Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>O>[ClH:11].[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH:4]([OH:13])[CH2:3][NH:2][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cccc(C=O)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(CNCC(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
The free base obtained from 70.0 g. of rac.-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated at reflux in 1 l. of benzene with 40.8 g. of 3-methoxybenzaldehyde using a water-separator for 2 hours until no more water is released. After concentration and dissolving in 1 l. of methanol, the product is reduced with 30 g. of sodium borohydride below 5°, evaporated and extracted with methylene chloride and water. The methylene chloride extract, acidified with ethanolic hydrogen chloride, crystallizes with ethyl acetate and, after recrystallization from methanol-ether, yields rac.-3,4-dichloro-α-{[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride, m.p. 198°-200°. The free base recrystallized from methanol-petroleum ether has a m.p. of 94°-95°.
Reaction SMILES: [CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14](F)[CH:13]=1)[CH:2]=[CH2:3].[CH3:29][O-:30].[Na+]>C1COCC1.CO>[CH2:1]([N:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=[O:19])=[C:14]([O:30][CH3:29])[CH:13]=1)[CH:2]=[CH2:3]
Reactant: C[O-]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(F)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(OC)c1
Reaction time: 8 h

Procedure:
8.97 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-fluoro-phenyl]-(4-bromo-phenyl)-methanone in 450 ml of THF are stirred with 37 ml of 5.4M sodium methanolate in methanol at room temperature for 14 hrs. and under reflux for 1 hr. The solution is evaporated and the residue is taken up in methylene chloride/10% sodium chloride solution. The organic phase is dried, dissolved in ether and stirred overnight with 2.08 g of fumaric acid. There are obtained 8.17 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methoxy-phenyl]-(4-bromo-phenyl)-methanone.fumarate (m.p. 108°-113° C.).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][CH3:10])=[CH:6][C:5]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:3]=1[O:15][CH2:16][O:17][CH3:18].[Li]CCCC.CN([CH:27]=[O:28])C>CCOCC>[CH3:18][O:17][CH2:16][O:15][C:3]1[CH:4]=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:6]=[C:7]([CH2:8][O:9][CH3:10])[C:2]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COCOc1cc(COC)c(Br)c(OCOC)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1cc(COC)c(C=O)c(OCOC)c1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 2-bromo-1,5-bis-methoxymethoxy-3-methoxymethyl-benzene (10.5 g, 32.8 mmol) in Et2O (100 mL) was treated with n-BuLi (28.7 mL, 71.9 mmol) at −78° C. for 1 h. Then, DMF (27.7 mL, 359 mmol) was added to the reaction and the resulting mixture was warmed to room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:1) affording the title compound (7.21 g). 1H NMR (300 MHz, CD3OD) δ 10.49 (s, 1H), 7.46 (s, 1H), 6.45 (s, 1H), 5.27 (s, 2H), 5.24 (s, 2H), 4.83 (s, 2H), 3.51 (s, 3H). 3.50 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]([NH2:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:28]([NH:36][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CC(C)(C)CC(C)(C)N
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC(C)(C)CC(C)(C)C)c(=O)n12
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml chloroform is dropped to the above mixture at a temperature between -12° C. and -18° C. during 20 minutes. After stirring for 5 minutes, 11.37 g (0.088 mol) of tert.-octylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -18° C. and -15° C. during 40 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 16.1 g (63.8%) of the named product as light yellow crystals after recrystallization from ethanol, m.p.: 126°-129° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of ethyl 2-(isonicotinamido)-4-methylthiazole-5-carboxylate (1.46 g, 5.0 mmol) and sodium hydroxide (0.40 g, 10.00 mmol) in methanol (100 mL) and water (25 mL) was stirred at ambient temperature overnight and then heated to reflux for 2 h. The mixture was concentrated and then neutralized with 5% hydrochloric acid solution to pH 5˜6. The precipitate obtained was collected by filtration and dried to give the title compound in 89% yield (1.17 g); 1H NMR (DMSO-d5, 300 MHz) δ 8.74 (d, J=6.0 Hz, 2H), 7.93 (d, J=6.0 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 264.1 (M+1).
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][NH:20]2)([O-:15])=[O:14].[H-].[Na+].CN1C(=O)CCC1>O>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[CH:23][CH:22]=3)[CH:18]=[N:19]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCSc1nccc(-n2ncc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a flask loaded with 2-butylsulfanyl-4-chloro-pyrimidine (202 mg) was added 4-nitro-1H-indazole (228 mg), followed by NaH (60% dispersion in mineral oil, 84 mg) and NMP (4 mL). The resulting mixture was stirred at RT overnight, water added, and the mixture extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 80:20) to give 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indazole (156 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([O:8][C:9]2[C:44]([F:45])=[C:43]([F:46])[C:12]([C:13]([C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33]CC5C=CC=CC=5)[CH:25]=4)=[C:17]([F:41])[C:16]=3[F:42])=[O:14])=[C:11]([F:47])[C:10]=2[F:48])=[CH:6][C:5]=1[O:51]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:18]2[C:17]([F:41])=[C:16]([F:42])[C:15]([C:13]([C:12]3[C:11]([F:47])=[C:10]([F:48])[C:9]([O:8][C:7]4[CH:49]=[CH:50][C:4]([NH2:1])=[C:5]([OH:51])[CH:6]=4)=[C:44]([F:45])[C:43]=3[F:46])=[O:14])=[C:20]([F:21])[C:19]=2[F:22])=[CH:25][C:26]=1[OH:33]
Reactant: [H][H]
Reactant: O=C(c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F)c1c(F)c(F)c(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c(F)c1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(C(=O)c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 72 h
Yield: 95 %

