Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@@H:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[C@@H:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (1.5 mL) was added oxalyl chloride (0.050 mL, 0.58 mmol) and DMF (1 drop). After 20 min at room temperature, the mixture was concentrated in vacuo and the residue was added to another flask containing 1-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.050 mL, 0.35 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 20 min, quenched with saturated aqueous NaHCO3 solution (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-6% MeOH/EtOAc) to afford the titled compound (0.022 g, 32%, TFA salt) as a white solid. 1H NMR (free form) (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.44 (m, 4H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.37 (d, J=1.2 Hz, 1H), 5.21 (q, J=7.2 Hz, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 2.86 (dd, J=6.4, 6.4 Hz, 2H), 2.46 (s, 3H), 1.72 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C20H19ClF3N5O [M+H]+ (free form) 438.1, found 438.1; The titled compounds were analyzed by chiral normal phase chromatography (RegisPack, 25 cm×4.6 mm, 5 micron, cat#793104, 0.1% DEA/IPA, 0.7 mL/min). The (S)-enantiomer (major) had a retention time of 8.4 min and the (R)-enantiomer (minor) had a retention time of 6.4 min (isolated in 18:1 er).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:19]=[C:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>ClCCl.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][C:20]1([CH3:19])[CH2:24][CH2:23][CH2:22][CH2:21]1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: C=C1CCCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](COC1(C)CCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
N-CBZ-L-serine methyl ester (3.15 g) was dissolved in 40 ml of dichloromethane at 0° C. under argon. Methylenecyclopentane (20 ml) was added, followed by 16 drops of concentrated sulfuric acid. The contents of the vessel were stirred at room temperature overnight then poured into dilute aqueous sodium hydrogen carbonate and extracted with chlorofrom (2×30 ml). The organic layer was dried over sodium sulfate and evaporated. The residual oil was chromatographed on silica gel with 50/50 petroleum ether/diethyl ether to give an oil (78% yield). The product, N-CBZ-O-(1-methylycyclopentyl)-L-serine methyl ester, was confirmed by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][C:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:29])=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2F)n1
Reactant: O=C(Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Temperature: 50 °C

Procedure:
150 mg (0.675 mmol) of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid were dissolved in 5 ml of THF. 440 mg (1.35 mmol) of cesium carbonate and 90.2 mg (0.675 mmol) of pyrrolidine-1-carbonyl chloride were added and the mixture was heated to 50° C. for 4 h. Then the mixture was filtrated and the filtrate containing the title compound directly used in the next step.
Reaction SMILES: N.[CH2:2]([P:4]([CH2:7][CH2:8][C:9]#[N:10])(=[O:6])[OH:5])[CH3:3].[H][H].[OH-].[Na+].S(=O)(=O)(O)O>O.[Ni].C(O)C>[CH2:2]([P:4]([CH2:7][CH2:8][CH2:9][NH2:10])(=[O:5])[OH:6])[CH3:3]
Reactant: [H][H]
Reactant: CCP(=O)(O)CCC#N
Agent: [Ni]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCP(=O)(O)CCCN
Yield: 66.9 %

Procedure:
In a glass autoclave, 240 g of ethanol, 68 g of ammonia, 52 g of water, 6.4 g of Raney® nickel (doped with 1.5% by weight of chromium), 54.4 g (0.37 mol) of ethyl-(2-cyanoethyl)phosphinic acid (produced as in Example 5) are reacted at 70° C. with hydrogen at 25 bar. Following a reaction time of 8 hours, the autoclave was let down, the reaction solution was filtered and the filtrate was concentrated in vacuo. The residue obtained is taken up in 150 g of water admixed with about 30 g (0.37 mol) of 50% sodium hydroxide solution and neutralized by addition of about 18.1 g (0.19 mol) of concentrated sulfuric acid, and thereafter the water is distilled off in vacuo. The residue is taken up in ethanol and filtered. The solvent of the filtrate is removed. The product is purified by chromatography to obtain 37.4 g (67% of theory) of ethyl(3-aminopropyl)phosphinic acid as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH:22]=[C:21]([CH2:23]O)[CH:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:23][C:21]2[CH:20]=[N:19][N:18]([C:14]3[CH:13]=[C:12]([C:10]4[CH2:9][C:8](=[O:25])[NH:7][C:6]5[CH:26]=[C:27]([C:28]([F:30])([F:31])[F:29])[C:3]([N:2]([CH3:1])[CH3:32])=[CH:4][C:5]=5[N:11]=4)[CH:17]=[CH:16][CH:15]=3)[CH:22]=2)[CH2:39][CH2:38]1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CNC4CC4)cn3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(4-hydroxymethyl-pyrazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 68) (133 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: ClC1=CCCN1C1=NCCC1
Reactant: Clc1ccc2c(c1)Oc1ccccc1N2
Agent: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 3-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-270° C. (dec.) (corr.), from ethanol-ether.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reaction time: 4 h

