Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@@H]1C[C@H](C(OC)=O)C=C1.[Cl-].[NH4+:22].N.CO>C(O)C>[NH4+:11].[NH4+:22].[C:8]([O-:10])(=[O:9])[CH:6]([CH:4]([C:1]([O-:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: COC(=O)[C@@H]1C=C[C@H](N)C1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 2 h

Procedure:
To a mixture of (1S,4R)-Methyl 4-aminocyclopent-2-ene-1-carboxylate L-tartrate (10 g, 34.3 mmol) and ammonium chloride (1.85 g, 34.3 mmol) in ethanol (79 g) was added a 2M solution of ammonia in methanol (17.2 mL, 34.4 mmol). The mixture was stirred for 2 h, resulting in precipitation of the tartaric acid di-ammonium salt. The solid was removed by filtration and the filtrate was concentrated to about 10 mL. The concentrated filtrate was diluted with methyl isobutyl ketone (MIK), resulting in precipitation of (1S,4R) Methyl-4-aminocyclopent-2-ene-1-carboxylate hydrochloride. The solid was collected by filtration and dried in a vacuum oven (100 mbar) at 50° C. for 24 h.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14]1([CH2:20][CH2:21]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:14]1([CH2:20][CH2:21][O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: OCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1

Procedure:
A solution of 1.80 g (10.0 mmol) of caffeic acid, 17.9 mL (150 mmol) of β-phenylethyl alcohol and 100 mg of p-toluenesulfonic acid in benzene (100 mL) were stirred overnight at reflux with a Dean Stark trap. Solvent and excess alcohol were removed by distillation and residue purified by silica gel chromatography (petroleum ether/CHCl3). Product was crystallized (ether/petroleum ether) to provide 67H-42-A as snow-white crystals, 1.0 g (35%): mp 128.0° C. 126°-128° C.) (Grunberger, D. et al., Experimentia, (1988) 44:230-2).
Reaction SMILES: C([O:3]C1C=CC=CC=1)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:3]
Reactant: CCOc1ccccc1
Reactant: COc1ccc(C)cc1
Product: COc1ccc(C)cc1O
Yield: 46.9 %

Procedure:
The reaction was carried out in the same manner as in Example 6 except that ethoxybenzene was replaced by 150 g. (1229.5 m.moles) of p-methoxytoluene and 4.11 g. (29.8 m.moles) of 2-methoxy-5-methylphenol was obtained in a yield of 46.9 %.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@@H:25]2[CH3:37])=[CH:19][N:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 135.5 %

Procedure:
A stirred solution of (S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (10.386 g, 15.79 mmol) in DCM (25.0 mL, 389 mmol) was cooled in an ice bath and slowly treated with TFA (25.0 mL, 324 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The sticky residue was taken up in DCM (100 mL) and cooled to −45° C. TEA (22.0 mL, 158 mmol) was then added via additional funnel, followed by slow addition of methanesulfonyl chloride (6.15 mL, 79 mmol) in DCM (20 mL). The heterogeneous mixture was stirred at −30° C. for 30 min and then quenched with water and NH4Cl(aq) (50 mL each). The organic layer was separated, and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated to give (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (13.6 g crude) as a pale-yellow foam, which was taken directly to the next step without further purification. m/z (ESI, +ve ion) 636 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:16][OH:17]>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(CCN2CCCC2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCN2CCCC2)CC1