Procedure:
32.5 g of 4,4'-bis(4-nitro-3-benzyloxyphenoxy)octafluorobenzophenone prepared as described in Example 3 (0.04 mol) are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 3 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and 100 ml n-hexane is added, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(CN)cc1F
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1F

Procedure:
Using methyl 4-aminomethyl-2-fluorobenzoate (181 mg) described in Preparation Example 199 and 3-chloropropane-1-sulfonyl chloride (0.14 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (233 mg) was obtained.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[N:23]1C=CC=CC=1>>[NH2:23][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1
Reactant: c1ccncc1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Product: Nc1nc(Cl)c2[nH]cnc2n1
Yield: 25 %

Procedure:
The synthesis of purine analogues needed more careful treatments. The key intermediate D-8 was condensed with 6-chloropurine and 2-fluoro-6-chloropurine to give the corresponding nucleosides D-21 and D-22 in 65% and 66% yield, respectively. To achieve a clean and high-yield conversion, the temperature of the reaction mixture had to be carefully controlled in such a manner that, after addition of TMSOTf at 0° C., the reaction mixture was stirred for 6 hours at room temperature and then for 2 hours at 60° C. The 6-chloropurine derivative D-21 was syn-eliminated by successive treatment with mCPBA and pyridine to give an inseparable mixture of 2′,3′-unsaturated nucleoside D-23 and its Δ1,2-isomer D-24 in 81% yield (3:1 determined by 1H NMR). Amination of the mixture of D-23 and D-24 by treatment with methanolic ammonia at 100° C. in a steel bomb gave the adenosine analogue, which was deprotected by TBAF in THF to give 2′-fluoro4′-thio-2′,3′-unsaturated adenosine 24 in 61% yield. The Δ1,2-isomer D-24, however, did not survive under reaction conditions and silica gel column chromatography due to its instability. The 2-fluoro-6-chloropurine derivative D-22 was also treated with mCPBA followed by pyridine to give an inseparable mixture of the syn-eliminated product D-25 and its Δ1,2-isomer D-26 in 71% yield. Dry ammonia gas was bubbled into a solution of D-25 and D-26 in ethylene glycol dimethyl ether (DME) at room temperature for 16 hours to give the 2-amino-6-chloropurine derivative D-29 and 2-fluoro-6-aminopurine derivative D-30 in 45% and 25% yield, respectively, which were readily separated by silica gel column chromatography. The Δ1,2-isomer D-26 was not stable enough to survive the reaction and purification conditions.
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].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:27][C:28]1[N:33]=[C:32]([C:34](=[N:36][NH2:37])[NH2:35])[CH:31]=[CH:30][CH:29]=1>ClCCl>[NH2:35][C:34]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=1)=[N:36][NH:37][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: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Cc1cccc(C(N)=NN)n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: Cc1cccc(C(N)=NNC(=O)C2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of 8.21 g (54.7 mmol) 1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid in 80 mL dichloromethane are added 8.86 g (54.7 mmol) carbonyl diimidazole within 30 min. After stirring for five minutes 11 g (54.7 mmol) 6-methylpyridine-2-carbohydrazonamide are added and the reaction mixture is stirred at room temperature for 3 hours. The solvent has been evaporated and the residue is treated with water. The formed precipitate has been filtered off and dried yielding 16.47 g (81.3%) of the desired compound as a mixture of tautomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[S:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:25])=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1ccc(C#N)cc1S(N)(=O)=O
Yield: 27 %