Procedure:
To a solution of the compound (7.82 g), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added dropwise under ice cooling, followed by stirring for 4 hours. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was washed with hexane-ether and the solvent was distilled off, whereby 1.00 g of the title compound was obtained. The product was provided for use in the subsequent reaction without purification.
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13](N)[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(#N)C.O.N([O-])=O.[Na+]>C(O)(=O)C>[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH:14]=[CH:13][C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O[C@@H]1[C@@H](CO)C=C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a well stirred solution of (−)-(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (6) (10.0 g, 25.5 mmol) in mixture of acetonitrile/water (1:1) was added sodium nitrite (8.8 g, 127.8 mmol) by portion wise at 0° C. After 15 minutes 50% aqueous acetic acid solution was added drop wise over a period of 0.5 hr and the mixture was vigorously stirred for 2 hr. The organic solvent was removed under reduced pressure and the rest of mixture was quenched with water. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash silica gel column chromatography (20% EtOAc/hexane) to give compound 7. [α]24D −156° (c 1.0, CHCl3); 1H NMR (500 MHz, DMSO-d6): δ 8.05 (m, 2H), 7.89 (m, 2H), 7.52 (m, 2H), 7.38 (m, 2H), 7.28 (m, 2H), 6.11 (m, 3H), 5.54 (m, 1H), 3.87-3.82 (m, 2H), 3.27 (m, 1H), 2.29 (m, 1H). HR-MS Calcd. For (C25H29NO7+H)+ 339.1154, found 339.1286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-chlorophenyl)propionic acid (2.45 g, 13.27 mmol) in toluene (65 mL) and methanol (10 mL) was added trimethylsilyldiazomethane (2M solution in hexane, 7.63 mL, 15.26 mmol). The mixture was allowed to stir for 1 hour and gas evolution was observed initially. After 1 hour, the mixture became homogeneous and was quenched via addition of 3.5 mL of acetic acid. The mixture was concentrated in vacuo, and purified via column chromatography on a Biotage 65i column eluting with 0% ethyl acetate in hexanes (1 CV) followed by a gradient to 50% ethyl acetate in hexanes (over 7 CV) to furnish the desired product. 1H NMR (CDCl3, 500 MHz) δ 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 2.92 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@@H:12]([CH3:14])[C@@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@@H:11]12
Reactant: COc1ccc(CN2C[C@@H](C)[C@@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNC[C@H]2NC(=O)O[C@@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7R,7aS)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7R,7aS)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+) at 0.16 min.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][C:6]1[C:7](=[O:17])[NH:8][C:9]([CH2:13][O:14][CH2:15][CH3:16])=[N:10][C:11]=1[NH2:12].C>O>[CH2:15]([O:14][CH2:13][C:9]1[NH:8][C:7](=[O:17])[C:6]2[C:11](=[N:12][CH:1]=[CH:3][N:5]=2)[N:10]=1)[CH3:16]
Reactant: CCOCc1nc(N)c(N)c(=O)[nH]1
Reactant: O=CC=O
Agent: C
Solvent: O
Product: CCOCc1nc2nccnc2c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
3.5 g (0.024 mole) of a 40% aqueous solution of glyoxal are added to a suspension of 3.7 g (0.020 mole) of 5,6-diamino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 30 ml of water. The mixture is brought gradually to reflux and kept refluxing for 1 hour. After the addition of Norit, refluxing is continued for a further 10 minutes and the reaction mixture is then filtered. The aqueous solution obtained is extracted with dichloromethane. These organic extracts are treated as in section c of Example 25. Yld: 2.5 g (61%), m.p. 168°-169° C. The product is identical to that obtained in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH:20](I)[CH2:19][C:9]21[CH2:18][CH2:17][C:12]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C2(CCC(=O)CC2)OCC1>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:21][CH2:20][CH2:19][C:9]21[CH2:18][CH2:17][C:12]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: IC1CN(Cc2ccccc2)C2(CCC3(CC2)OCCO3)C1
Agent: [Pd+2]
Agent: O=C1CCC2(CC1)OCCO2
Agent: [OH-]
Solvent: CO
Product: c1ccc(CN2CCCC23CCC2(CC3)OCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 669 mg (1.62 mmol) of 9-benzyl-11-iodo-1,4-dioxa-9-aza-dispiro[4.2.4.2]tetradecane (prepared starting from 1,4-dioxa-spiro[4.5]decan-8-one according to the procedure published in J. Bonjoch et al., Tetrahedron Lett. 2003, 44, 8387) in methanol (30 mL) was treated with 50 mg of 20% palladium hydroxide on activated carbon and the mixture was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give crude 9-benzyl-1,4-dioxa-9-aza-dispiro[4.2.4.2]tetradecane, which was directly dissolved in a 1:1 mixture of acetone and 6N aqueous hydrochloric acid (10 mL) and stirred at room temperature. After the reaction went to completion, the mixture was poured onto a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organics were washed with brine and water, dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography (SiO2, 0%→100% ethylacetate in heptane) gave 180 mg (0.74 mmol) of 1-benzyl-1-aza-spiro[4.5]decan-8-one, which was dissolved in ethanol (10 mL) and cooled to 0° C. Then, sodium borohydride (14 mg, 0.37 mmol, 0.5 eq.) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h before being concentrated and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The mixture was stirred vigorously for 15 min, before the phases were separated and the aqueous phase was extracted three times with dichloromethane and twice with a mixture of dichloromethane and 2-propanol (3:1). The combined organic phases were concentrated in vacuo to give crude trans-1-benzyl-1-aza-spiro[4.5]decan-8-ol. The alcohol was dissolved in ethanol (4 mL) containing acetic acid (15 μL) and was treated with 15 mg of palladium on charcoal (10%). The mixture was stirred under a hydrogen atmosphere (1 atm) until conversion was complete. The catalyst was filtered off and the reaction mixture was evaporated to dryness, then lyophilized from 1N HCl and water, successively, to give the crude title compound as its hydrochloride. Rt=0.17 min (Method 3). Detected mass: 156.2 (M+H+).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:22]3[C:17]([CH2:18][O:19][CH2:20][CH2:21]3)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Li])CCC.IC>CCCCCC>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:22]3[C:17]([CH:18]([CH3:23])[O:19][CH2:20][CH2:21]3)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2nccc(-c3cnc4n3CCOC4)n2)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Product: CC1OCCn2c(-c3ccnc(Nc4ccccc4)n3)cnc21
Yield: 39 %

