Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([N:16]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)C(=O)C(F)(F)F)[CH2:13][CH2:12][N:11]1[C:34]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O>CO>[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([NH:16][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)[CH2:13][CH2:12][N:11]1[C:34]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(c1ccc2ccccc2c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
28 mg (0.73 mmol) of sodium borohydride are added in three portions over the course of 20 minutes to a solution of 106 mg (0.182 mmol) of (2R*,4S*)-2-benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 1.5 ml of methanol at 0°, and the mixture is subsequently stirred at 0° for 3 hours. 0.06 ml (0.81 mmol) of acetone is then added to the reaction mixture, and the stirring is completed for 10 minutes. The methanol is removed in a rotary evaporator, and the solid white residue is partitioned between ethyl acetate and water. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting white foam is chromatographed with methylene chloride/methanol/conc. ammonia (1500:50:1) on silica gel. The title compound of the formula ##STR28## as white foam is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.34, FD-MS: M+ =485.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].CN(C)C(=N)N(C)C.[C:17]([O:21][C:22](N=[N+]=[N-])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22]([CH:5]([CH2:4][CH2:3][CH2:2][NH2:1])[C:6]([OH:8])=[O:7])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCCN)C(=O)O
Yield: 70 %

Procedure:
5-Amino pentanoic acid (0.585 g, 5 m mol) was stirred for two days in dimethylformamide (5 ml) containing tetramethylguanidine (1.14 g, 10 m mol) and tert.butoxycarbonylazide (1.1 g, 7.5 m mol). The solution was evaporated and the residue partitioned between ethyl acetate (20 ml) and 10% citric acid solution (20 ml). The organic layer was washed with 10% citric acid (2×15 ml), water (3×15 ml) and brine (1×15 ml). Each aqueous wash was back extracted with ethyl acetate (20 ml). The combined organic layers were dried over anhydrous magnesium sulphate and evaporated to give an oil which slowly crystallised. Recrystallisation from diisopropyl ether/petrol gave 0.745 g (70% yield), mp. 47.5°-48.5° C., Rf silica gel 0.40 (benzene:dioxan:acetic acid 95:75:4).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H][H]>CCOC(C)=O.[Pd]>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: CCOC(=O)CCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc2c(n1)NCCC2

Procedure:
A solution of 19-3 (2.3 g, 9.4 mmol) in 50 mL EtOAc was treated with 10% Pd/C (230 mg) and a hydrogen balloon. After 4 d the reaction filtered through celite, concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane), providing 19-4 as a yellow oil.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4](C#N)=[C:5]([NH:8][CH:9]=[NH:10])[C:6]#[N:7].Cl>O>[CH:9]1[NH:8][C:5]([C:4]([NH2:3])=[O:1])=[C:6]([NH2:7])[N:10]=1
Reactant: [OH-]
Reactant: N#CC(N)=C(C#N)NC=N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1[nH]cnc1N

