Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][O:5][CH2:4]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:17][N:16]=[C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([O:2][CH3:1])[CH2:6][O:5][CH2:4]2)=[CH:14][CH:13]=1)[NH2:12]
Reactant: COC1(c2ccc(C#N)cc2)COC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC1(c2ccc(C(N)=NO)cc2)COC1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of 4-(3-methoxyoxetan-3-yl)benzonitrile (Step 1, 500 mg, 2.64 mmol), hydroxylamine hydrochloride (403 mg, 5.81 mmol) and triethylamine (810 μL, 5.81 mmol) in ethanol (12.5 mL) was stirred and heated at reflux for 2 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with a mixture of water (5 mL) and diethyl ether (0.5 mL). The solid was isolated by filtration, washed with a small amount of cold water and dried in a vacuum oven to afford the title compound as a colorless solid (520 mg, 86%): 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.73 (d, 2H), 7.43 (d, 2H), 5.84 (broad s, 2H), 4.79-4.75 (m, 4H), 3.01 (s, 3H); DCI(NH3)-MS m/z 223 (MH)+; HPLC RT (Method I) 2.54 min.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])C.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].ClCCl>CO>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cnc2ccc(Br)cn12

Procedure:
Add 6-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (0.11 g, 0.41 mmol) to a sealed tube containing N,N-dimethyl-ethane-1,2-diamine (5 mL). Heat the reaction at 150° C. for 24 h. Flash chromatography using appropriate mixtures of dichloromethane/2M ammonia in methanol gives 0.14 g of the product as a yellow oil. This material is progressed further without characterization. MS ES− m/e 269.0, 311.0 (M−1).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:5]([O:12][S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])[CH3:15]
Reactant: CCN(CC)C(=O)C(O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@@H](OS(C)(=O)=O)c1ccccc1

Procedure:
To a solution of N,N-diethyl-2-hydroxy-2-phenyl-acetamide (0.18 g, 0.9 mmol), Et3N (0.36 mL, 2.6 mmol), and CH2Cl2 (10 mL) at 0° C. was added methane sulfonyl chloride (0.08 mL, 1.0 mmol). After stirring for an hour, the reaction mixture was quenched with H2O (5 mL) and extracted with CH2Cl2 (3×25 mL). The orgranic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the resulting residue (Si02: EtOAc:Hex) yielded the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30]C1C(C)=CC=CC=1N1CCNCC1>>[CH3:30][C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:13][CH2:14]1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: Cc1cccc(N2CCN(CCn3cnc4ccccc4c3=O)CC2)c1C

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2,3-dimethylphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[C:10]([Br:17])[C:11]([Br:16])=[C:12]([N+:13]([O-:15])=[O:14])[C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24]>CCO>[Br:16][C:11]1[C:10]([Br:17])=[CH:9][C:5]2[N:6]([CH2:7][CH3:8])[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:24])=[N:3][C:4]=2[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CCn1c(Br)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Reactant: O=C1CNCCN1
Solvent: CCO
Product: CCn1c(N2CCNCC2=O)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 170 °C
Yield: 95.7 %

Procedure:
2,5,6-tribromo-1-ethyl-4-nitro-1H-1,3-benzodiazole (100 mg, 0.23 mmol) and 2-piperazinone (117 mg, 1.17 mmol) were dissolved in EtOH (3.0 ml). The resulting mixture was stirred at temperature 170° C. under microwave conditions until the reaction was complete (20 min) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was filtered off, washed with EtOH and dried to afford-(5,6-dibromo-1-ethyl-4-nitro-1H-1,3-benzodiazol-2-yl)piperazin-2-one (97 mg, 0.22 mmol); m/z 462.9; rt 3.1 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH:26][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: Cc1nc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)c[nH]1

Procedure:
The title compound was prepared as in Example 12 starting from 2-methyl-1H-imidazole-4-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using CH—2Cl2/MeOH as a gradient eluent (100:0-97:3). The product was dissolved in DCM, ethyl acetate saturated with hydrogen chloride was added and the precipitated product as a hydrogen chloride salt was filtered. Recrystallization from MeOH/EtOAc. The HCl salt: 1H NMR (400 MHz, MeOH-d4): 2.62 (3H, s), 3.02 (1H, t), 3.69 (1H, t), 6.26 (1H, d), 6.76 (1H, d), 7.49 (1H, distorted d), 6.53 (1H, distorted dd), 7.71 (1H, d), 7.82 (1H, s).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+]([O-])=O)[C:5](O)=[O:6].CC[N:16]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl[Sn]Cl>CCO.CN(C=O)C>[C:5]([NH2:16])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1

