Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(CN)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added. and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 162 mg. To a solution of tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3,4-di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3,4-Di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 54 mg; 13C-NMR (CD3OD, rotamers): δ 25.9, 27.3, 40.0, 40.1, 43.5, 43.8, 44.1, 51.4, 53.5, 54.6, 55.4, 110.2, 111.0, 111.9, 112.2, 114.0, 114.2, 118.6, 119.4, 127.1, 127.4, 129.9, 130.0, 130.5, 132.1, 148.2, 148.7, 149.2, 149.7, 158.98, 159.05, 173.3, 173.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[C:16]([C:17](=[O:19])[CH3:18])[C:13](=[O:15])[CH3:14]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Product: COc1ccc(C=C(C(C)=O)C(C)=O)cc1OC
Reaction time: 8 h

Procedure:
3-(3,4-dimethoxybenzylidene)-2,4-pentanedione (hereinafter “Compound 2”) was prepared by the condensation of 3,4-dimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of Compound 2 is about 67% with a purity, as determined by GC, of about 99.5%. Compound 2 is an off-white free-flowing powder having a melting point of 104-108° C. with a λmax at 335 nm.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:20][C:21]([C:23]2[NH:32][C:26]3=[CH:27][N:28]=[C:29]([Cl:31])[CH:30]=[C:25]3[CH:24]=2)=[O:22])[C:9]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)OCC[O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CC(C)=O>[CH2:7]([C@H:8]([NH:20][C:21]([C:23]1[NH:32][C:26]2=[CH:27][N:28]=[C:29]([Cl:31])[CH:30]=[C:25]2[CH:24]=1)=[O:22])[C:9](=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C1(c2ccccc2)OCCO1)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)c1ccccc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-phenyl-1-(S)-(2-phenyl-[1,3]dioxolan-2-yl)ethyl]amide (Preparation 96, 47 mg, 0.105 mmol) in acetone (20 mL) was added aqueous hydrochloric acid (1 mL, 1M). After stirring under reflux for 3 days the solvent was removed in vacuo. The residue was distributed between ethyl acetate (100 mL) and saturated sodium carbonate solution (50 mL). After separation the organic layer was washed with brine (50 ml), dried (MgSO4) and concentrated to a residue which was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate: 50/50) to give the title compound as colourless solid. m/z (ES+)=404.21 [M+H]+; RT=3.58 min.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2[CH:25]=[C:24]3[C@@:12]([CH3:35])([C@@H:13]4[C@@H:21]([CH2:22][CH2:23]3)[C@:20]3([OH:26])[C@@:16]([CH3:34])([C@@H:17]([C:27]5[CH:33]=[CH:32][C:30](=[O:31])[O:29][CH:28]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[C@H](O)[C@H](O)[C@H]1O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:35][C@@:12]12[C@H:13]3[CH2:14][CH2:15][C@:16]4([CH3:34])[C@@H:17]([C:27]5[CH:33]=[CH:32][C:30](=[O:31])[O:29][CH:28]=5)[CH2:18][CH2:19][C@:20]4([OH:26])[C@@H:21]3[CH2:22][CH2:23][C:24]1=[CH:25][C@@H:9]([OH:8])[CH2:10][CH2:11]2
Reactant: C[C@@H]1O[C@@H](O[C@@H]2C=C3CC[C@@H]4[C@H](CC[C@]5(C)[C@@H](c6ccc(=O)oc6)CC[C@]45O)[C@@]3(C)CC2)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 87.5 %

Procedure:
Proscillaridin (3 g, 5.6 mmol) was dissolved in ethanol (57 ml) at 40° C. while stirring, to this solution was added 171 ml of sodium acetate buffer (pH=4, 0.02 M) at 40° C., followed by naringinase (1.03 g). The reaction was stirred for 24 hours, when ethanol was added (200 ml) and the solvent was removed in vacuo, an additional 100 ml ethanol was added and the solvent was removed in vacuo. Material was purified by flash chromatography (DCM to 9:1 DCM:MeOH) to give 9 as an off-white solid (1.9 g, 4.9 mmol, 90%). 1H-NMR (CDCl3, 300 MHz): 7.89 (dd, J=9.7, 2.6 Hz, 1H), 7.26 (dd, J=2.6, 0.9 Hz, 1H), 6.27 (dd, J=9.7, 0.9, 1H), 5.31 (s, 1H), 4.31 (m, 1H), 2.47 (dd, J=9.3, 6.2 Hz, 1H), 2.25-0.98 (m, 19H), 1.04 (s, 3H), 0.73 (s, 3H) 13C-NMR (CDC13, 75 MHz): 163.28, 148.77, 147.59, 146.42, 123.90, 123.35, 115.22, 85.01, 67.65, 51.20, 50.38, 48.46, 42.65, 40.82, 37.58, 35.71, 32.65, 32.36, 29.17, 28.89, 28.76, 21.43, 19.10, 16.69.
Reaction SMILES: Cl.FC1C=CC=C(F)C=1C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=O.[O:36]=[C:37]1[C:42]([C:43]([OH:45])=O)=[CH:41][CH:40]=[CH:39][N:38]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:43]([C:42]2[C:37](=[O:36])[N:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:39]=[CH:40][CH:41]=2)=[O:45])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:23][C:16]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1cccn(-c2ccccc2)c1=O