Procedure:
Water (50 ml) and an aqueous solution of 25% NaOH (43.0 g) were added to 8 g of N-(2-amino-1,2-dicyanovinyl) formamidine (hereinafter abbreviated as AMD), and reacted under reflux for 2 hours. This aqueous solution was cooled to room temperature or below and adjusted the pH to 7 by adding 35% hydrochloric acid. The reaction solution was concentrated and exsiccated under reduced pressure followed by adding ethanol, and subsequently insoluble sodium chloride was filtrated and removed. The filtrate was treated with activated carbon and then concentrated to afford an ethanol solution of AICA. To lower the pH to 3 or less, 35% hydrochloric acid was added to this, cooled to 10° C. or less, and subsequently generated crystal was filtrated. This crystal was dried to yield 8.1 g of 4(5)-aminoimidazole-5-carboxamide (hereinafter abbreviated as AICA) hydrochloride (yield: 84%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.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>[CH2:29]([O:28][C:26]1[CH:27]=[C:22]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:23]=[N:24][CH:25]=1)[CH3:30]
Reactant: CCOc1cncc(Br)c1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cncc(-c2ccc3c(c2)CC(=O)N3C)c1
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (137 mg, 0.5 mmol) was added 3-bromo-5-ethoxy-pyridine (CAS#17117-17-8, 112 mg, 0.55 mmol), tripotassium phosphate (266 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (300 mg, 0.027 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 5%) to furnish 5-(5-ethoxy-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1287 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, J=6.9 Hz, 3H), 3.27 (s, 3H), 3.62 (s, 2H), 4.18 (q, J=66 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.46-7.57 (m, 2H), 8.26 (d, J=2.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H).
Reaction SMILES: O[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]2[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:13]([CH3:14])[C:3]=12.P(Cl)(Cl)(Cl)=O.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-:34].[NH4+]>>[Cl:34][C:2]1[C:7]([C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[CH:6][N:5]=[C:4]2[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[C:13]([CH3:14])[C:3]=12
Reactant: [Cl-]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1nn(-c2ccccn2)c2ncc(C(=O)O)c(O)c12
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)c3ccccc3)c(Cl)c12
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
A solution of 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 7.4 mmol) in phosphorous oxychloride (19 mL, 200 mmol) was heated and stirred at 100° C. for 1.5 hours. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. To the solution, a solution of phenylmagnesium bromide (1M tetrahydrofuran solution, 30 mL, 30 mmol) was added dropwise at the same temperature, and the mixture was stirred for 1 hour, and at room temperature further for 0.5 hour. The mixture was poured into an aqueous saturated ammonium chloride solution and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1) gave the title compound (0.83 g, 38% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([I:13])[C:10]([OH:14])=[C:9]([I:15])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:16]=O.Cl>COCCOC>[OH:14][C:10]1[C:9]([I:15])=[C:8]2[C:7]([CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH:1][CH2:16]2)=[CH:12][C:11]=1[I:13]
Reactant: N[C@@H](Cc1cc(I)c(O)c(I)c1)C(=O)O
Reactant: C=O
Agent: Cl
Solvent: COCCOC
Product: O=C(O)[C@@H]1Cc2cc(I)c(O)c(I)c2CN1
Temperature: 72 °C
Yield: 45.4 %

Procedure:
A thick-walled reaction flask with a screw top was charged sequentially with (S)-2-amino-3-(4-hydroxy-3,5-diiodophenyl)propanoic acid (Chem-Impex Int'l Inc., 5.0 g, 12 mmol), 1,2-dimethoxyethane (5.0 mL), formaldehyde (37% wt. in H2O, 4.5 mL, 60 mmol), and conc. HCl (60.2 mL, 1981 mmol). The resulting tan slurry was sealed with a screw top and heated to 72° C. slowly over 30 min and then maintained at 72° C. for 12 h. The resulting brown reaction slurry was then cooled to 0° C., filtered while cold, and washed with small amounts of 1,2-dimethoxyethane to give the title compound (2.42 g, 5.45 mmol, 47%) as a white solid. 1H NMR (DMSO-d6) δ 9.93 (br s, 1H), 9.69 (br s, 1H), 7.75 (s, 1H), 4.34 (d, J=7.7 Hz, 1H), 4.21-3.94 (m, 2H), 3.93-3.47 (m, 1H), 3.33-3.16 (m, 1H), 3.15-2.97 (m, 1H); MS (ESI+) m/z 445.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[CH2:19]([Cl:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[Cl-:33].[CH2:19]([N+:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:18])[CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CN(C)CCCNC(=O)c1ccc(N(C)C)cc1
Reactant: CCCCCCCCCCCCCCCl
Product: CCCCCCCCCCCCCC[N+](C)(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: [Cl-]
Reaction time: 4 h

Procedure:
50 g of N-(3-dimethylaminopropyl)-p-dimethylaminobenzamide (0.201 mole) from Example 1 and 47 g of tetradecylchloride (0.195 mole) were melted together and kept at 130° C. for 4 hours. Product was crystallized from 250 ml of ethylacetate; the crystals were washed with another 150 ml of ethylacetate. Yield was 71 g (74% of theoretical yield).
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][OH:23]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCBr
Yield: 108.1 %

Procedure:
According to the procedure given for the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced with LiBH4 (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH2Cl2 (400 mL) to give 206a (78.0 g, 100%) as an oil. 1H NMR (DMSO-d6): δ 4.42 (s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t, 2H, J=8.3), 0.78 (s, 6H). 13C NMR (DMSO-d): δ 69.7, 36.9, 35.7, 34.5, 27.4, 24.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH3:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc(C(=O)O)cc(Br)c1OC
Product: COc1cc(C(C)=O)cc(Br)c1OC

