Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH3:9].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].Cl>O>[C:33]([O:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:18][N:17]=2)=[CH:14][CH:15]=1)[CH3:9])(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(=O)CC)cc2)nc1
Yield: 97 %

Procedure:
Into 20 ml of pyridine were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in the Preparation Example [starting material compound (VI)] 70, and then 0.56 g (6 millimole) of propionic chloride was added thereto, to subject to reaction at 30° to 40° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, adjusted to pH 1 to 2 with 4N hydrochloric acid, and then extracted with 200 ml of toluene, followed by separation thereof. The organic phase was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After drying over anhydrous magnesium sulfate, the residue obtained by distilling the organic solvent off under reduced pressure was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 2.00 g (yield: 97%) of (+)-2-{4-(1-Propanoyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([C:37]2[NH:41][N:40]=[N:39][N:38]=2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([C:37]2[N:41]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[N:40]=[N:39][N:38]=2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnn[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, diisopropylethylamine (1.5 mL) and trimethylsilylethoxymethyl chloride (1.6 mL) were added to a CHCl3 (70 mL) solution of methyl 3-benzyloxy-5-(tetrazol-5-yl)benzoate (2.32 g), and stirred at room temperature for 1 hour. Sodium bicarbonate water was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a brown oil. Not purified, this was used in the next step.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.O.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39]([OH:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(O)CCC.C1C=CC=CC=1>[N:1]#[N:2].[C:33]1([CH3:43])[CH:34]=[CH:35][C:36]([S:39]([OH:42])(=[O:40])=[O:41])=[CH:37][CH:38]=1.[CH2:38]([O:30][C:29](=[O:31])[C@H:21]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])[NH:20][S:17]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=1)(=[O:18])=[O:19])[CH2:33][CH2:34][CH3:35]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCO
Solvent: c1ccccc1
Product: CCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Yield: 92 %

Procedure:
A mixture of 1.0 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of butyl alcohol and 30 ml of benzene was refluxed for 5 hours, while removing the water formed during the reaction. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl ether to yield a crystalline substance which was collected by filtration, washed several times with ethyl ether to afford N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine butyl ester p-toluenesulfonate: yield 92%, m.p. 113-115° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[Cl:12][CH2:13][CH2:14]CC(Cl)=O.CO.Cl>C1(C)C=CC=CC=1>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:14][CH2:13][Cl:12]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC(=O)CCCCl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, methyl acetoacetate (480 g, 4.14 mol), calcium hydroxide (80.0 g, 1.08 mol) and toluene (4822 ml) were added to a 10 liter capacity flask, and dehydration/draining was carried out under toluene reflux. After 1 hour, by cooling to 60° C., 4-chlorobutanoic acid chloride (254 g, 1.8 mol) was added dropwise thereto, followed by stirring at 60° C. Further 1 hour thereafter, methanol (1325 g, 41.4 mol) was added thereto, followed by stirring for 6 hours under methanol reflux. After completion of the reaction, the reaction was stopped with 432 ml (2.16 mol) of 5 N hydrochloric acid, and then the organic layer was separated and the organic layer was washed with 5% sodium carbonate aqueous solution and water. After evaporation of the solvent under a reduced pressure using an evaporator, the residue was distilled under a reduced pressure (75 to 85° C./0.1 ton) to obtain crude 6-chloro-3-oxo-hexanoic acid methyl ester (1); 214.9 g (GC purity; δ 0.3%).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH:2]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].[Sn](Cl)(Cl)(Cl)Cl>O>[C:15]([C:9]1[CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([CH2:11][CH:10]=1)[C:1]([O:13][CH3:14])=[O:12])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1CC=CCC1C(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C1CC=C(C(C)=O)CC1C(=O)OC