Procedure:
Prepared in a similar manner as Example 239 using 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (Compound E of Example 237) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid. 1H NMR (DMSO-d6) δ 12.87 (s, 1H), 12.18 (s, 1H), 9.39 (s, 1H), 8.70–8.85 (m, 2H), 8.60 (d, 1H, J=7.1 Hz), 8.00–8.25 (m, 3H), 7.94 (s, 1H), 7.30–7.75 (m, 8H), 6.77 (t, 1H, J=6.6 Hz), 6.45 (d, 1H, J=4.6 Hz), 4.21 (s, 2H), 3.68 (s, 2H), 2.43 (s, 6H); LC/MS(ESI+) m/z 518 (M+H)+.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[CH3:32].[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[CH3:32])=[CH:41]/[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C/c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C
Yield: 75 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.20 g, 1.7 inmol) was added to a solution of rac.-N-[4-[[(3-hydroxybenzyl)anlino]carbonyl]-2-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 140; 0.40 g, 0.9 mmol) and benzaldehyde (0.10 g, 0.9 mmol) in dichloromethane (50 mL) at room temperature and the reaction was stirred at ambient temperature over the weekend. The solution was diluted with dichloromethane (200 mL) and washed in turn with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4) and evaporated to give (Z)-2-[[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]amino]-3-phenylpropenoic acid methyl ester (300 mg, 78% yield) which was used directly in a subsequent step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1>>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:4][C:5]([Cl:9])=[CH:6][C:7]=2[CH3:8])=[O:24]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Product: COC(=O)c1c(C2CC2)nc2c(C)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-5-chloro-3-methyl-phenyl)-phenyl-methanone and methyl 3-cyclopropyl-3-oxopropanoate. Off-white solid. MS (ESI): 352.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH3:15][C:16]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:17]=1[O:18][CH2:19][CH2:20][NH2:21]>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:21][CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:16]=2[CH3:15])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Reactant: Cc1ccc(OCCN)c(C)c1
Product: CCOC(=O)c1c(NCCOc2ccc(C)cc2C)cc(C)nc1C

Procedure:
was synthesized analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 2-(2,4-dimethylphenoxy)ethylamine.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:7]2=[N:6][C:5]=1[CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:7]5=[N:6][C:5]=4[CH3:16])[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2c(C)cccn2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 47.6 %

Procedure:
A mixture of 4.8 parts of 3-(2-bromoethyl)-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 3.9 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 10 parts of sodium carbonate, a few crystals of potassium iodide and 144 parts of 4-methyl-2-pentanone was stirred overnight at room temperature. After cooling, the reaction mixture was poured into water. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile, yielding 3 parts (47.6%) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]-pyrimidin-4-one; mp. 199.9° C. (comp. 1).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[N:30]([CH2:33][CH2:34][S:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[CH:42][S:41][C:40]=12)=[N+:31]=[N-:32].[Cl-].[NH4+]>C1COCC1>[N:30]([CH2:33][CH2:34][S:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[C:42]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:41][C:40]=12)=[N+:31]=[N-:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [N-]=[N+]=NCCSc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCN=[N+]=[N-])c2s1

Procedure:
Tri-n-butylstannyl chloride (3.53 ml) and 12.34 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added to a solution of 2.32 g of 7-(2-azidoethyl)thioimidazo[5,1-b]thiazole in 75 ml of THF at −65° C. under an argon atmosphere. The temperature of the mixture was raised to −30° C. over a period of 2 hr, during which time a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (1.0 ml) was added to the mixture four times. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to prepare 4.62 g of the title compound.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[C:18]3[CH2:17]2)=[O:15])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]([I:1])=[C:18]3[CH2:17]2)=[O:15])=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
N-iodosuccinimide (70 mg, 0.31 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.1 g, 0.28 mmol) in chloroform (1 mL). The mixture was stirred at 65° C. for 1 hour. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.13 g, 96% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CC(C)C(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methylpropanimidamide (Monatsh.Chem.; 113; 1982; 781-792) (174 mg, 1.70 mmol) was then added and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 18 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([N:21]=[N+]=[N-])[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:24])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N=[N+]=[N-])ccc2F)COC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N)ccc2F)COC1

