Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].N>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([O:25][CH2:24][CH2:23][O:11]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)CCC21OCCO1

Procedure:
A mixture of 5-bromo-1-indanone (13.0 g, 61.8 mmol), p-toluenesulfonic acid (23 mg, 0.12 mmol) and ethylene glycol (27.6 mL, 494.6 mmol) in benzene (140 mL) was refluxed for about 24 hours, using a Dean-Stark trap to remove water. The mixture was cooled, poured into excess 5% aqueous sodium bicarbonate and was extracted with toluene. The combined organic extracts were washed with brine, dried with MgSO4, filtered, and evaporated in vacuum. The residue was purified by flash column chromatography using dichloromethane as the mobile phase to give the above intermediate. MS (DCI/NH3): m/z 254, 256 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[F:31][C:32]([F:37])([F:36])[C@H:33]1[O:35][CH2:34]1>CC(O)C>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C@H:33]([OH:35])[C:32]([F:37])([F:36])[F:31])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Solvent: CC(C)O
Product: O[C@@H](CN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (54 mg, 0.120 mmol) in 2-propanol (0.4 mL) was added (S)-(−)-3,3,3-trifluoro-1,2-epoxypropane (10.4 uL, 0.120 mmol). The mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated. The resulting residue was purified by reverse phase HPLC and lyophilized to give 32 mg of (S)-3-(trans-4-(3,5′-dichloro-6-((tetrahydro-2H-pyran-4-yl)methyl)amino-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)-1,1,1-trifluoropropan-2-ol as its TFA salt. LCMS (m/z): 562.3 (MH+), retention time=0.70 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.33 (m, 4H) 1.35-1.65 (m, 4H) 1.64-1.84 (m, 1H) 1.93-2.23 (m, 4H) 2.94-3.18 (m, 4H) 3.17-3.35 (m, 3H) 3.53-3.69 (m, 1H) 3.81 (dd, J=11.35, 2.74 Hz, 2H) 4.33-4.48 (m, 1H) 6.38 (s, 1H) 6.55 (d, 1H) 6.82 (br. s., 1H) 6.93 (br. s., 1H) 7.23 (br. s., 1H) 7.48 (d, 1H) 8.02 (s, 1H) 8.72 (br. s., 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1>O1CCCC1.C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzamide (2 g, 7.2 mmol) in tetrahydrofuran (50 mL) and ethyl acetate (50 mL) was added Raney nickel (0.2 g) and the mixture was placed under hydrogen (4.1 bar) in a high pressure apparatus. After shaking overnight, the mixture was filtered and concentrated in vacuo and purified by flash chromatography to give 1.5 g (83%) of an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12].Cl>C(O)C.O1CCOCC1>[CH2:11]([O:13][C:14]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17]1)=[O:15])[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)C1CC(=O)c2cc(N)ccc21
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1CC(=O)c2cc(Nc3ncccc3[N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.48 g, 9.03 mmol), (R/S)-5-Amino-3-oxo-indan-1-carboxylic acid ethyl ester (1.98 g, 9.03 mmol) and 4M HCl in dioxane (2.3 mL, 9.0 mmol) in ethanol (15 mL) is refluxed for 9 h. The reaction mixture is left at rt overnight then a further equivalent of 4M HCl in dioxan is added. After 4 h refluxing, the solvent is evaporated and the crude mixture purified by MPLC eluting with EtOAc/Hexane to give (R/S)-5-(3-Nitro-pyridin-2-ylamino)-3-oxo-indan-1-carboxylic acid ethyl ester as a red solid. Title compound: ES-MS: 342.19 [M+H]+, tR=1.6 min (System 2)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: Cc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 3-methyl-4-nitrobenzoic acid and 1-methylpiperazine following the method used to prepare Intermediate 27. δH (DMSO-d6) 8.03 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.44 (dd, J8.4, 1.9 Hz, 1H), 3.66 (m, 2H), 3.26 (s, 2H), 2.53 (s, 3H), 2.37 (s, 2H), 2.25 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:26])=[N:11][CH:12]=[C:13]([C:15]3[S:23][C:22]4[CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:18][C:17]=4[CH:16]=3)[CH:14]=2)[CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[CH2:24]([N:19]1[CH2:20][CH2:21][C:22]2[S:23][C:15]([C:13]3[CH:14]=[C:9]([C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=5)[N:7]=[CH:6][C:5]=4[NH2:8])[C:10]([F:26])=[N:11][CH:12]=3)=[CH:16][C:17]=2[CH2:18]1)[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCN1CCc2sc(-c3cnc(F)c(-c4cc(Cl)ncc4N)c3)cc2C1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1CCc2sc(-c3cnc(F)c(-c4cc(-c5cnn(C)c5)ncc4N)c3)cc2C1