Procedure:
The title compound was synthesized as described for Example 178 in 27% yield, starting from 2-amino-5-cyanobenzenesulfonamide and 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonyl chloride.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]2.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C>C(#N)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]3)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCN1Cc2cc(N)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN1Cc2cc(NCc3ccc(Cl)cc3)ccc2C1=O
Reaction time: 8 h
Yield: 16.1 %

Procedure:
Sodium triacetoxyborohydride (1.28 g, 6.10 mmol) was added to a stirred solution of 5-amino-2-ethyl-2,3-dihydro-isoindol-1-one (540 mg, 3.05 mmol), 4-chlorobenzaldehyde (854 mg, 6.10 mmol) and acetic acid (183 μl, 3.05 mmol) in anhydrous acetonitrile (12 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (0 to 20% ethyl acetate in dichloromethane) to yield the title compound as a light brown solid (148 mg, 16%). HPLC retention time 4.23 min. Mass spectrum (ES+) m/z 301 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([CH2:14][Br:16])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(C(=O)OC)c1

Procedure:
4-Methyl-isophthalic acid dimethyl ester (1.06 g, 5.10 mmol), N-bromosuccinimide (1.00 g, 5.61 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (0.31 g, 1.27 mmol) were suspended in carbon tetrachloride (22 mL) and the resulting mixture was refluxed for 16 hours under N2. The orange solution was concentrated under reduced pressure and the resulting orange residue was purified via column chromatography on silica gel (hexanes:EtOAc, 7:1, v/v). 4-Bromomethyl-isophthalic acid dimethyl ester was isolated as a yellow crystalline solid (1.05 g, 72%). 1H NMR (CDCl3) δ 3.95 (s, 3H), 3.97 (s, 3H), 4.96 (s, 2H), 7.57 (d, 1H, J=9.0 Hz), 8.13 (dd, 1H, J=9.0, 3.0 Hz), 8.62 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][N:5]1[CH2:17][C:16](=O)[C:15]2[C:14]3[C:13]([C:19]([O:21]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:41][N:42]=C(C=2C=34)CC1>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:21])[NH:41][N:42]=[C:16]([C:15]=2[C:14]=34)[CH2:17]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(CCN(C)C)C3
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Agent: NN
Solvent: O
Product: CN(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 60 was prepared from methyl 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR δ 9.92 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.13 (dd, 1H, J=8.4, 7.8 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.41 (s, 2H), 2.51-2.54 (m, 2H), and 2.18 (s, 6H). MS (ESI) m/e [M+1]+ 298.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: ClCc1cc(-c2ccccc2)on1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(-c2ccccc2)on1)OCC
Yield: 62.7 %

Procedure:
3-Chloromethyl-5-phenylisoxazole (2.07 g, 10 mmol) and triethylphosphite (1.72 ml, 10 mmol) were heated at reflux for 2 h then the mixture distilled under reduced pressure to yield the title compound (1.85 g, 6.27 mmol, 63%); b.p. 192° at 0.5 mm Hg; νmax (film) 2980, 2900, 1610, 1590, 1570, 1500, 1450, 1420, 1390, 1250, 1160, 1060-1010, 970, 760, 690 cm-1 ; δH (CDCl3) 1.30(3H,t, J 7 Hz,OCH2CH3), 3.30(2H,d,J 21 Hz,CH2 -P), 4.20(2H,m,OCH2CH3), 6.60(1H,s,CH-het), 7.2-7.9(5H,m,Ph).
Reaction SMILES: [I-].[CH2:2]([N+:4]1([CH2:15][CH3:16])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:3].[OH2:17]>>[OH-:17].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16].[CH2:15]([N+:4]1([CH2:2][CH3:3])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH:5]1[CH3:14])[CH3:16]
Reactant: O
Agent: CC[N+]1(CC)C(C)CCC2CCCCC21
Agent: [I-]
Product: [OH-]
Temperature: 25 °C