Procedure:
In one embodiment, intermediate [1C] is prepared according to Scheme 5A. In this route, 3-fluoro-4-nitro benzoic acid [Q1] is converted to corresponding amide [R1] using R7R8NH, EDCI.HCl, HOBt, TEA, and DMF at about rt for about 10 h. Amide [R1] is then reduced using SnCl2 in EtOH at reflux for about 3-4 h to provide benzamide [S1]. Benzamide [S1] is then converted to urea [T1] using 4-bromophenylisocyanate in the presence of TEA and DCM at about rt. Conversion of urea [T1] to intermediate [1C] is accomplished using Pd(dppf)Cl2.DCM, bis(pinacolato)diboron, KOAc, and 1,4-dioxane, at about 110° C. for about 10 h.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Yield: 93.7 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (15 g, 72.1 mmol) in chloroform (200 ml) were added N-bromosuccinimide (14.11 g, 79.3 mmol) and 2,2′-azobis(isobutyronitrile) (590 mg, 3.60 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and water (100 ml) was added. The mixture was extracted with chloroform. The extract was washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (19.4 g, purity 56%, 53%). This compound was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]5[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=5)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:34])=[C:24]([C:27]5[O:31][C:30]([CH2:32][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:29][CH:28]=5)[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cc2F)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cc2F)o1

Procedure:
Prepared according to Procedure D from 5-(4-(4-Phenylsulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR (400 MHz, DMSO-d6) δ: 10.38(s, 1H), 8.87(d, 1H), 8.62(s, 1H), 8.11(d, 2H), 7.95(m, 4H), 7.63(m, 4H), 6.94(m, 1H), 6.51 (d, 1H), 3.84(s, 2H), 3.25(m, 2H), 2.98(s, 3H), 2.95(m, 2H). ESI-MS m/z 579(M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11][CH3:12])=[CH:10][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([CH3:12])=[O:22])=[CH:10][C:4]=2[O:3]1
Reactant: CSc1ccc2c(c1)OC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc2c(c1)OC(C)(C)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 19.6 g of 2,2-dimethyl-5-(methylthio)-1,3-benzodioxol in 500 ml of methylene chloride was treated at 0° C. with 20.3 g of 85% m-chloroperbenzoic acid. The mixture was subsequently stirred at 0° C. for 1 hour. A white precipitate resulted. The reaction mixture was extracted with 400 ml of 17% aqueous sodium carbonate solution and 400 ml of water. The organic phase was dried over sodium sulphate and freed from solvent in a vacuum. The residue was taken up in a small amount of methylene chloride and chromatographed on silica gel, with elution being carried out with ethyl acetate/n-hexane/methylene chloride (1:1:1, v/v/v). After crystallization from ethyl acetate/n-hexane, there was obtained 2,2-dimethyl-5-(methyl-sulphinyl)-1,3-benzodioxol as white crystals having a melting point of 87°-88° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[SH:10].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[S:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nnc(S)n(N)c1=O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nnc(SCc2ccccc2)n(N)c1=O
Temperature: 80 °C

Procedure:
0.272 g of 4-amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one (which can be prepared by the method of A. Dornow, H. Menzel, P. Marx, Chem. Ber. 97, 2173 (1964)) was suspended in 0.86 ml of a 2N solution of sodium hydroxide in water. A solution of 0.218 g of benzyl chloride in ethanol was subsequently added dropwise, and the mixture was heated at 80° C. for 30 minutes. The resultant precipitate was filtered off with suction, giving 4-amino-3-benzylsulfanyl-6-methyl-4H-1,2,4-triazin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[C:10](OC)(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1cc(F)cc(F)c1
Product: COC(=O)CC(=O)Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Procedure A using 3,5-difluoroaniline (5.00 g, 38.7 mmol) and dimethyl malonate to give methyl 3-(3,5-difluorophenylamino)-3-oxopropanoate. Mass Spectrum (ESI) m/e=230.1 (M+1).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][CH:6]([CH3:23])[CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH:21]=O>CO>[CH3:3][O:2][N:4]=[CH:21][C:9]1[N:8]([CH2:7][CH:6]([CH3:23])[CH3:5])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
Methoxylamine hydrochloride (0.659 g, 7.90 mmol) was added to a stirred suspension of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde (1.00 g, 3.95 mmol) in methanol (10 mL), and the reaction was stirred at room temperature overnight. The methanol was removed under reduced pressure, and the residue was diluted with saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with dichloromethane (3×30 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.16 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime as a pale yellow oil that solidified upon standing.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[N:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)nc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2Br)nc1
Reaction time: 18 h