Temperature: 120 °C
Yield: 54.6 %

Procedure:
A degassed mixture of 6′-chloro-5-(5-ethyl-4,5,6,7-tetrahydro thieno[3,2-c]pyridin-2-yl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.05 g, 2.70 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (842 mg, 4.10 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (221 mg, 0.27 mmol) in 1N aqueous potassium fluoride solution (9 mL) and acetonitrile (9 mL) was heated under microwave irradiation at 120° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (641 mg, 55%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.44 (dd, J=2.5, 1.1 Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 8.07 (dd, J=8.7, 2.5 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H), 3.61 (s, 2H), 3.00-2.94 (m, 2H), 2.93-2.85 (m, 2H), 2.68 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCCCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 1 g (4.76 mM) of [5-(3-thienyl)tetrazol-1-yl]acetic acid and 590 mg (5.71 mM) of 1,5-pentanediol in 10 ml of N,N-dimethylformamide was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=60/0) for separation and purification, to give 670 mg (yield 47.5%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 5-hydroxypentyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5].N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].N>CC(N(C)C)=O.O.CO>[CH3:19][O:20][CH2:21][C:22]([NH:5][C:4]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:23]
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: COCC(=O)Cl
Agent: N
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
[step 1] 2-Methoxy-6-nitroaniline (4.0 g, 23.8 mmol) was dissolved in DMA (24 mL), pyridine (5.8 mL, 71.4 mmol) and 2-methoxyacetyl chloride (6.5 mL, 71.4 mmol) were added at 0° C., and the mixture was stirred at room temperature for 1 hr. Under ice-cooling, methanol and aqueous ammonia solution were added to the mixture, and the mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-30/70 v/v) to give 2-methoxy-N-(2-methoxy-6-nitrophenyl)acetamide (5.4 g, 95%).
Reaction SMILES: [NH2:1][C:2]1([C:23]([O:25]C)=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][C:13]4([CH2:21][CH2:20][CH2:19][CH2:18]4)[C:12]=3[N:11]=[C:10]([NH2:22])[N:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[NH2:1][C:2]1([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][N:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][C:13]4([CH2:21][CH2:20][CH2:19][CH2:18]4)[C:12]=3[N:11]=[C:10]([NH2:22])[N:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)C1(N)CCN(c2nc(N)nc3c2CCCC32CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N2CCC(N)(C(=O)O)CC2)c2c(n1)C1(CCCC1)CCC2
Reaction time: 16 h

Procedure:
A solution of the product from Example 11 (30 mg, 0.083 mmol) in MeOH (5 mL) was treated with NaOH solution (1 mL, 10%) and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the resulting oil was chromatographed on silica gel (6:1:1 EtOAc/HCO2H/H2O, eluant). The fractions containing the still-impure product were combined and concentrated under reduced pressure, then the residue was again chromatographed on silica gel, this time eluting with NH4OH/MeOH/CH2Cl2 (1.5:13.5:85), to provide the title product. 