Procedure:
1-(2-(1-pyrrolidinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(1-pyrrolidinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7])([O-])=O.[H][H].C(#N)C>C(O)C.[Pt]>[NH2:1][C:4]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: CC#N
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
In 10 ml of ethanol, 1 g (2.88 mmol) of 2-nitro-4,5,3',4'-tetramethoxybenzophenone (prepared according to Example 2) was hydrogenated on 100 mg of platinum/activated carbon (5 percent Pt, moist, H2O content 50 percent) at 40° C. and a hydrogen pressure of 2 bar. After 5 h, the reaction mixture was cooled to room temperature, and 10 ml of acetonitrile was added. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 0.88 g of 2-amino-4,5,3',4'-tetramethoxybenzophenone as a beige solid. The yield of the product was 96 percent of theory.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OCC)=[O:31])=[C:24]([F:35])[C:23]=3[F:36])=[C:18]([C:37]([F:40])([F:39])[F:38])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][OH:31])=[C:24]([F:35])[C:23]=3[F:36])=[C:18]([C:37]([F:38])([F:40])[F:39])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(F)(F)F)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.83 (t, J=7.8 Hz, 1H), 6.72 (t, J=7.5 Hz, 1H), 5.08 (s, 2H), 3.71 (q, J=7.0 Hz, 2H), 2.72 (m, 4H), 1.87 (m, J=9.5 Hz, 2H), 1.25 (t, J=9.1 Hz, 3H).
Reaction SMILES: CC[O-].[Na+].Cl.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](=[NH:11])[NH2:10].[C:17]([OH:25])(=[O:24])/[C:18](=[C:20](\[CH:22]=O)/[Br:21])/Br>CCO>[Br:21][C:20]1[C:18]([C:17]([OH:25])=[O:24])=[N:11][C:9]([C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[N:10][CH:22]=1
Reactant: N=C(N)c1c(F)cccc1F
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1nc(-c2c(F)cccc2F)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.68 M NaOEt in EtOH solution (3 eq) was added to an ice-bath cooled mixture of 2,6-difluorobenzimidamide hydrochloride (2 eq) in EtOH (0.1 M). The resulting mixture was allowed to warm to rt and stirred under N2 for 30 min. To the reaction mixture was added drop wise a solution of mucobromic acid (1 eq) in EtOH and the reaction was heated in a 50° C. oil bath for 2.5 hr. After cooling to rt the reaction mixture was concentrated in vacuo. H2O and 1.0 N NaOH were added and the aqueous mixture was washed with EtOAc. The aqueous phase was acidified to pH=4 with 1.0 N HCl then extracted with EtOAc. Combined organic extracts were washed once with brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-bromo-2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid. The crude product was used for the next step without further purification. LC/MS (m/z): 316.9 (MH+). LC: Rt: 2.426 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:43]=[O:44])C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10]([CH:43]=[O:44])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of THF (20 mL) was added N-[4-(4-amino-7-bromo-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea (230 mg, 0.430 mmol) which was cooled to −77° C. n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol) was slowly added to the solution via syringe. The solution was stirred for 10 min and then DMF (0.20 mL, 2.58 mmol) was added. The cooling bath was removed and the reaction was allowed to warm to ambient temperature over the following 17 h. EtOAc (20 mL) and water (20 mL) were added to the reaction which was then transferred to a separatory funnel. The organic layer was washed with aq 1 N NaOH (20 mL) followed by water (20 mL). The organic was isolated, dried (MgSO4), filtered, and concentrated to dryness yielding 207 mg (0.428 mmol, yield 99%) of product. 1H-NMR (DMSO-d6) δ 10.38 (s, 1H), 9.43 (s, 1H), 8.99 (d, J=2.7 Hz, 1H), 8.68 (br s, 1H), 8.61 (dd, J=6.8, 1.8 Hz, 1H), 8.27 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.52 (m, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.40 (m, 1H), 6.06 (br s, 1H); MS [M+H]+=484.1; LCMS RT=3.34.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([OH:10])=[O:9])[CH:2]2[C:11]([OH:13])=[O:12].[OH-].[Na+:15]>O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:15].[Na+:15]
Reactant: O=C(O)C1C2C=CC(C2)C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]

