Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 92 %

Procedure:
4-Bromo-2,6-dimethylaniline (5.92 g) and cyclopentylacetyl chloride (4.87 mL) were dissolved in acetonitrile (26 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0° C., the product filtered off and washed with cold acetonitrile (50 mL) affording 8.43 g (92% yield) of the title compound as a brown solid. The crude product was used without further purification. LC-MS (m/z) 312 (MH+); tR=3.10, (UV, ELSD) 89%, 99%. 1H NMR (500 MHz, CDCl3): 1.22 (m, 2H), 1.52 (m, 2H), 1.63 (m, 2H), 1.77 (m, 2H), 2.06 (s, 6H), 2.31 (m, 1H), 2.64 (d, 2H), 7.15 (s, 2H), 9.98 (b, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](OC(C)=O)=[O:17]>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:16](=[O:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c(F)cccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c(F)cccc12
Yield: 95.9 %

Procedure:
A solution of 141 mg (0.74 mmol) of compound 208A in 2 mL of AcOH was heated to reflux and treated with small portions of iron powder (118 mg, 2.11 mmol). The mixture was kept at reflux for 15 min before 73 μL (0.78 mmol) of Ac2O was added. After an additional 15 min at reflux, the mixture was cooled and filtered eluting with CH2Cl2. The filtrate was then concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 20 to 50% EtOAc in to give 145 mg (0.71 mmol, 97%) of compound 209A as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1
Reactant: COC(=O)c1ccccc1-c1nc(COc2ccc(C=O)cc2OC)c(C)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1-c1nc(COc2ccc(CO)cc2OC)c(C)o1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of methyl 2-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.30 g) in tetrahydrofuran (20 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.13 g) at room temperature. After stirring for 2 hrs, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give methyl 2-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.20 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:24][C:23]4[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccc(O)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 67 %

Procedure:
Using a procedure analogous to that described in Example 104, the title compound, m.p. 199°-200° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and hydroquinone. The yield was 67% of theory.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:13].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:37][CH2:36]2)[CH:30]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:40])[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:34][N:35]([CH3:40])[S:36]([N:13]1[CH2:14][C:5]2[CH:4]=[C:3]([Cl:2])[CH:26]=[CH:25][C:6]=2[N:7]2[C:11](=[N:10][N:9]=[C:8]2[C@H:15]2[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)[CH2:12]1)(=[O:38])=[O:37]
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(S(=O)(=O)N(C)C)C3)CC1
Reaction time: 65 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.070 g, 0.18 mmol) and triethylamine (0.037 ml, 0.26 mmol) in dichloromethane (3 ml) was added N,N-dimethylsulfamoyl chloride (0.028 ml, 0.26 mmol) at room temperature. After stirring for 65 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.063 g, 77%) as white solid. MS m/e: 468 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:14](OCC)(OCC)OCC>C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[CH:14]=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: CCOC(OCC)OCC
Solvent: CCOCC
Product: Brc1ccc2ncc3nncn3c2c1
Temperature: 25 °C

Procedure:
The solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in triethyl orthoformate (3 mL) was heated to 100° C. for 4 h; after cooling to r.t., the mixture was diluted with ethyl ether, and the precipitate was collected by filtration and dried in vacuo to afford the title product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxaline as yellow solid in 87% yield (180 mg). m/z 251 (M+H)+.
Reaction SMILES: [CH2:1]1[S:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].[C:9](=O)=O.Cl>C=O.C(O)=O>[CH3:9][N:3]1[CH:2]([C:6]([OH:8])=[O:7])[CH2:1][S:5][CH2:4]1
Reactant: O=C=O
Reactant: O=C(O)C1CSCN1
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CSCC1C(=O)O
Temperature: 80 °C