Procedure:
10 g of dimethyl 1,2,3,6-tetrahydro-phthalate (II) was treated at -5° C. with 25 ml of acetic anhydride in the presence of 9 ml of tin tetrachloride. The reaction mixture was poured into iced water and extracted with diethyl ether. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and then with water, and was then evaporated to dryness under vacuum. The obtained oil was dissolved in benzene, treated with a methanolic solution of hydrogen chloride. The solution was evaporated to dryness and the residue was purified by chromatography on column of silica gel to give 9 g of the title compound in 75% overall yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (50 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](O)(=O)C.C(N)=N>CCO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([Cl:12])[C:7]2[N:11]=[CH:21][NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1Nc1ccccc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(Cl)c1Nc1ccccc1
Temperature: 80 °C
Reaction time: 44 h
Yield: 100.3 %

Procedure:
4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80° C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3×), saturated NaHCO3, and brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 302.3 (M+1) detected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].[CH3:15][OH:16]>>[CH3:12][O:13][C:2]1[N:7]=[C:6]([O:16][CH3:15])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: CO
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [Na+]
Product: COc1ncc([N+](=O)[O-])c(OC)n1

Procedure:
2,4-Dichloro-5-nitropyrimidine (9.7 g), prepared using the procedure in J. Chem. Soc., 1951, 1565, was added to a solution of sodium methoxide in methanol (obtained from sodium (2.8 g) and methanol (50 ml)) at 0-5° C. The mixture was heated at reflux for 2 hours and poured onto ice water (200 ml). The suspended solid was collected by filtration and dried under vacuum to give 2,4-dimethoxy-5-nitropyrimidine (7.6 g) as a solid, m.p. 92-93° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[O:8][CH:9]=1)[CH2:3][OH:4].C([Si](CC)(CC)[C:20]1OC=[C:22]([CH:25]=[O:26])[CH:21]=1)C.C[Si](C1C=COC=1C=O)(C)C.C([Si](Cl)(CC)CC)C.[C:50](Cl)(=O)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]CCC>C(N(CC)CC)C>[OH:1][CH:2]([C:5]1[CH:6]=[C:7]([Si:10]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:15][CH3:16])[O:8][CH:9]=1)[CH2:3][O:4][C:25](=[O:26])[CH2:22][CH2:21][CH2:20][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(C(O)CO)co1
Agent: CC[Si](Cl)(CC)CC
Agent: C[Si](C)(C)c1ccoc1C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(=O)OCC(O)c1coc([Si](CC)(CC)CC)c1

Procedure:
4-(1,2-Dihydroxyethyl)-2-triethylsilylfuran (prepared by the procedure of Example 1 using 5-triethylsilyl-3-furaldehyde in place of the corresponding trimethylsilyl furaldehyde and preparing the 5-triethylsilyl-3-furaldehyde by the alternative procedure using triethylsilyl Chloride) is reacted with dodecanoyl chloride in the presence of triethylamine to give 4-(1-hydroxy-2-tridecanoyloxyethyl)-2-triethylsilylfuran. Treating this 1-hydroxy compound with acetic anhydride and pyridine gives 4-(1-acetoxy-2-tridecanoyl-oxyethyl)-2-triethylsilylfuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-5-fluoro-4-nitrotoluene (0.605 g, 3.19 mmol, as prepared above) in DMF (3.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (0.310 g, 3.19 mmol, Aldrich, used as received) in water (3.0 mL). The resulting suspension was stirred overnight at 70° C. The suspension was cooled to room temperature and the resulting red solid was filtered, washed with chloroform (10 mL) and dried under vacuum to give 0.360 g (46%) pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ2.276 (s, 3H), 3.431 (d, 2H, J=4.2 Hz), 6.848 (s, 1H), 7.963 (s, 1H), 8.773 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].NC1N=C(C2C(Cl)=CC=CN=2)C=CC=1C(N)=O.[C:35](OCC)(=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([C:35]1[N:17]=[C:15]([OH:16])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1)=[O:37])[CH3:40]
Reactant: Cc1cccnc1-c1ccc(C(N)=O)c(N)n1
Reactant: CCOC(=O)C(=O)OCC
Agent: NC(=O)c1ccc(-c2ncccc2Cl)nc1N
Product: CCOC(=O)c1nc(O)c2ccc(-c3ncccc3C)nc2n1
Temperature: 160 °C

