCC)C>[CH2:2]([C:18]1[CH2:17][CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:19]=1)[CH2:3][CH3:4]
Reactant: CC(C)(C)C1=CC(=O)CC1
Reactant: C1CCOC1
Agent: CCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C
Yield: 57 %

Procedure:
To a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 120 ml of dehydrated diethyl ether and 89 ml (178 mmol) of tetrahydrofuran solution of 2.0M n-propyl magnesium bromide were charged under a nitrogen atmosphere. In the ice bath, 20.6 g (149 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, twice with water and twice with saturated brine, and dried over magnesium sulfate and the solvent was distilled off. Thereafter, the resulting product was purified by column chromatography to obtain 16.8 g (GC purity 82%) of a pale yellowy transparent liquid. The yield was 57%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1.O=[C:16]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:17]([CH:16]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH3:14])[CH2:3]1)[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CN1CC(N)C(=O)Nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1CN(C)c2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one (0.267 g) is dissolved in 5 ml of methanol and 0.288 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated and the residue purified to give 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-5-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].C(N(CC)CC)C.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[C:22]([F:28])[CH:21]=1.[Cl:29]CCl>>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:7](=[O:8])[C:6]2[CH:10]=[CH:2][C:3]([Cl:29])=[CH:4][C:5]=2[OH:11])=[C:22]([F:28])[CH:21]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: ClCCl
Reactant: O=C(Cl)c1cc(Cl)ccc1O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Br)cc1F)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
A solution of 5-chloro-2-hydroxy-benzoyl chloride (4.00 g, 23.2 mmol) in dichloromethane (46 mL, 0.5 M) was treated with triethylamine (6.46 mL, 46.4 mmol) and 4-bromo-2-fluorobenzylamine (6.10 g, 30.1 mmol). After stirring at room temperature for 16 h, the solution was washed successively with 2 N HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by MPLC (10–50% ethyl acetate in heptane, 23 mL/min, 70 min) gave N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide as a white crystalline solid (4.4 g, 53%): mp 159–161° C.; Rf 0.49 (30% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 12.56 (br s, 1 H), 9.28 (br t, J=5.4 Hz, 1 H), 7.88 (d, J=6.0 Hz, 1 H), 7.50 (dd, J1=9.9 Hz, J2=1.8 Hz, 1 H), 7.37 (dd, J1=8.4 Hz, J2=1.8 Hz, 1 H), 7.33 (dd, J1=15.9 Hz, J2=8.1 Hz, 1 H), 6.99–6.93 (m, 2 H), 4.50–4.46 (m, 2 H). ESI-LC/MS m/z calcd for C14H10BrClFNO2: 358.6; found 360.0 (M+1)+. Anal. calcd for C14H10BrClFNO2: C, 46.89; H, 2.81; N, 3.91; Cl, 19.78. Found C, 46.89; H, 2.81; N, 3.90; Cl, 19.73.
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:28]1C2C=CC3C(=CC(C=O)=C4C=3C=CC=C4)C=2C=CC=1.NC(CC)(CO)CO>CCO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][CH3:28])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: CCC(N)(CO)CO
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-ethyl-1,3-propanediol hydrochloride, mp 241°-243° (dec), (EtOH/Et2O), (C,H,Cl,N).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33](O)=O)[CH:18]=1>>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[CH:18]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.230 g, 1.06 mmol) and 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.12) (0.30 g, 1.00 mmol) according to the general procedure V. Obtained as a white solid (0.100 g, 22%). MS (ISP) 513.2 [(M+H)+]; mp 211° C.