Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:11](F)=[C:10](F)[C:9](OC)=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2C1CC1.N1CCCCC1>>[O:22]=[C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[NH:7][CH:6]=[C:5]1[C:19]([OH:21])=[O:20]
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCNCC1
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
5-Amino-1-cyclopropyl-6-fluoro-8-methoxy-7-{(4-amino/substituted amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and isomers were prepared by a procedure described in Method 1 by using 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and appropriate {4-(amino/substituted amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)}piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.C=O.[C:12](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1cc(Cl)ncc1I
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
2-Chloro-5-iodopyridin-4-amine (2.0 g, 7.86 mmol) and paraformaldehyde (0.472 g, 15.7 mmol) were dissolved in AcOH (56.1 mL) and stirred for 2.5 hours at 40° C. Sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred at 40° C. for 1.5 hours. Further sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred for a further 19 hours. The reaction mixture was reduced in volume by half by evaporation in vacuo. Water was added to the mixture, followed by basification with NaHCO3. The mixture was extracted with EtOAc (3×70 mL) and the combined organic layers were dried over MgSO4. Silica was added and the solution was concentrated. Gradient chromatography, eluting with 5-10% EtOAc in c-Hex for 4 column volume and then 10% EtOAc in c-Hex for a further 11 column volume, gave 2-chloro-5-iodo-N-methylpyridin-4-amine (1.65 g, 6.14 mmol, 78% yield) as a white crystalline powder.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29]CC5C=CC=CC=5)=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[BrH:39]>C(O)(=O)C.CCOCC>[BrH:39].[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:37])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(OCc3ccccc3)cn2)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccc(O)cn2)cc1
Yield: 62 %

Procedure:
To a stirred solution of N-cyclopropyl-4-methyl-3-{[4-(5-benzyloxypyridin-2-ylmethoxy)benzoyl]amino}benzamide (1.0 g, 1.97 mmol) in glacial acetic acid (10 mL) was added a solution of HBr (48% in acetic acid, 30 mL). After 6 hours at 25° C. the solution was diluted with ether (100 mL) and the resultant precipitate filtered off and dried to give the title compound as a pale yellow solid (610 mg, 62%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.25 (s, 3H), 2.84 (m, 1H), 5.36 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.78-7.84 (m, 3H), 8.00 (d, 2H), 8.36 (m, 2H), 9.86 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: Cl.[CH:2]1[C:14]2[C:13](=[CH:15][C:16]3[CH:24]=[CH:23][C:19]([CH:20]([NH2:22])[CH3:21])=[CH:18][CH:17]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[CH:11]1[C:12]2[C:13](=[CH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:20]([N:22]=[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]4)[CH3:21])=[CH:23][CH:24]=3)[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(N)c1ccc(C=C2c3ccccc3-c3ccccc32)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C2c3ccccc3-c3ccccc32)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-(fluoren-9-ylidenemethyl)-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above results in the formation of 2-[[1-[ρ-(fluoren-9-ylidenemethyl)phenyl]ethylimino]]-hexahydro-1H-azepine, having a M.P. of 265.5°-7.5° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])([CH3:20])[CH2:7][C:8](C=O)([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:9]2=O)=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6]([CH3:20])([CH3:21])[CH2:7][C:8]1[CH2:13][CH2:14][C:15](=[O:17])[CH2:16][C:9]2=1
Reactant: CC(=O)CCC1(C=O)CC(C)(C)c2ccc(Br)cc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CC2=C(CC(=O)CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
A solution of 7-bromo-4,4-dimethyl-2-formyl-2-(3-oxo-butyl)-1-oxo-1,2,3,4-tetrahydronaphthalene (1.71 g, 4.87 mmol) in methanol (170 ml) was treated with a solution of lithium hydroxide hydrate (0.854 g, 20.35 mmol) in water (85 ml) the reaction was stirred at room temperature for 45 minutes and then the temperature was raised to 50° C. and the mixture was stirred for another 2 hours. The reaction was quenched with water and adjusted to pH 5 with 4M hydrochloric acid. The aqueous phases were extracted with ethylacetate (3×) and the combined organic phases were washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel chromatography (hexane/ethylacetate 95:5 to 90:10) to give the title material (0.631 g, 42%) along with 6-bromo-9,9-dimethyl-3-oxo-1,2,3,4,9,10-hexahydrophenanthrene (0.371 g, 25%).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:21][NH2:22]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=2[C:1](=[O:6])[NH:22][NH:21]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c1CCCC2
Yield: 84.4 %