Procedure:
Dissolve 6-amino-3′-methyl-[2,2′]bipyridinyl-5-carboxylic acid amide (1.00 g, 4.38 mmol, prepared in a manner analogous to that described above for the preparation of 6-amino-3′-chloro-[2,2′]bipyridinyl-5-carboxylic acid amide) in diethyl oxalate (24 mL) and heat the mixture at 160° C. for 8 hours or until all starting material is gone as indicated by TLC. Pour the hot mixture onto ice and extract with CH2Cl2 (2×100 mL). Dry the combined organic extracts over Na2SO4. Remove the solvent under reduced pressure. Chromatograph the crude product on silica gel eluting first with CH2Cl2 followed by CH2Cl2/MeOH (95:5) to yield the title compound. MS 311.12 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.C1CCC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:21][CH:20]=3)[C:15]3[C:11]([C:12]=2[CH3:49])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:36][CH:37]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: C1=CCCC=C1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indole No. 165 (2.35 g) in tetrahydrofuran (25 mL) and ethanol (25 mL) was added to 2.3 g of 10% palladium on carbon. Cyclohexadiene (10 mL) was added and the reaction allowed to stir at room temperature for 18 hours. The catalyst was filtered through celite and the reaction mixture was concentrated and chromatographed on silica gel using dichloromethane/methanol (4:1) to elute the product (0.8 g) as a white foam: Mp=125-130° C.; 1H NMR 9.68 (s, 1 H), 8.70 (s, 1 H), 7.15 (d, 2 H, J=8.6 Hz), 7.05 (d, 1 H, J=8.8 Hz), 6.85 (d, 2 H, J=8.6 Hz), 6.80 (d, 1 H, J=2.4 Hz), 6.74 (d, 4 H, J=2.6 Hz), 6.57 (dd, 1 H, J=8.6, 2.2 Hz), 5.09 (s, 2 H), 3.88 (t, 2 H, J=6.4 Hz), 3.60-3.15 (m, 2 H), 2.62-2.38 (m, 4 H), 2.09 (s, 3 H), 1.92-1.78 (m, 2 H), 1.55-1.43 (m, 4 H), 1.42-1.30 (m, 2 H); IR (KBr) 3400 (br), 2900, 1620, 1515 cm−1; MS eI m/z 470.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2.[N-:20]=[N+]=[N-].[Na+].O>CN(C)C=O>[ClH:1].[NH2:20][CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCN
Product: Cl
Temperature: 70 °C
Yield: 94.9 %

Procedure:
To a solution of 4-(2-chloroethyl)-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 62, step 3, 109 mg, 0.396 mmol) in N,N-dimethylformamide (7 ml) was added sodium azide (77 mg, 1.2 mmol) at room temperature. The resulting mixture was heated at 70° C. for 9.5 h. After cooling to room temperature, water (50 ml) was added and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give 110 mg (99%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[ClH:17]>[C].[Pd].CO>[ClH:17].[ClH:17].[NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(N)CNCC12CC2
Reaction time: 13 h
Yield: 80 %