Procedure:
The hydroxide version of N,N-diethyl-2-methyldecahydroquinolinium cation was prepared by ion exchange as described in the procedure below. To a solution of 20 gm (0.06 mol) of N,N-diethyl-2-methyldecahydroquinolinium iodide in 80 ml water, 80 gm of OH-ion exchange resin (BIO RAD® AGI-X8) was added, and the resulting mixture was allowed to gently stir at room temperature for few hours. The mixture was filtered and the ion exchange resin was rinsed with additional 30 ml water (to ensure removing all the cations from the resin). The rinse and the original filtrate were combined and titration analysis on a small sample of the filtrate with 0.1N HCl indicated a 0.5M OH ions concentration (0.055 mol cations). Scheme 1 below depicts the synthesis of the templating agent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[C:10]([F:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1nc[nH]c2nccc1-2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1c[nH]c2ncnc(Cl)c12
Yield: 58 %

Procedure:
Combine 4-Chloropyrrolo[2,3-d]pyrimidine (2.985 g, 19.40 mmol), [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)] (Selectfluoro) (10.523 g, 29.704 mmol)], acetonitrile (200 mL), and acetic acid (40 mL) and heat to 70° C. for 24 hours. Monitor loss of starting material by HPLC then concentrate. Add two portions of toluene (50 mL) and evaporate. Filter crude material thru a pad of celite, washing with 1:1 EtOAc/CH2Cl2. Finally, concentrate the filtrate and chromatograph on a silica column eluting with CH2Cl2/MeOH [0-10% MeOH gradient]. Check fractions by MS and combine product fractions to provide 1.931 g (58%) of 4-Chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([OH:15])([CH3:14])[CH3:13].S(OC)(O[CH3:22])(=O)=O.C(O)(=O)C>CN(C)C=O>[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([O:15][CH3:22])([CH3:13])[CH3:14]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(O)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(C)(C)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (38.1 mg, 50% in mineral oil) in N,N-dimethylformamide (1.14 ml) was added dropwise a solution of (6R, 7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (84.6 mg) in N,N-dimethylformamide (25.4 ml) at 0° C. After stirring for 30 minutes at 0° C., thereto was added a solution of dimethyl sulfate (75.13 μl) in N,N-dimethylformamide (0.676 ml), and the resultant mixture was stirred for 3 hours at 0° C. and for additional 1.5 hours at ambient temperature. Acetic acid (0.046 ml) was added to the mixture, and the solvent was distilled off in vacuo. The residue was diluted with ethyl acetate (20 ml) and then washed with an aqueous sodium chloride, 10% aqueous sodium bicarbonate, and a saturated aqueous sodium chloride in turn. The aqueous washings were extracted with ethyl acetate, and this extract was washed with an aqueous sodium chloride. The combined extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue (92.9 mg) was chromatographed on silica gel (2.5 g) eluting with a mixture of ethyl acetate and methylene chloride (1:100 to 1:3) to give (6R, 7S)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (69.1 mg) as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO.C(O)C.[C].[Pd]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:15]1[N:16]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:18][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(=O)Nc1nc(-c2ccco2)c(N2CCN(Cc3ccccc3)CC2)s1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(-c2ccco2)c(N2CCNCC2)s1
Yield: 19.3 %

Procedure:
Compound 79 (274 mg, 0.72 mmol) was dissolved in methanol (7 mL), and 10% palladium-carbon (274 mg) was added thereto, followed by stirring in an atmosphere of hydrogen at 50° C. for 24 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to afford a free form of the entitled Compound. The resulting free form was dissolved in ethanol (5 mL), fumaric acid (83.0 mg, 0.51 mmol) was added thereto, and the precipitated solid was collected by filtration to afford the entitled Compound 80 (40.1 mg, 14%).