Procedure:
A solution of [5-(5-azido-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (2.18 g, 6.24 mmol) in EtOAc:EtOH 1:1 (150 ml) was hydrogenated over 10% Pd/C (0.21 g) and Lindlar catalyst (0.21 g) with 0.1 bar H2 for 4.5 h at rt. The reaction mixture was filtered through celite and concentrated to leave the title compound that was used in the next step without further purification.
Reaction SMILES: C12CC(CC1)CCO2.[CH3:9][C:10]1[CH2:14][C:13](C(OCC)=O)([C:15]([O:17]CC)=[O:16])[CH2:12][CH:11]=1>>[CH3:9][C:10]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH:11]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(C)C1
Agent: C1CC2CCC(C2)O1
Product: CC1=CCC(C(=O)O)C1

Procedure:
When m is 1, n is 2 and p is 1, the ring system is a 2-oxabicyclo[3.2.1]octane, another subclass of this invention. For example, compound XIIp ##STR27## in which R2, R5 and R6 are methyl, can be prepared by saponification and decarboxylation of diethyl 1-methylcyclopent-1-ene-4,4-dicarboxylate, prepared by the procedure of E. E. Schweiger and G. J. O'Neill, J. Org. Chem., 30, 2082 (1965), to provide 1-methylcyclopent-1-ene-4-carboxylic acid. The resulting carboxylic acid is homologated in the manner proscribed for the compounds XIp, and subsequently treated similarly to the acid of subclass IX.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1Cl
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
245.0 g of 1A was mixed with 1.6 liters of glacial acetic acid, and the resulting solution was stirred at 8°-10° C. while 109.6 g of 90% aqueous nitric acid was added (two hours). The mixture was stirred at 10°-15° C. for five hours, poured over ice water and extracted with ether/hexane. The extract was washed with water, dried and stripped to dryness. The residue was stirred with 3 liters of hexane and the hexane solution was filtered through silica gel. The filtrate was held at -20° C. for 16 hours, filtered, and the filtrate was concentrated to one liter, charcoaled, then held at -30° to -35° C. for two hours and filtered, to give 3-chloro-4-methyl-6-nitrophenol (1B).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[C@@H:7]([C:33](=[O:43])[NH:34][O:35]CC2C=CC=CC=2)[CH2:6]1.C1CN([P+](ON2N=[N:69][C:64]3C=[CH:66][CH:67]=[CH:68][C:63]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.C(ON)C1C=CC=CC=1.CN1CCOCC1>CN(C=O)C>[OH:35][NH:34][C:33]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3](=[O:2])[N:69]2[CH2:66][CH2:67][CH2:68][CH2:63][CH2:64]2)[CH2:10][CH2:9][C@@H:8]1[C:11]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:31])[CH:22]=2)=[CH:17][CH:18]=1)=[O:32])=[O:43]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COC(=O)CC1CC[C@H](C(=O)Nc2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NOCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 93 %

Procedure:
Part 8: [3-(S)-Benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl]-acetic acid methyl ester. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: 5-methoxycarbonylmethyl-2-(S)-[4-(2-methylquinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexane-(S)-carboxylic acid (212 mg, 0.43 mmol), anhydrous DMF (3 mL), PyBOP reagent (320 mg, 0.61 mmol), O-benzylhydroxylamine hydrochloride (100 mg, 0.627 mmol), and 4-methyl morpholine (0.160 mL, 1.47 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 15% methanol in methylene chloride over 30 min) to afford 238 mg (93%) of the pure amide. LCMS (ESI): 596 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:8]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]2=[O:25])#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[C:2][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[CH:12][CH:11]=3)[C:6](=[O:25])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: C#Cc1ccc2c(c1)c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#Cc3ccnc(C(F)(F)F)c3)cc2c1=O
Yield: 45.1 %

Procedure:
Compound R (20 mg, 0.06 mmol), 4-bromo-2-(trifluoromethyl)pyridine (16.2 mg, 0.07 mmol), CuI (1.1 mg, 0.006 mmol), triethylamine (25 μL, 0.18 mmol), PdCl2(PPh3)2 (2.7 mg, 0.003 mmol), and DMF (600 μL) were added to a small microwave vial. The vial was capped and placed in microwave reactor at 150° C. for fifteen minutes. The reaction was filtered over Celite®, washed very well with a 5% MeOH in DCM solution and concentrated to dryness. Purification by reverse phase HPLC afforded 13 mg (45%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=4.96 Hz, 1H), 8.52-8.5 (m, 2H), 8.17 (s, 1H), 7.93 (d, J=5.04 Hz, 1H), 7.87 (dd, J=8.8 Hz, 1H), 7.81-7.77 (m, 2H), 7.55 (t, J=8.64, 8.68 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 4.24 (q, J=7.04, 7.08 Hz, 2H), 1.28 (t, J=7.12, 7.08 Hz, 3H); ES-MS [M+1]+: 481.2.