Procedure:
Methanol (91 mL) was added to (−)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (16.2 g) for dissolution. To the solution, 5% palladium carbon (5.33 g, water content: 50%) and concentrated hydrochloric acid (15.8 mL) were added. A reaction vessel was purged with hydrogen gas, and the mixture placed in the reaction vessel was stirred for 13 hours. The catalyst was removed through filtration and washing with ethanol. All the organic layers were combined and concentrated under reduced pressure. Ethanol and isopropyl alcohol were added to the residue, and the mixture was concentrated under reduced pressure several times under azeotropic conditions. After azeotropy, isopropyl alcohol was added to the residue, and the mixture was stirred at room temperature so as to precipitate crystals. The crystals were collected through filtration and dried under reduced pressure, to thereby yield first crystals of the title compound (9.75 g, yield: 80%). Through elemental analysis, the obtained first crystals were found to be a dihydrochloride salt. To another residue obtained through concentration of the filtrate, methanol and isopropyl alcohol were added, and the mixture was cooled so as to precipitate crystals. The crystals were collected through filtration and dried under reduced pressure, to thereby yield second crystals of the title compound (1.41 g, yield: 12%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH2:17])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.O.C(OCC)(=O)C>[Cl:18][C:9]1[C:10]([NH2:17])=[C:11]2[CH2:16][CH2:15][CH2:14][C:12]2=[N:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(-c2cccc(Cl)c2)nc2c1CCC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(Cl)c(-c2cccc(Cl)c2)nc2c1CCC2
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A 25-mL round bottom flask was charged with 2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.250 g, 1.02 mmol) in DMF (6 mL). N-Chlorosuccinimide (0.136 g, 1.02 mmol) was added at rt and the resultant solution was stirred for 3 h. Further N-chlorosuccinimide (0.036 g, 0.27 mmol) was added and the reaction was stirred for 2 h. The reaction was diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×25 mL). The combined extract acetate extract was washed with saturated sodium chloride (2×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexanes/ethyl acetate (10:0 to 9:1) as the eluent to afford the title compound (0.110 g, 38%) as a white solid. MW=279.16. 1H NMR (CD3, 500 MHz) δ 7.62-7.59 (m, 1H), 7.52-7.48 (m, 1H), 7.37-7.32 (m, 2H), 4.54 (s, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H); ESI MS m/z 279 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:22])[N:8]2[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)([CH2:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccncc1
Reactant: O=C1Cc2ccc(Br)cc2N1Cc1cccc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc3ccccc23)c2cc(Br)ccc2C1(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
6-Bromo-1-naphthalen-1-ylmethyl-1,3-dihydro-indol-2-one (195 mg, 0.554 mmol) was dissolved in 1 ml of THF and was then added to a previously degassed solution of 3 ml of THF and 5 ml of aqueous 1 N KOH under an atmosphere of dry N2. To this solution was added 4-picolyl chloride hydrochloride (275 mg, 1.67 mmol). The reaction mixture was then stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated under vacuum to give a green oil. The oil was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give a dark oil which was chromatographed on flash silica gel eluting with a gradient from EtOAc/hexanes (50:50) to EtOAc to EtOAc/MeOH (95:5) to give 140 mg of the titled compound as a colorless oil.
Reaction SMILES: Br[CH:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:18]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH:2]([C:23]1[NH:24][CH:25]=[C:21]([N+:18]([O-:20])=[O:19])[N:22]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc2ccccc2c1)c1nc([N+](=O)[O-])c[nH]1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A yellow slurry consisting of ethyl 2-bromo-2-(2-naphthyl)acetate (384.04 grams, 1.31 mol), 4-nitroimidazole (148.13 grams, 1.31 mol), potassium carbonate (362.11 grams, 2.62 mol), and dimethyl formamide (2500 mL) was stirred at ambient temperature until complete as determined by hplc (16 hours). The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (4×500 mL). The organic extracts were combined and washed with saturated sodium bicarbonate solution (2×500 mL), 10% citric acid solution (2×500 mL), saturated sodium chloride solution (2×500 mL), dried using sodium sulfate, and evaporated. A portion (50 grams) of the crude product was purified by column chromatography on silica gel eluting with dichloromethane:heptane (16:3) gradient to dichloromethane:heptane:methanol (16:3:0.2) giving 30.99 grams of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate which was 90% pure by hplc. A 1 gram sample of the product was purified a second time using a Biotage Flash 40S system eluting with dichloromethane:heptane:methanol (16.9:3:0.1) to give 0.90 grams (46%) of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate as a tan oil. MS (FIA) m/z 326.4 [(M+H)+]. 1H nmr (CDCl3): δ 1.25-1.31 (t, 3H), 4.28-4.39 (m, 2H), 6.16 (s, 1H), 7.36-7.44 (dd, 1H), 7.54-7.62 (m, 3H), 7.84-7.90 (m, 3H), 7.90-7.95 (m, 2H).