Procedure:
3-Bromo-4,5-dimethoxybenzoic acid (2.0 g) was converted to the benzamide derivative analogously to O3.043, and the latter was converted to the title compound analogously to O2.059. 1.22 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 73.4 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.57 g of 5-[4-{2(R)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 45), 2 ml of trifluoroacetic acid and 2 ml of methylene chloride were used, to give 280 mg of the title compound, melting at 52° C. to 53° C. and having [α]D =-39.7° (methanol, c=0.965).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2SC)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:31][S:32]([O-:34])=O.[K+].[CH3:36]O>O>[C:1]([O:5][C:6]([N:8]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:32]([CH3:36])(=[O:34])=[O:31])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccccc1-c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccccc2S(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 23 h
Yield: 56 %

Procedure:
2-[Bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyrimidine (2.13 g, 5.1 mmol) was dissolved in MeOH (20 mL) and cooled to 0° C. In a separate beaker, a solution of Oxone (5.49 g) was generated by dilution to 27 mL with water. A portion of this solution (17 mL, 5.6 mmol) was removed and adjusted to pH 4.2 with sat. Na3PO4 solution (4.7 mL). This mixture was added to the reaction and stirred 23 hours at room temp. The resulting mixture was diluted with water and extracted with CHCl3. The organics were combined, washed with water and brine, dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc/hexanes) to yield the sulfone (1.28 g, 56%). 1H NMR (CDCl3): δ8.81 (s, 2H) , 8.28 (dd, 1H, J=7.6, J'=1.4), 7.72 (m, 2H), 7.39 (dd, 1H, J=7.3, J'=1.4), 2.76 (s, 3H), 1.50 (s, 18H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1.CCN(C(C)C)C(C)C.[CH3:32][C:33]1[C:34]([CH2:39][N:40]([CH2:47][C:48]2[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:41]2[CH2:46]CNCC2)=[N:35][CH:36]=[CH:37][CH:38]=1>C(Cl)Cl.CN(C=O)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:12][C:11]=2[N:10]=[C:9]1[NH:8][C:1]([N:3]1[CH2:4][CH2:46][CH:41]([N:40]([CH2:39][C:34]2[C:33]([CH3:32])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:47][C:48]2[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=2)[CH2:6][CH2:7]1)=[O:2]
Reactant: Nc1nc2ccccc2s1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2nc3ccccc3s2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (86.2 mg, 0.531 mmol), 2-aminobenzothiazole (72.6 mg, 0.483 mmol), and DIPEA (0.17 mL, 0.97 mmol) in CH2Cl2 (5 mL) and DMF (3 mL) was stirred at room temperature for 4 h. The mixture was concentrated to a minimum volume, diluted with DMF (3 mL), and COMPOUND 249 (150 mg, 0.482 mmol) was added and stirred at 60° C. for 16 hours. The solution was concentrated to dryness, treated with saturated aqueous NaHCO3 (30 mL) and H2O (10 mL), and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) provided COMPOUND 291 (107 mg, 45%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.76 (m, 2H), 1.94 (d, 2H, J=11.7 Hz), 2.05 (s, 6H), 2.62-2.84 (m, 3H), 3.79 (s, 4H), 4.26 (d, 2H, J=11.7 Hz), 7.02-7.11 (m, 2H), 7.16-7.27 (m, 1H), 7.29-7.40 (m, 3H), 7.58 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=7.5 Hz), 8.33 (d, 2H, J=3.9 Hz), 9.91 (br s, 1H); 13C NMR (CDCl3) 18.36, 27.44, 44.89, 54.89, 57.59, 119.09, 121.83, 122.84, 123.55, 126.34, 131.83, 133.77, 138.46, 146.27, 147.01, 154.75, 157.37, 163.38; ES-MS m/z 509 (M+Na). Anal. Calcd. for C27H30N6OS.1.0 CH2Cl2: C, 58.84; H, 5.64; N, 14.70. Found: C, 58.69; H, 5.57; N, 14.82.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(OI1(OC(C)=O)(OC(C)=O)O[C:31](=O)[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2)=O.[H-].[Na+].C1C[O:47][CH2:46][CH2:45]1>C(Cl)Cl>[O:8]=[C:5]1[N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:3](/[CH:2]=[CH:45]/[C:46](=[O:47])[CH2:31][C:30]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:7][S:6]1
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1CO