Procedure:
L-thiazolidine-4-carboxylic acid (13.3 g) in a mixture of 37% formaldehyde (22.5 ml) and 96% formic acid (39.3 ml) was heated to 80° C. After one hour CO2 evolution ceased. The heating was continued until most of the solvent was removed. The residue was dissolved in methanol and evaporated on the rotovap three times. One equivalent of concentrated hydrochloric acid was added and the resulting salt crystallized from methanol and ethyl ether. Yield 17.0 g (92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.C([Li])(CC)C.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(OCC)(=O)C>O1CCCC1.C1CCCCC1>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Reactant: BrCCCCBr
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml), 1.3 M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromoatography over a silica gel column. The 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:37])[C:7]=1[CH:8]=[C:9]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[C:18]2[C:17]3[CH:19]=[C:20]([NH:23][S:46]([CH3:45])(=[O:48])=[O:47])[CH:21]=[CH:22][C:16]=3[O:15][C:14]=2[C:13]([O:26][CH3:27])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc(NS(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
Crude benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-amino-dibenzofuran-1-yl)-vinyl ester (1.17 g, obtained as described in Example 8 starting from 1.68 g of benzoic acid 2-(3,5-dichloro-pyridin-4-yl)-1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-vinyl ester) is dissolved in dry DCM (5 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and triethylamine (0.390 mL, 2.80 mmoles) and methanesulphonyl chloride (0.220 mL, 2.83 mmoles) are added sequentially dropwise. The resulting solution is stirred at room temperature for 1 hour. The mixture is diluted with water (2.5 mL) and saturated NaHCO3 solution (10 mL) and extracted with DCM; the combined organic layers are dried over Na2SO4 and evaporated to dryness. The crude is purified by preparative HPLC to yield 330 mg of pure product as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:16][CH:15]([OH:17])[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=1>CN(C=O)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[CH2:14][CH:15]([O:17][C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:16]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(Cl)cn1
Reactant: O=C(N1CCN(C2CCC2)CC1)N1CC(O)C1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCN(C4CCC4)CC3)C2)cn1
Yield: 66.7 %