Procedure:
3,4,5,6-Tetrahydrophthalic anhydride (25 g, 0.164 mol) was dissolved in 40% aqueous acetic acid (500 ml) with sodium acetate trihydrate (26.8 g, 0.197 mol) and hydrazine hydrate (9.58 ml, 0.197 mol). The reaction mixture was heated under reflux overnight and then allowed to cool. The resulting solid was collected by filtration, washed with water and diethyl ether and dried in vacio to give the title-product (23 g, 84%), 1H NMR (250 MHz, d6-DMSO) δ1.64 (4 H, br s, 2 of CH2), 2.34 (4 H, br s, 2 of CH2), 11.30 (2 H, br s, 2 of NH); MS (ES+) m/e 167 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:29]1[C:33]2C=CC=CC=2N=N1.Cl.CN.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:33][NH:29][C:25](=[O:27])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine (7.4 g, 20 mM), 1-hydroxybenzotriazole (3 g, 20 mM), methylamine HCl (1.3 g, 20 mM) and N-methylmorpholine (2 g, 20 mM) in CH2Cl2 (20 ml) stired and cooled to 0° was added DCC (4.2 g, 20 mM). After being allowed to stir and warm to room temperature overnight the reaction mixture was filtered and washed with saturated aqueous sodium bicarbonate solution, 3N citric acid and brine. The dried organic extract was then concentrated in vacuo to give N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine N-methylamide as a solid. Recrystallisation from dichloromethane/hexane gave (4.5 g); m.p. 165°-172°; (Found: C, 68.85; H, 7.43; N, 7.39. C22H28N2O4 requires C, 68.73; H, 7.34; N, 7.29%); δ (CDCl3) 1.40 (9H, s, OC(CH3)3); 2.73 (3H, d, J=5 Hz, CONHCH3); 2.96 (2H, m, CH2Tyr); 4.25 (1H, m, α-CH); 5.03 (2H, s, CH2C6H5); 5.80 (1H, br, CONH); 6.86 (2H, d, J=8 Hz, Tyr); 7.12 (2H, d, J=8 Hz, Tyr); 7.3-7.5 (5H, m, C6H5).
Reaction SMILES: [CH2:1]([C:4]1([CH2:21][OH:22])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:5]1)[CH:2]=[CH2:3].O1C2C=CC=CC=2OC[CH:24]1CN1CCCC(COC)(C)C1>>[CH2:1]([C:4]1([CH2:21][O:22][CH3:24])[CH2:9][CH2:8][CH2:7][N:6]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: C=CCC1(CO)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCC1(COC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from [3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]methanol using the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH:36]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:36]1([C:42]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)=[O:20])=[CH:7][CH:8]=2)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in pyridine was added EDC, DMAP, and cyclohexanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl cyclohexanecarboxylate (E142).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:11])=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.5 %

Procedure:
A suspension of 22.32 g (0.167 mol) of aluminum chloride in 35 ml of dichloromethane is prepared. It is cooled to 0° C. and a mixture of 8.3 g (0.0728 mol) of glutaric anhydride (dihydro-2H-pyran-2,6(3H)-dione) and 8.4 ml (0.0895 mol) of fluorobenzene in 20 ml of dichloromethane is added slowly. The mixture is stirred for 15 hours at room temperature and then hydrolyzed in acidified iced water. The precipitated product is filtered off, washed with water and then dried under reduced pressure. The crude product is then recrystallized from 90 ml of ethyl acetate to give 8.8 g of the expected product in the form of beige crystals (yield=57.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[N:40]1([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:43]2[CH2:42][CH2:41][N:40]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:45][CH2:44]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (200 mg, 0.34 mmoL), tert-butyl piperazine-1-carboxylate (224 mg, 1.20 mmoL) and NaHCO3 (116 mg, 1.38 mmoL) in NMP (5 mL) was heated at 130° C. overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate: LCMS tR=3.04 Min (5 min run, UV254nm). Mass calculated for, M+ 731.4, observed LC/MS m/z 732.4 (M+H).
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C:30]([NH2:32])=[S:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:32][C:30]1[S:31][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[C:19]([C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)[N:29]=1
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Reactant: NC(N)=S
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Bromine (1.0 mL, 19 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(3,5-dimethylphenyl)ethanone (6.4 g, 19 mmol) in acetic acid (80 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (100 mL), to the solution were added thiourea (1.5 g, 19 mmol) and triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was collected by filtration and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 5.0 g (13 mmol, yield 68%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1/[CH:13]=[CH:14]/[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1/[CH:13]=[CH:14]/[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a stirred solution of ethyl (E)-4-[2-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]ethenyl]benzoate (700 mg, 2.03 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL) and the resulting mixture was stirred for 3 hr. The mixture was concentrated and the residue was made basic by the addition of sat. NaHCO3. The mixture was extracted with CHCl3 (2×100 mL). The combined extracts were dried over Na2CO3 and concentrated in vacuo to give 434 mg (87%) ethyl (E)-4-[2-(2-pyrrolidinyl) ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ 1.39 (3 H, t, J=7.3 Hz), 1.52–2.06 (4 H, series of m), 2.93–2.99 (1 H, m), 3.07–3.13 (1 H, m), 3.74 (1 H, q, J=7.3 Hz), 4.37 (2 H, q, J=7.3 Hz), 6.34 (1 H, dd, J=15.6, 7.3 Hz), 6.54 (1 H, d, J=15.6 Hz), 7.41 (2 H, d, J=8.3 Hz), 7.97 (2 H, d, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl>O>[ClH:1].[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC(N)=O
Reactant: CC12CC3CC(C)(C1)CC(Cl)(C3)C2
Agent: Cl
Solvent: O
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Reaction time: 0.08 h