Procedure:
3-Bromo-2-chloropyridine (7.27 g, 37.8 mmol), 5-aminopyridin-2-ol (4.99 g, 45.3 mmol), freshly ground cesium carbonate (36.9 g, 113 mmol), and DMSO (37.8 ml, 37.8 mmol) were added into a glass round bottom pressure vessel equipped with a stir bar. The vessel was sealed and placed in a preheated oil bath at 130° C. After 18 h, the reaction was diluted with EtOAc (4×250 mL) and the whole solution was sonicated. After the solid was settled, the top solution was decanted through a pad of celite and silica gel (each layer was 1 cm). This procedure was repeated for the salt residue which left in the flask to remove the product and DMSO from the salt. The filtrate was concentrated to give an oil which included the product and DMSO. The product was extracted with EtOAc (3×300 mL) and DCM (1×100 mL). The EtOAc and DCM layers were washed separately with a minimum amount of brine. The organic phases were dried separately over a minimum amount of MgSO4. The MgSO4 was filtered off and the filtrates were combined and concentrated. A wet, light green solid was obtained. The solid was triturated with hexanes. The solid was filtered off, collected, and dried under vacuum. The product, 6-(3-bromopyridin-2-yloxy)pyridin-3-amine was collected as tan solids. A second batch was obtained from the filtrate. The filtrate was concentrated to give an oil. The oil was purified by ISCO column chromatography using 90:10 DCM:(90:10:1 DCM:MeOH:NH4OH). A light yellow solid, was obtained, dried under vacuum, and given a sample ID: A wet, green solid was obtained, dried under vacuum. MS Calcd for C10H8BrN3O: [M]+=265. Found [M+1]+=266.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C.Cl.[NH2:35][C@H:36]([C@H:44]1[O:48][C:47](=[O:49])[C@H:46]([CH2:50][CH2:51][C:52]([F:55])([CH3:54])[CH3:53])[CH2:45]1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.C(OCC)C>[F:55][C:52]([CH3:54])([CH3:53])[CH2:51][CH2:50][C@H:46]1[C:47](=[O:49])[O:48][C@H:44]([C@@H:36]([NH:35][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:13])[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:45]1
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O
Reactant: O=C(O)c1cnc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of quinoxaline carboxylic acid (5.05 g, 29.0 mmol) in methylene chloride (100 mL) was added dimethylaminopyridine (DMAP) (3.55 g, 29.0 mmol) and EDCl (5.55 g, 29.0 mmol). The solution was stirred 10 minutes, then the product from Method D, above, (5.68 g, 19.4 mmol) was added in one portion. The solution was stirred for 12 hours, then diluted with diethyl ether and washed with saturated aqueous brine. The organics were dried over magnesium sulfate, and then filtered and concentrated. The crude product was purified by silica gel chromatography to yield the title compound (5.62 g, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH:27]=[N:26][C:25]([NH2:28])=[N:24]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH:27]=[N:26][C:25]([NH:28][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:24]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2cnc(N)n2)cc1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: COc1ccc(Cn2cnc(Nc3ccc(-n4cnc(C)c4)c(C#N)c3)n2)cc1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-methoxy-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless oil (Yield=34%). MS ISP (m/e): 386.2 (100) [(M+H)+].
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]1([C:23]2[N:24]=[CH:25][C:26]3[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=3[N:28]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:8]([CH:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:23]1[N:24]=[CH:25][C:26]2[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=2[N:28]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)Cc2cnc(N3CCNCC3C(=O)c3ccccc3)nc21
Yield: 75.8 %

Procedure:
One gram of triethylamine, 50 ml of methylene chloride and 0.6 g (4.3 mmoles) of benzoyl chloride were added to 1.0 g (4.3 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H) pyrrolo[2,3-d]pyrimidine, and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and after adding an aqueous solution of sodium hydrogen carbonate, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.1 g (yield 76%) of the desired compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:6]=12.[C:22]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:11][C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:23]#[C:22][C:24]3[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3cnc(N)nc3)cnn12

Procedure:
The title compound was prepared from 3-iodo-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12 step 2) (202 g, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2, step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (90 mg, 46%). MS (ISP) 395.0 [(M+H)+]; mp 246-248° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:15]([NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) and benzylamine (2.7 mL, 25.1 mmol) in MeOH (30 mL) was added HOAc (1.9 mL, 32.6 mmol), followed by NaCNBH3 (2.0 g, 32.6 mmol) and the reaction was stirred at room temperature overnight. The resulting mixture was quenched with H2O (5 mL) and concentrated in vacuo. The residue was diluted with 0.1 N HCl and washed with Et2O. The aqueous layer was then basified with 2 N NaOH and extracted with Et2O. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(benzylamino)piperidine-1-carboxylate (8.1 g, 56%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:2]#[CH:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:25](=[O:26])[CH2:24][Cl:23])[C:2]#[CH:3]
Reactant: C#CCNCC(OC)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CCN(CC(OC)OC)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-dimethoxyethyl)amine (9 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was cooled to a temperature of 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. Stirring was then continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase, was washed with water and was dried. The dried solution was then filtered and the filtrate stripped of solvent to yield the desired product N-propargyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]2/[C:24](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[O:27][CH2:28][C:22]=2[CH:21]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[CH:38]=[CH:37][C:23]3/[C:24](=[C:33](/[CH3:36])\[C:34]#[N:35])/[C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[O:27][CH2:28][C:22]=3[CH:21]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CCl)cc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
[step 1] 2-Ethylbenzimidazole (163 mg, 1.12 mmol) was dissolved in DMF (5.0 mL), potassium carbonate (0.700 g, 5.07 mmol) was added, and the mixture was stirred for 15 min. To this mixture was added (E)-2-(8-chloromethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (300 mg, 1.01 mmol) obtained in Reference Example B5, and the mixture was stirred at 60° C. for 3 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/5) to give (E)-2-[8-(2-ethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (318 mg, 70%).