Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N>>[OH:12][C:10]([C:8]1[NH:7][C:6]2[CH:40]=[CH:41][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[CH3:11]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: COc1cc(C)c2[nH]ccc2c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was converted in the title compound using the same procedure described in Example 24-B. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (s, 1H) 10.86 (br. s., 1H) 8.10 (s) 7.63-7.84 (m) 7.38-7.55 (m, 2H) 7.21 (q, J=3.12 Hz, 1H) 6.47-6.77 (m, 1H) 6.00 (d, J=1.01 Hz, 1H) 3.26-3.30 (m, 3H) 2.40-2.45 (m, 3H) 2.03 (s, 3H). HRMS calcd. for C20H18N4O2 (M+H)+ 347.1508. found 347.1510.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].C[CH2:10][O:11]CC.ClC(O[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=O>C(=O)(O)[O-].[Na+].O>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][C:10]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: COCCOCCOC(=O)Cl
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCCOCCC(=O)SC[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
L-cysteine hydrochloride (2.00 g, 12.7 mmol) was dissolved in 1M aqueous sodium bicarbonate (25.4 ml) and the solution was diluted with water (75 mL). The solution was cooled in an ice bath and then covered with ether (50 ml). (2-(2-methoxyethoxy)ethyl) chloroformate (2.31 g, 12.7 mmol) was added to the solution in one portion with vigorous stirring for one hour at 0° C. The temperature was allowed to rise to 10° C. and stirred for an additionional two hours. The solvents were then removed under reduced pressure. The resulting solid was washed with methanol and the methanol layer was evaporated to yield the product as a white oil (2.21 g, 65%). FTIR: 1709 cm−1. 1H NMR (D2O); δ4.43 (m,1lH), 4.24 (m, 2H), 3.833.47 (m, 8H), 3.41 (s, 3H).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)=O.[OH-].[K+].[OH-].[Na+].O>O1CCOCC1.CCOC(C)=O>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH2:12][CH:13]([CH2:15][OH:14])[O:3][C:4]=2[CH:9]=1
Reactant: O=COc1cc(Br)ccc1OCC1CO1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCC1COc2ccc(Br)cc2O1
Yield: 91.4 %

Procedure:
5-bromo-2-(oxiran-2-ylmethoxy)phenyl formate (12.6 g, 46.0 mmol) was dissolved in dioxane (50 ml) and KOH (10%)/NaOH (20%) was added. Water and EtOAc was added and the phases were separated. The combined organic phases were washed with brine and dried to give the title compound (10.3 g). MS m/z (rel. intensity, 70 eV) 245 (M+, 96) 244 (M+, bp), 213 (29), 189 (46), 188 (49).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(OC(ON1C(=O)CCC1=O)=O)(C)(C)C>>[NH2:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:11]1[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To di-tert-butyl {4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}imidodicarbonate (77 mg, 0.13 mmol), 4.0 M HCl in dioxane (1.0 mL, 4.0 mmol) was added. After 1 h, the volatile solvents were removed under reduced pressure then the residue (HCl salt) was dried under high vacuum for 20 min. The residue was dissolved in DCM (0.9 mL) at 0° C. and DIPEA (0.35 mL, 2.0 mmol) and 1-[(tert-butoxycarbonyl)oxy]pyrrolidine-2,5-dione (28.9 mg, 0.134 mmol) were added. The mixture was stirred at room temperature for 90 min., then quenched with aq. NaHCO3 and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc (×2). The combined organic layers were dried, then concentrated under reduced pressure to give a yellow residue. The residue was purified by chromatography on silica using a CombiFlash® apparatus (0 to 25% MeOH in hexanes) to give the sub-title compound as a light yellow powder (36 mg, 72%). LCMS calc. for C18H28N7O2 (M+H)+: m/z=374.2. Found: 374.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14]C)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccnc(-c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: O
Product: O=c1ccnc(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
2-(4-Chlorophenyl)-4-methoxypyrimidine (161 mg, 0.730 mmol) in water (1.5 ml) was treated with concentrated hydrochloric acid (608 μl, 7.30 mmol) at ambient temperature. The suspension was heated to reflux during which the reaction became a clear solution. After 12 hours, the reaction was cooled to ambient temperature and the resulting white suspension was diluted with water and filtered. The solids were washed with water and dried under high vacuum to provide the title compound (100 mg, 0.484 mmol, 66.3% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](SC)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][CH:3]=1.F[C:25]1C=CC(C2N=C3N(C=2)C=CS3)=CC=1.O[O:40][S:41]([O-:43])=O.[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([S:41]([CH3:25])(=[O:43])=[O:40])[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cn3ccsc3n2)cc1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3sccn23)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3sccn23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of the mixture (1.1:1) of 6-(4-fluorophenyl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[2,1-b]thiazole (K) and 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (J) (0.205 g, 0.6 mmol) in methanol (25 mL) is added drop-wise a solution of oxone (1.23 g, 1.8 mmol) in water (5 mL). The reaction is stirred at room temperature for 16 hours. The volatiles are removed in vacuo at room temperature. To the residue is added dichloromethane. The organic phase is washed sequentially with water and a saturated, aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent evaporated in vacuo. The crude product is purified by silica gel column chromatography, eluting with ethyl acetate hexane (1:1) to yield 6-(4-fluorophenyl)-5-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[2,1-b]thiazole (L) (Compound CXL, Table 2) as a white solid (0.113 g, 98%); m.p. 197-198° C.;
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][Br:12]
Reactant: Cc1c(F)c(F)cc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c(F)c(CBr)c1F
Temperature: 25 °C