Procedure:
In a similar fashion (Route 20, GP I; except using DMF instead of DMSO as solvent), 1-[(4-cyclobutylpiperazin-1-yl)carbonyl]azetidin-3-ol (150 mg, 0.63 mmol) and 5-chloro-N-methylpyridine-2-carboxamide (214 mg, 1.26 mmol) gave the title compound (156 mg, 0.42 mmol, 66%) as white solid after purification by FCC [SiO2 eluting with DCM/MeOH/NH3 98:2:0.5].
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[N:12]=[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:15]=1[C:16]#[N:17])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[Cl-].[Na+]>C(O)C.C(OCC)(=O)C>[C:34]([O:33][C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:14]2[C:15]([C:16]#[N:17])=[C:11]([CH:3]([OH:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:12]=[C:13]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:20][CH:21]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCc1nc(C(=O)c2ccccc2)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nc(C(O)c2ccccc2)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
50.5 mg of sodium borohydride were added to a solution of 691 mg of 4-benzoyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-cyanoimidazole [prepared as described in step (a) above] in 10 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then neutralized with aqueous hydrochloric acid, after which it was mixed with ethyl acetate and with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 589 mg of the title compound as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=C)[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=[O:29])[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(-n2ncc3c2CCc2cc(C=O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(4-propylphenyl)-7-vinyl-4,5-dihydro-3H-benzo[e]indazole (Preparation 136E, 85 mg, 0.270 mmol) in THF (5 mL) were sequentially added NMO in water (0.090 mL, 0.433 mmol) and osmium tetroxide in water (0.066 mL, 10.81 μmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (116 mg, 0.541 mmol) in water (2 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated out. Water (2 mL) was then added and the solid was filtered, washed with water (2×2 mL) and dried to give 65 mg crude product which was used directly for the next step. LC/MS M+1=317.1. The product had an HPLC retention time=3.92 min. (condition A);
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CO[C:7]1[C:8]([N+:45]([O-:47])=[O:46])=[C:9]([C:21]2[O:22][C:23]([C:26]3[C:31]([N+:32]([O-:34])=[O:33])=[C:30](OC)[C:29]([N+:37]([O-:39])=[O:38])=[C:28](OC)[C:27]=3[N+:42]([O-:44])=[O:43])=[N:24][N:25]=2)[C:10]([N+:18]([O-:20])=[O:19])=[C:11](OC)[C:12]=1[N+:13]([O-:15])=[O:14]>CO>[OH:2][CH2:1][CH2:3][NH:4][C:28]1[C:27]([N+:42]([O-:44])=[O:43])=[C:26]([C:23]2[O:22][C:21]([C:9]3[C:8]([N+:45]([O-:47])=[O:46])=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:4][CH2:3][CH2:1][OH:2])[C:10]=3[N+:18]([O-:20])=[O:19])=[N:25][N:24]=2)[C:31]([N+:32]([O-:34])=[O:33])=[C:30]([NH:4][CH2:3][CH2:1][OH:2])[C:29]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])c(OC)c([N+](=O)[O-])c(OC)c3[N+](=O)[O-])o2)c1[N+](=O)[O-]
Reactant: NCCO
Solvent: CO
Product: O=[N+]([O-])c1c(NCCO)c([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c(NCCO)c3[N+](=O)[O-])o2)c([N+](=O)[O-])c1NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.65 g (0.0106 mole) of ethanolamine in 40 ml of methanol was stirred in an ice bath while 1.55 g (0.00253 mole) of 2,5-bis(3,5-dimethoxy-2,4,6-trinitrophenyl)-1,3,4-oxadiazole was added. After 1 hr. at 0° C., the mixture was stirred for 5 hr. at room temperature before the insoluble solid (1.6 g, mp 230° C. dec.) was removed. The product was dissolved in dimethyl sulfoxide and methanol was added to give 1.4 g (76%), mp 237° C., 1H NMR (DMSO-d6 +D2O): 3.12 (m, 8H), 3.63 (m, 8H). Anal. Calcd. for C22H24N12O17 : C, 36.27; H, 3.32; N, 23.07. Found: C, 36.61; H, 3.32; N, 23.13.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])[CH3:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:38]3[CH2:39][CH2:40][N:35]([CH:32]([CH3:34])[CH3:33])[CH2:36][CH2:37]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(Cl)nc(N2CCN(C(C)C)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure described in Synthesis Example 2 was repeated by use of 4-t-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) and 1-isopropylpiperazine, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:55][CH2:54]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[N:53]2[CH2:58][CH2:57][CH:56]([NH:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:55][CH2:54]2)=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reaction time: 16 h
Yield: 24.6 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.1 g, 0.00038 mole) in DMF (1 mL) was added DIPEA (0.245 g, 0.0019 mole), HOBt (0.056 g, 0.00042 mole) and EDCI.HCl (0.145 g, 0.00076 mole). After 2 minutes piperidin-4-yl-o-tolyl-amine dihydrochloride (0.106 g, 0.00042 mole) was added and the resulting mixture was stirred for 16 hours. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel (60-120 mesh) (1% methanol in chloroform) afforded 0.04 g (25%) of N-biphenyl-4-yl-3-oxo-3-(4-o-tolylamino-piperidin-1-yl)-propionamide. LC-MS purity: 428.23 (M+1)+, 93.11%, 1H NMR (DMSO-d6): δ 7.7 (m, 6H), 7.5 (t, 2H), 7.3 (t, 1H), 7.2 (q, 2H), 6.65 (q, 2H), 4.5 (d, 1H), 4.0 (d, 1H), 3.6 (m, 1H), 3.5 (s, 2H), 3.3 (s, 1H), 3.0 (t, 1H), 2.2 (m, 3H), 2.1 (s, 2H), 1.5 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:18])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.N1(C(OCC(C)(C)C(N[C@H]2CC[C@H](N)CC2)=O)=O)CCOCC1>CO.O>[NH2:1][C:2]1[C:7]2=[C:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:18])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1cc(-c2ccncc2)n2ncnc(N)c12
Agent: CC(C)(COC(=O)N1CCOCC1)C(=O)N[C@H]1CC[C@H](N)CC1
Solvent: CO
Solvent: O
Product: NCCCNC(=O)c1cc(-c2ccncc2)n2ncnc(N)c12
Yield: 19 %