Reactant: C1CCOC1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-6 (0.56 g, 2.0 mmol) in 10 mL CH2Cl2 was added Dess Martin periodinane (0.98 g, 2.3 mmol) in portions and the resulting solution was stirred for 2 hours. The solution was concentrated in vacuo, to which toluene was added and concentrated thrice to remove acetic acid. The concentrate was then filtered through celite with CH2Cl2 and concentrated in vacuo. The crude product was then diluted in 5 mL of THF and added to a solution of the Wittig reagent dimethyl 2-oxo-3-phenylpropylphosphonate (0.75 g, 3.1 mmol) and 60% sodium hydride (0.12 g, 2.9 mmol) in 5 mL of THF at 0° C. which was premixed for half an hour. The reaction mixture was stirred for 15 minutes at the initial temperature and was allowed to warm up to room temperature for one hour and was stored at 4° C. overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and was extracted with ethyl acetate. The organic phases were then combined, sequentially washed with H2O, brine and dried over Na2SO4. After filtration and concentration in vacuo, the compound was purified by flash chromatography using 50% ethyl acetate/hexanes to yield 400 mg of 3-7 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40–7.21 (m, 5H), 6.75 (dd, 1H), 6.31 (d, 1H), 4.14 (q, 2H), 3.89 (s, 2H), 3.57–3.45 (m, 3H), 3.01 (dd, 1H), 2.75 (m, 1H), 2.31 (t, 2H), 1.64–1.22 (m, 8H), 1.28 (t, 3H); MS (+ESI): m/z 404.2 (M+1)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:23]([C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[N:6]=[C:7]([NH:20][CH3:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCC
Product: CCCCC#Cc1nc(N)c2nc(NC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-methylaminoadenosine (7, 50 mg, 0.12 mmol) and 1-hexyn (0.58 mmol). The mixture was purified by column chromatography (5% MeOH in CH2Cl2). Yield 36 mg (0.09 mmol, 79%), mp 161–163÷C; Rƒ 0.23 (5% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 7.01 (d, 1H, J=4.81 Hz, NH), 6.61 (s, 2H, NH2), 5.84 (d, 1H, J=7.55 Hz, H-1′), 5.78 (t, 1H, J=4.47 Hz, OH-2′), 5.26 (d, 1H, J=6.87 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.58 (q, 1H, J=5.83 Hz, H-2′), 4.10–4.03 (m, 1H, H-3′), 3.95 (bs, 1H, H-4′), 3.62 (bs, 2H, H-5′), 2.87 (s, 3H, J=4.46 Hz, NHCH3), 2.36 (t, 2H, J=6.87 Hz, ≡CCH2), 1.53–1.39 (m, 4H, CH2CH2), 0.89 (t, 3H, J=6.87 Hz, CH3); MS m/z 376 (M+H)+; Anal. (C17H24N6O4) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])=[CH:11][CH:10]=1.[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([CH2:37][CH2:38][OH:39])=[CH:32][C:29]=1[CH:30]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:27][C:28]1[C:35]([F:36])=[CH:34][C:33]([CH2:37][CH2:38][OH:39])=[CH:32][C:29]=1[CH2:30][N:24]1[CH2:25][CH2:26][C:20]2([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]3[S:13][C:9]([CH3:8])=[CH:10][CH:11]=3)=[O:15])[CH2:21]2)[CH2:22][CH2:23]1
Reactant: O=Cc1cc(CCO)cc(F)c1F
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cc(F)c4F)CC3)C2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(5-Methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.53 g) was added to a solution of 2,3-difluoro-5-(2-hydroxyethyl)benzaldehyde (example 32, step b) (0.25 g) and acetic acid (0.08 mL) in methanol (5 mL). The reaction was stirred for 30 min and cooled in an ice bath. Sodium cyanoborohydride (0.13 g) was then added, the mixture allowed to warm to RT and stirred for 18 h. The reaction was concentrated in vacuo. Purification was by silica gel chromatography eluting with 99:1:0.1 to 97:3:0.3 DCM:methanol:‘880’ aqueous ammonia gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.08 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2:18][NH2:19]>>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[N:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[NH2:19]
Reactant: Clc1ccnc2ccncc12
Reactant: NN
Reactant: C1CCNCC1
Product: NNc1ccnc2ccncc12
Product: c1cc2nccc(N3CCCCC3)c2cn1

Procedure:
Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show the synthesis and NMR spectra of various 4-substituted-1,6-naphthyridines, for example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr3 or POCl3 to obtain 4-bromo-1,6-naphthyridine or 4-chloro-1,6-naphthyridine, respectively. Also shown is the reaction of 4-bromo-1,6-naphthyridine with dimethylamine to produce 4-dimethylamino-1,6-naphthyridine and the reaction 4-chloro-1,6-naphthyridine with piperidine or hydrazine to produce 4-(1-piperidinyl)-1,6-naphthyridine or 4-hydrazino-1,6-naphthyridine, respectively.