Procedure:
A mixture of 2,3,5,6-tetrafluorotoluene (1.7 g), N-bromosuccinimide (1.9 g), dry carbon tetrachloride (10 ml) and benzoyl peroxide (0.01 g) was heated at the reflux temperature for 20 hours, cooled to the ambient temperature (ca. 25° C.) filtered and the filtrate diluted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvents to yield 2,3,5,6-tetrafluorobenzyl bromide as a mobile colourlessoil.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][C:12]([CH3:25])([O:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH3:13]>CCCCCC.O1CCCC1>[CH3:13][C:12]([CH3:25])([O:14][C:15]([NH:17][C@@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[CH:23]([C:7]1[S:6][CH:10]=[CH:9][N:8]=1)[OH:24])=[O:16])[CH3:11]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)c1nccs1
Reaction time: 0.58 h

Procedure:
2.5 n-Butyllithium in hexane (8 ml.) is added to a solution containing thiazole (1.7 g., 20 mmole) in dry tetrahydrofuran (60 ml.) cooled to -70° under argon. After stirring a short time, the solid material begins to come out of solution. The reaction remains heterogeneous after 35 minutes at -40° to -35° . After cooling the reaction to -50° , a solution containing N-[(1,1-dimethylethoxy)carbonyl]-L-leucinal (2.2g., 10 mmole) in tetrahydrofuran (5 ml.) is added. After 90 minutes the reaction is warmed to -10° and quenched with saturated ammonium chloride (10 ml.). The reaction mixture is extracted into ether and the organic extract is rinsed with water and brine, dired (MgSO4) and concentrated in vacuo to give 1.8 g. of amide product. Two flash chromatographies on first 100 g. and then 150 g. of silica gel (LPS-1) eluting with petroleum ether:acetone (20:1 ) fails to remove a minor impurity from the co-eluting desired diastereimeric product mixture. A total of 1.2 g. of (2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methyl-1-(2-thiazolyl)-1-pentanol is obtained. TLC (silica gel; petroleum ether:acetone, 4:1) Rf =0.37. 8 α]D =-38.6° (c=1, chloroform).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([NH2:46])=[O:45])[CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([NH2:46])=[O:45])[CH2:39]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)C1CCCNC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(C(N)=O)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-3-carboxylic acid amide (nipecotamide, Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H41N6O3Cl2 [(M+H)+] 651.2612, observed 651.2616.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:33][C:34](=O)[CH2:35][CH3:36]>C(#N)C>[CH2:35]([C:34]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]4[CH:12]=3)=[O:10])[CH:5]=[CH:4][N:3]2[CH:33]=1)[CH3:36]
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Reactant: CCC(=O)CBr
Solvent: CC#N
Product: CCc1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)cc2n1
Temperature: 150 °C
Yield: 54.4 %

Procedure:
0.125 g (0.29 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, 0.088 g (0.58 mmol) of 1-bromobutan-2-one and 4 mL of acetonitrile are placed in a 10 mL pressure tube specific for microwave reactors. The tube is then sealed and heated in the microwave reactor at 150° C. for two 1-hour cycles. After this time, the reaction mixture is concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.076 g of the expected product is thus obtained in the form of a yellow solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:31](=[O:47])[N:32]([CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:31](=[O:47])[N:32]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1
Reaction time: 1 h
Yield: 35.6 %

Procedure:
Ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.050 g, 0.075 mmol) was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 0.012 g (35%) of ethyl 4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Zn]C#N)#[N:25]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20]([C:24]#[N:25])[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Yield: 68.1 %