Procedure:
20 was prepared from 19 (40 mg, 0.097 mmol) by the general method shown for 15D. 20.2TFA (10 mg, 19% yield) was obtained as a sticky, off-white solid. HPLC: 0.83 min (YMC S5 ODS, 4.5×50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 12 min). MS (ES): m/z=312 [M+H]+. 1H NMR (400 MHz, DMSO-d6+MeOH-d4) δ ppm 8.81 (d, 2H, J=6.8 Hz); 8.41 (d, 2H, J=6.5 Hz); 8.18 (s, 1H); 8.09 (s, 1H); 3.39 (t, 2H, J=6.5 Hz); 2.87 (t, 2H, J=7.7 Hz); 1.80-1.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[CH2:12][CH2:13][N:15]([CH3:16])[CH3:17]
Reactant: CN(C)C(=O)CC1CCOc2ccc(N)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCC1CCOc2ccc(N)cc21
Yield: 88.6 %

Procedure:
6-Amino-N,N-dimethylchroman-4-acetamide (D8, 0.49 g, 2.1 mmol) was dissolved under Ar in dry THF (20 ml), and added to a stirred suspension of lithium aluminium hydride (0.16 g, 4.2 mmol) in dry THF (2 ml ). The mixture wa s stirred at reflux for 3 h, cooled, and treated successively with water (0.16 ml), 10% NaOH (0.16 ml) and water (0.48 ml) The solid was filtered off, and the filtrate was evaporated to give the title compound (0.41 g, 97%) as a red oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-].C[Si](Cl)(C)C.C([O-])(O)=O.[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CC#N.CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=4)[C:16]=3[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cn1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(=O)[nH]c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
Into the suspension of 4-[4-(6-methoxypyridin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (68.4 mg, 79% purity, 0.127 mmol) and NaI (19.1 mg, 0.127 mmol) in CH3CN (10 mL) was added trimethylsilyl chloride (1 M in THF, 0.765 mL, 0.765 mmol) at rt. The mixture was then heated at 80° C. in a flask under N2 for 48 h. After that time, the mixture was cooled at 0° C. and the aqueous solution (H2O, 8 mL) of NaHCO3 (159 mg) and NaS2O4.5H2O (318 mg) was added while stirring. The solid was filtered off and washed with water to obtain a brown-red solid. Boc2O (30.8 mg, 0.140 mmol), DMAP (17.1 mg, 0.140 mmol) and the above solid were dissolved in pyridine and the mixture was stirred at rt for 18 h. After that time, the mixture was concentrated in vacuo to obtain a green-yellow oil that was submitted for MS directed purification. One obtained the title compound as off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.44 (s, 9H), 2.46 (brs, 2H), 3.56 (t, 2H, J=5.4 Hz), 4.00 (brs, 2H), 6.38 (s, 1H), 6.40 (s, 1H), 6.67-7.70 (m, 1H), 8.02 (d, 1H, J=2.4 Hz), 8.20 (s, 1H), 9.06 (s, 1H), 11.40 (brs, 1H), 11.92 (s 1H). MS (ES+): m/z 409.05 (100) [MH+]. HPLC: tR=2.33 min (ZQ2000, polar—5 min).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:20]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N1CCCCC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCCCC1
Yield: 29 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.7 g) and 5-amino-2-piperidinobenzonitrile (2.0 g), the title compound (1.0 g) was obtained. melting point: 219-245° C.