1H NMR (300 MHz, CD3OD) δ 3.70-3.81 (m, 2 H), 3.45-3.57 (m, 2 H), 2.52 (t, J=5.43 Hz, 2 H), 2.25-2.36 (m, 2 H), 1.98-2.09 (m, 2 H), 1.76-1.94 (m, 6 H), 1.61-1.74 (m, 6 H). MS (DCI+) m/z 346 (M+H) and 368 (M+Na).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.072 g, 0.16 mmol) in DMF (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.061 g, 0.160 mmol), HBTU (0.100 g, 0.192 mmol), and TEA (0.045 mL), 0.320 mmol). This mixture was stirred at room temperature for 3 h. The reaction mixture was purified using a Gilson HPLC (with 0.1% TFA) to afford the title compound. LC-MS m/z 815 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[N:4]=1.B1C2CCCC1CCC2.[OH-:29].[Na+].OO>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:29])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To the solution of 2-(trifluoromethyl)-6-(4-vinylphenoxy)pyridine (2.4 g, 9.05 mmol) in dry THF (25 mL), was added 9-BBN (30 ml, 15.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (12 mL, 36.0 mmol), and 30% H2O2 (12 mL). The reaction mixture was heated at 50° C. for 1 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (3.68 g, 8.44 mmol, 93% yield) as a white oil. LCMS: rt=3.00 min, [M+H+]=284
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[C:24]([N:28]1[N:32]=[N:31][C:30]([NH2:33])=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[N:32]=[N:31][C:30]([NH:33][C:2]2[CH:23]=[CH:22][C:5]3[N:6]=[C:7]([NH:10][CH:11]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]=5[O:20][CH3:21])[CH2:13][CH2:12]4)[O:8][CH2:9][C:4]=3[CH:3]=2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Reactant: CC(C)(C)n1nnc(N)n1
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nnn(C(C)(C)C)n4)cc3CO1)CC2
Yield: 15.7 %

Procedure:
The title compound (34 mg, 16%), off-white foam, MS (ISP): m/e=434.4 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) and commercially available 2-tert.-butyl-2H-tetrazole-5-yl-amine (141 mg, 1.0 mmol).
Reaction SMILES: [NH:1]([CH2:5][C:6]([O-:8])=O)[C:2]([NH2:4])=[O:3].[NH2:9][OH:10]>O1CCOCC1>[OH:10][NH:9][C:6](=[O:8])[CH2:5][NH:1][C:2]([NH2:4])=[O:3]
Reactant: NC(=O)NCC(=O)[O-]
Reactant: NO
Solvent: C1COCCO1
Product: NC(=O)NCC(=O)NO

Procedure:
The ArgoGel-Wang or ArgoGel-OH resin bound 2-ureidoacetate 6 (0.25 g) was treated with dioxane (1 mL) and aqueous 50% hydroxylamine (2 mL). After 24 h the resin was filtered, washed with acetonitrile and the filtrates combined and purified by preparative reverse-phase (C18) HPLC to yield product N-hydroxy-2-ureidoacetamide (I).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:21]([BH3-])#[N:22].[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:22][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CNCc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 75(b), by reacting 22.5 g (77 mmol) of 2-benzyloxy-5-bromobenzaldehyde, 26.1 g (386 mmol) of methylamine hydrochloride and 7.3 g (116 mmol) of sodium cyanoborohydride, and after purification by chromatography on a column of silica eluted with a dichloromethane/methanol mixture (9/1) and 0.5% isopropylamine, 12.2 g (51%) of the expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1CCCC1=O>[CH3:1][N:2]1[CH2:15][CH:14]([CH3:16])[C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)C(C)CN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,4,8-trimethyl-1H-pyrido[4,3-b]indole (200 mg, 0.934 mmol) in N-methyl-2-pyrolidone (2.5 mL) was added powdered KOH (463 mg, 8.27 mmol) and allow to stir for 10 min at RT. 2-Trifluoromethyl-5-vinyl pyridine (323 mg, 1.87 mmol) was added and stirred further for 12 h at RT. The reaction was monitored by TLC. After completion of reaction, water (10 mL) was added and the mixture filtered. Water was added to the filtrate and the product extracted with EtOAc (50 mL). The organic layer was dried over sodium sulfate, evaporated in vacuum and purified by HPLC to obtain the product.