Procedure:
To a suspension of norborn-5-en-2,3-dicarboxylic acid (5.01 g, 27.5 mmole) in H2O (50 mL) was added 1N aq. NaOH (55 mL, 55.0 mmol) at rt and the reaction mixture was stirred until a homogeneous solution was obtained. The solvent was removed in vacuo and the resulting colorless, crystalline product was dried: 5.57 g (90%), mp=385C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C:24]([C:26]3[CH:36]=[CH:35][C:29]([C:30](OCC)=[O:31])=[CH:28][CH:27]=3)=[O:25])=[C:11]([C:37]3[CH2:41][CH2:40][CH2:39][CH:38]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@H:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:35][CH:36]=3)[OH:25])=[C:11]([C:37]3[CH2:41][CH2:40][CH2:39][CH:38]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)c2c(C(C)C)nc3c(c2C2=CCCC2)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCCC3)c1[C@@H](O)c1ccc(CO)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
410 mg (S)-ethyl 4-(5-(tert-butyldimethylsilyloxy)-4-cyclopentenyl-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbonyl)benzoate are dissolved in 5 ml tetrahydrofurane and treated dropwise with 1.5 ml of a 1 M solution of lithiumaluminium hydride in tetrahydrofurane. The mixture is stirred for 8 hours at room temperature, cooled to 0° C. and the reaction is quenched by careful addition of 130 μl water and 130 μl of 4 M aqueous sodium hydroxide. After diluting with ethylacetate the mixture is dried with magnesium sulphate and filtered. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 60:40).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[C:10]1[N:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>CN(C=O)C>[Br:16][C:13]1[CH:12]=[N:11][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[N:15][CH:14]=1
Reactant: OCC(F)(F)F
Reactant: Brc1cnc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
To sodium hydride (303 mg) under an argon atmosphere at 0° C. was added dropwise 2,2,2-trifluoroethanol (775 μl) and the mixture was then stirred at RT for 90 min. A solution of 2,5-dibromopyrimidine (1.5 g) in DMF (8 ml) was then added and stirring continued at RT for 2 hours. The reaction mixture was poured into ice (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to afford 5-bromo-2-(2,2,2-trifluoro-ethoxy)-pyrimidine (790 mg, 49%) as a yellow oil which was used in the next step without further purification. MS (EI): 258 ([{81Br}M]+), 256 ([{79Br}M]+), 189 ([{81Br}M−CF3]+), 187 ([{79Br}M−CF3]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Li]CCCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)=[C:3]([CH2:9][OH:10])[CH:4]=1
Reactant: OCc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2CO)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A solution of (2-bromo-5-chlorophenyl)methanol (1.48 g, 6.68 mmol) in anhydrous THF (30 mL) was cooled to −78° C. and treated with the dropwise addition of n-BuLi (1.6 M in hexanes) (8.77 mL, 14.03 mmol), and the mixture was stirred for 30 minutes at −78° C., during which a thick white precipitate was observed. The dianion was treated with the dropwise addition of a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.465 g, 7.35 mmol) in THF (10 mL), and the mixture was stirred for 1 hour at −78° C., during which a yellow homogeneous solution was observed, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride and the mixture was extracted 3× with ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was split into two equal fractions, and each was purified over a 40 g silica gel column via ISCO, eluting with a 10-100% EtOAc/Hexanes gradient over 15 minutes. The fractions from each run which contained the desired product were combined to yield the title compound (1.4 g, 4.10 mmol, 61.3% yield) as a colorless foam. MS (ESI+)=268, (M+H-tBuOH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH2:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: CCOc1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-ethoxy-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5]2)[O:3]C1.Cl>CCOCC>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 7 (7.44 g, 28.1 mmol) in ether (300 mL) was treated with 5% aqueous HCl (150 mL). The mixture was stirred at room temperature (5 d). The reaction was quenched with solid sodium bicarbonate. The aqueous layer was extracted with three additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (20% ethyl acetate/hexane) afforded the title compound (8).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccnc2)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of N,5-dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide (0.40 g, 1.4 mmol) in THF (10 ml) was added dropwise 1 M MeMgBr in THF (3.0 ml, 3.0 mmol) at −78° C. After stirring at −78° C. for 2 h, the mixture was quenched with water (0.5 ml) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 (25 ml) and brine. The aqueous layer was extracted with CHCl3 (25 ml×3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 62% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.97 (3H, s), 7.49-7.56 (1H, m), 7.95 (1H, s), 8.01-8.08 (1H, m), 8.72 (1H, dd, J=4.7, 1.3 Hz), 8.95 (1H, d, J=2.6 Hz).
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CO>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: CCCCN
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a microwave vial charged with [(2-bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (387 mg, 1.31 mmol) was added methanol (3 mL) and n-butylamine (520 uL, 5.24 mmol). The reaction temperature rose approximately 30° C. and everything went into solution. After 25 minutes, additional n-butylamine (260 uL, mg, 2.6 mmol) and triethyl amine (182 uL, 1.3 mmol) were added. The reaction was stirred at room temperature overnight and then concentrated to afford the title compound which was used without further purification (420 mg, 99%). 1H NMR (300.132 MHz, CDCl3) δ 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.5 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.8, 1.2 Hz, 1H), 7.01 (dt?ddd, J=6.1 Hz, J=8.0 Hz, J=1.5 Hz, 1H), 6.22 (bs, 1H), 3.40 (dt, J=5.9, 7.2 Hz, 2H), 1.65-1.35 (m, 4H), 0.96 (td, J=7.3, 1.9 Hz, 3H). MS APCI, m/z=323/325 (M+H). HPLC 2.94 min
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([N:13]([CH3:12])[C@H:14]2[CH2:33][N:18]3[C:19]4[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]3[CH2:16][CH2:15]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CC(=O)O
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: Cc1noc(C)c1CC(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (3,5-dimethylisoxazol-4-yl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 396.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:14]([OH:16])[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH2:24].C(Cl)CCl>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH:24][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:14]([OH:16])[CH3:15]
Reactant: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Yield: 100 %

Procedure:
To a solution of (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid (33.0 g, 148.7 mmol) in dichloromethane (300 mL) is added 2-tetrahydropyranyloxyamine (18.3 g, 156.1 mmol) and EDC (31.2 g, 163.5 mmol). The resulting solution is stirred at 23.degree. C. for 16 h. then diluted with dichloromethane (500 mL) and washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The reaction mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (47.8 g, 100% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](C(O)=O)[C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)C(C(=O)O)c1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)Cc1ccc2sccc2c1
Yield: 98.3 %

Procedure:
To xylene (2 mL) suspension of 0.10 g of 2-(1-benzothiophen-5-yl)malonic acid was added 4 mg of p-toluenesulfonic acid monohydrate, which was then refluxed for 1 hour. The solvent was distilled off under reduced pressure, and to the resultant residue was added cyclohexane. The precipitate was collected by filtration to provide 0.08 g of 2-(1-benzothiophen-5-yl)acetic acid as white solid form.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[F:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20]>CO>[F:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=1
Reactant: COC(CCn1cc(-c2ccncc2F)c(=O)[nH]c1=O)OC
Solvent: CO
Product: O=CCCn1cc(-c2ccncc2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(3-fluoro-pyridin-4-yl)-1H-pyrimidine-2,4-dione (Prep 68, 75 mg, 0.24 mmol) was dissolved in MeOH (2 ml) and 1N HClaq (500 μl) was added. The mixture was stirred at room temperature for 16 hours. MeOH was evaporated under vacuum and dioxane was added. After heating the mixture at 60° C. for 6 hours the solvents were evaporated to give the title compound that was used in the next step without further purification (63 mg, quantitative yield).