Procedure:
To a mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide (100 mg, 0.265 mmol) and dicyanozinc (62.4 mg, 0.53 mmol) in DMA (2 mL), tetrakis(triphenylphosphine)palladium (61.4 mg, 0.051 mmol) was added. After degassing for 5 min with N2, the reaction mixture was heated under microwaved for 1 h at 130° C. in a heavy walled sealed tube. After removal of the volatile solvent, the residue was purified by preparative HPLC to give the title compound (58 mg). LCMS m/z=322.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.43-0.47 (m, 1H), 1.24 (td, J=7.8 and 5.0 Hz, 1H), 1.48 (s, 9H), 2.24-2.31 (m, 1H), 2.75-2.80 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7 and 6.2 Hz, 1H), 6.73 (bs, 1H), 7.39 (dd, J=5.0 and 1.4 Hz, 1H), 8.16 (s, 1H), 8.61 (d, J=5.0 Hz, 1H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][N:6]([CH3:9])[CH:7]=O.[NH:10]1[C:19](=O)[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]=[C:11]1[NH2:12].O.C(=O)([O-])O.[Na+]>>[CH3:5][N:6]([CH:7]=[N:12][C:11]1[N:13]=[C:14]2[C:18]([NH:17][CH:16]=[N:15]2)=[C:19]([Br:2])[N:10]=1)[CH3:9]
Reactant: CN(C)C=O
Reactant: BrP(Br)Br
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)C=Nc1nc(Br)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
203.0 g (0.75 mol) of phosphorus tribromide was added to 263.1 g (3.6 mol) of N,N-dimethylformamide, and 45.3 g (0.3 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added followed by stirring at 100° C. for 8 hours. After cooling, the reaction mixture was added to 2000 ml of water containing 315.0 g (3.75 mol) of sodium hydrogen carbonate. The precipitating crystal was collected by filtration and washed with 500 ml of water to yield a crystal of 2-dimethylaminomethyleneamino-6-bromopurine, whose properties are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:17]C(=O)OCC1C=CC=CC=1)[CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:10]2[NH:11][N:12]=[N:13][C:9]=2[CH:8]=1)=[O:4]>C(O)=O.CO>[NH2:17][C@H:5]([CH2:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:10]2[NH:11][N:12]=[N:13][C:9]=2[CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]nnc2c1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O=CO
Product: COC(=O)[C@H](N)Cc1cc(C)c2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl (R)-1-(methoxycarbonyl)-2-(7-methyl-1H-benzo[d][1,2,3]triazol-5-yl)ethylcarbamate (146 mg, 0.40 mmol) was dissolved in 12 mL of a solution of 4.4% formic acid in methanol. The reaction flask containing this solution was equipped with a magnetic stirbar and then flushed with nitrogen over several minutes. To the solution was added palladium on carbon (10%, 200 mg) and the reaction was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite® washing the pad several times with methanol. The filtrate was evaporated to give the title compound (quantitative yield). 1H-NMR (CDCl3, 300 MHz) δ 8.40 (bs, 1H), 7.55 (s, 1H), 7.14 (s, 1H), 4.29-4.24 (m, 1H), 3.78 (s, 3H), 3.39-3.19 (m, 2H), 2.69 (s, 3H). LC/MS: tR=1.18 min, 235 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4].[C:26]([Cu])#[N:27].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([C:26]#[N:27])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (164 mg, 0.41 mmol) and CuCN (73 mg, 0.82 mmol) was refluxed for 35 min under nitrogen atmosphere. After the mixture was cooled to r.t., CH2Cl2 (100 mL) was added. 4M HCl was added with stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc/hexanes+2% AcOH) to give 100 mg of the title compound as a white solid. MS: (+) m/z 350.06 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>CS(C)=O>[CH3:11][C:5]1[CH:6]=[C:7]([N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: CS(C)=O
Product: Cc1cc(N(CCO)CCO)ccc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 65.2 %

Procedure:
In 8 ml of DMSO, 5.0 g (64.5 mmol) of 2-nitro-5-fluorotoluene and 8.2 g (78 mmol) of diethanolamine were dissolved. The resultant solution was stirred under heat at 140° C. for 7 hours, followed by extraction with ethyl acetate. After the solvent was distilled out under reduced pressure, the residue was washed with ethyl acetate, whereby 10.1 g of yellow powder were obtained (yield: 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16]N(C)CCCN=C=NCC.O.[OH:28][N:29]1[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:16][O:28][N:29]([CH3:33])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 879.8 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (D25) (5 g, 24.85 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.39 g, 75.55 mmol), 1-hydroxybenzotriazole hydrate (0.38 g, 2.48 mmol) and N,N-diisopropylethylamine (34.6 ml, 198 mmol) in dimethylformamide (80 ml) was stirred overnight at room temperature. The reaction mixture was then concentrated to half volume in vacuo, poured into water (60 ml) and extracted with ethylacetate (3×60 ml). The combined organic phases were washed with saturated aqueous NH4Cl (100 ml), saturated aqueous NaHCO3 (100 ml), water and brine (100 ml), dried with Na2SO4 anhydrous (50 g) and concentrated under reduced atmosphere. Collected organics after solvent evaporation afforded the title compound (D26) (5.33 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:18][CH:17]=1.Cl>CCCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24]/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:7]=1
Reactant: O=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of n-buthyllithium in hexane (47.0 ml of a 1.6M solution) was added dropwise to a solution of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (6.35 g) in dry THF (100 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-one (7.49 g) in THF (15 ml) was added dropewise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was then poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (6.2 g). M.p. 177-179° C.; Retention Time HPLC 2.19 min; MS (ES+) 461 (M+H+).