Procedure:
1.99 grams of 1-chloro-3,5-dimethyl-adamantane were heated with 0.9 gram urea for about 40 minutes at 220° C. The heating was carried out in a closed vessel in an oil bath with a thermostat. After cooling, the reaction product was pulverized and made into a paste with 50 ml. water. The water phase was brought to a pH between 3 and 5 by dropwise addition of concentrated HCl. The acidified water phase was extracted with two 10-ml. ether portions. Next the water phase was brought to a pH between 12 and 13 by addition of sodium hydroxide, and stirred for 5 minutes. After stirring, the alkaline water phase was extracted with four portions of ether, 10 ml. each. The combined ether extracts were dried over potassium hydroxide. By bubbling dried hydrogen chloride through the solution, 1-amino-3,5-dimethyl-adamantane hydrochloride was precipitated. The yield was 1.7 grams (78% of the theoretical yield). The product did not melt until 300° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([OH:10])[CH3:9].[CH:11]([O:14][C:15]([N:17]1[C:30]2[C:22](=[CH:23][C:24]3[CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C@@H:21]([N:31]([CH2:37][C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=2)[C:32]2[N:33]=[N:34][NH:35][N:36]=2)[CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].Cl>CN(C)C=O>[CH:11]([O:14][C:15]([N:17]1[C:30]2[C:22](=[CH:23][C:24]3[CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C@@H:21]([N:31]([CH2:37][C:38]2[CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=2)[C:32]2[N:33]=[N:34][N:35]([CH2:9][CH2:8][OH:10])[N:36]=2)[CH2:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3
Reactant: CC(O)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
Add potassium carbonate (40 mg, 0.29 mmol) and bromoethanol (0.018 mL, 0.26 mmol) to a solution of (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (50 mg, 0.086 mmol) in dimethylformamide (0.3 mL). Stir at room temperature for 18 hrs in a sealed tube. Then add bromoethanol (0.018 mL, 0.26 mmol) and stir for 2 hrs. Add a 1N solution of hydrochloric acid and extract with dichloromethane. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate in vacuo. Purify the residue using silica gel cartridge, eluting with ethyl acetate/hexanes to afford the title compound (26 mg, 49%). MS (ES+): 627 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(OCc2ncccc2[N+](=O)[O-])cc1
Yield: 85 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 4-methylphenol, the titled compound was obtained as yellow solid. (Yield: 85%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C1C=C([O:15]O)C(C(O)=O)=C(C(O)=O)C=1>>[C:1]([C:3]1[CH:4]=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: N#Cc1cccnc1
Product: N#Cc1ccc[n+]([O-])c1

Procedure:
Other methods known to one skilled in the art are also useful in the preparation of certain compounds within the scope of the present invention. For example, in a method to prepare 2,4-diamino-5-chloro-6-substituted-5-deazapteridine derivatives, 3-cyanopyridine is oxidized with monoperoxyphthalic acid, magnesium salt, hexahydrate, affording 3-cyanopyridine N-oxide. The oxide is in turn nitrated with potassium nitrate and fuming sulfuric acid, yielding 4-nitro-3-cyanopyridine N-oxide. The nitro compound is then chlorinated with phosphorous oxychloride, giving the corresponding 2,4-dichloro-3-cyanopyridine. The dichloro compound is then cyclized with guanidine carbonate in N,N-dimethylformamide, yielding the corresponding 2,4-diamino-5-chloro-5-deazapteridine. The so-prepared 5-deazapteridine is in turn brominated using N-bromosuccinimide in N,N-dimethylformamide, affording 2,4-diamino-6-bromo-5-chloro-5-deazapteridine. This compound is then reacted with an appropriate boronic acid, for example, 3,5-di(trifluoromethyl)phenylboronic acid, yielding the targeted 2,4-diamino-5-chloro-6-substituted-5-deazapteridines, for example, 2,4-diamino-5-chloro-6-[3,5-di(trifluoromethyl)phenyl]-5-deazapteridine. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][C:13](OCC)=[O:14])[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH2:12][CH:13]=[O:14])[O:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1(c2ccccc2)OCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCC1(c2ccccc2)OCCO1
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 65A (2.36 g) in toluene (30 mL) was added diisobutylaluminium hydride (1.5M in toluene, 8 mL) at −78° C. After stirring for 10 minutes the reaction mixture was quenched by addition of water. The precipitate was removed by filtration through diatomaceous earth. The filtrate was washed with water and brine and dried over Na2SO4. Filtration and evaporation of solvent provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[N:23]([CH:10]([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in dimethylformamide (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120° C. for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2×100 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to 2% ethyl acetate in hexane give the title compound.