Reaction SMILES: [CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5])([CH3:3])[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14]>C(O)(C)C>[CH3:2][CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:12])[CH2:13][OH:14])=[O:5])[CH3:3]
Reactant: OCC1CO1
Reactant: CC(C)C(=O)NCCN
Solvent: CC(C)O
Product: CC(C)C(=O)NCCNCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
To 39 g (0.3 mol) of 2-(isopropylcarbonylamino)ethylamine in 150 ml of isopropyl alcohol was added 22.2 g (0.3 mol) of glycidol. The reaction mixture was stirred at 25° C. for 24 hours and evaporated in vacuo. The residual oil was chromatographed (silica gel/ethanol) to give 18.6 g (30%) of product. This compound was identified by NMR and IR spectroscopy.
Reaction SMILES: [CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]#[N:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:39]=[N+:40]=[N-:41].[Na+].O>C1(C)C=CC=CC=1>[CH:1]1([CH:7]([O:37][CH3:38])[C:8]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:9]=2[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:12]2[N:39]=[N:40][NH:41][N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To solution of (2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)(3,5-bis(trifluoromethyl)benzyl)cyanamide (144 mg, 0.26 mmol) in toluene was added sodium azide (84.9 mg, 1.31 mmol) followed by TEA-HCl (178.8 mg, 1.3 mmol). The mixture was stirred at 115° C. overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 5-50% ethyl acetate in heptane) to afford the title compound (90.9 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 0.90-1.16 (m, 5H) 1.23-1.32 (m, 1H) 1.49-1.61 (m, 3H) 1.69 (s, 1H) 1.97 (d, J=12.45 Hz, 1H) 3.21 (s, 3H) 4.05 (d, J=7.88 Hz, 1H) 4.74-4.93 (m, 4H) 7.31 (s, 1H) 7.41 (d, J=7.88 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.69 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][NH:16][C:17](=O)[O:18]C1C=CC=CC=1>CN(C)C=O>[CH3:15][NH:16][C:17]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)=[O:18]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Sodium hydride (60% in oil, 228 mg, 5.7 mmol) was gradually added to a N,N-dimethylformamide (0.5 ml) solution of 5-nitroindole (0.841 g, 5.19 mmol) while stirring at room temperature; phenyl N-methylcarbamate (1.02 g, 6.74 mmol) was added thereto; and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate. This was concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, sequentially ethyl acetate) to yield the title compound (600 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[Cl:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a suspension of sodium hydride (50%, 8.0 g, 164 mmol) in dimethylformamide (200 ml) was added p-hydroxybenzoic acid (10.0 g, 82 mmol) portionwise. The mixture was stirred at room temperature for two hours, treated with 1-chloro-3-bromopropane (16 ml, 164 mmol) and allowed to stir at room temperature for 48 hours. The mixture was quenched with methanol, acidified with concentrated hydrochloric acid and filtered through Celite. The filtrate was diluted with diethyl ether (500 ml), washed with water (3×200 ml) and dried over Na2SO4. The ether solution was concentrated to give 4-chloropropoxybenzoic acid (1.1 g, 6% yield) as an off-white solid, mp 136°-138° C. 1H NMR (DMSO): δ 12.00 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 4.24 (t, J=5.0 Hz, 2H), 3.54 (t, J=5.1 Hz, 2H), 2.23 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH2:4]1)[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][C:23]([NH2:25])=[NH:24]>>[ClH:19].[ClH:19].[NH2:25][C:23]1[N:24]=[C:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2=[N:21][CH:22]=1
Reactant: N=C(N)CN
Reactant: CCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Agent: Cl
Product: CCN1CCc2nc(N)cnc2C1

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-1,2,5,6-tetrahydro-3,4-bis(trimethylsilyloxy)-pyridine and α-amino-acetamidine dihydrochloride.