Procedure:
By an analogous process to Example 10, 2-Anilino-4-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyrimidine (Example 5; 163 mg, 0.556 mmol) was treated with n-butyllithium (0.73 ml of a 1.6M solution in hexane, 1.168 mmol) and iodomethane (36 μl, 0.583 mmol) to give the title compound (67 mg, 39%) as a pale yellow solid. NMR: 1.5 (d, 3H), 3.9 (m, 1H), 4.18 (m, 1H), 4.32 (m, 1H), 4.63 (m, 1H), 4.87 (q, 1H), 6.95 (t, 1H), 7.13 (d, 1H), 7.3 (t, 2H), 7.67 (d, 2H), 7.75 (s, 1H), 8.37 (d, 1H), 9.4 (s, 1H); m/z 308.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cc(Cn3cc([N+](=O)[O-])cn3)cs2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cc(Cn3cc(N)cn3)cs2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-ylmethyl]-4-nitro-1H-pyrazole (220 mg, 0.75 mmol), iron powder (126 mg, 2.24 mmol) and NH4Cl (201 mg, 3.73 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (25 mL) was added followed by 1M NaOH (25 mL). The aq. layer was extracted with CH2Cl2 (2×25 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a red oil. LC-MS-conditions 02: tR=0.63 min; [M+H]+=266.09.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][OH:12])[CH2:6][CH2:5]2.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:12]/[N:11]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([C:19]1[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=1)[C:13]#[N:14])[CH:3]=2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: ON=C1CCc2cc(Br)ccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)CC/C3=N\O)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
To a stirred solution of 5-bromoindan-1-one oxime (0.25 g, 1.10 mmol) in glyme (11 mL) was added 3-cyanophenyl boronic acid (0.21 g, 1.44 mmol), sodium carbonate (0.35 g, 3.30 mmol) dissolved in deionized (D.I.) water (2 mL), and tetrakis(triphenylphosphine) palladium (0) (0.06 g, 0.05 mmol). The resulting solution was heated to reflux for 2 hours. The solution was cooled to room temperature and partitioned between ammonium chloride solution (sat.) and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate/hexane) and triturated with ether to give 3-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile as a white solid (0.12 g, 43%). MS (ESI) m/z 249; HRMS: calcd for C16H12N2O+H+, 249.10224; found (ESI, [M+H]+), 249.1033.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[C:20](O)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].C1COCC1.C(Cl)CCl>C(OCC)C.CCCCCC>[F:14][C:15]1[C:20]([O:12][C:1](=[O:13])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An oven dried single necked round bottom flask was charged with 15.0 g quinaldic acid (86.6 mmol), 20.8 g pentafluorophenol (113 mmol), and 200 mL THF. The suspension was stirred, and 18.3 g EDC (95.3 mmol) was added in one portion. Vigorous stirring was continued at room temperature for two hours, during which time a gummy precipitate formed at the bottom of the flask. The solution was decanted from the gum, and the gum was washed with CH2C12. The combined organic layers were diluted with hexane and washed once with 50 mL 0.1N NaHSO4, twice with 50 mL 1N K2CO3, and once with 50 mL brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, affording a pale pink solid. The solid was dissolved in 30 mL hot diethyl ether and 400 mL hot hexane was added. The solution was allowed to cool to room temperature, and then to 0° C. over a period af 1.5 hours. The desired product was collected as colorless needles (21.6 g, 73%) by filtration.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]#[N:12])=[O:4].[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[CH:13]1([NH:18][CH2:2][C:3]([N:5]2[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]2[C:11]#[N:12])=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCCC1
Solvent: CC#N
Product: C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Reaction time: 8 h

Procedure:
(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carbonitrile (50 mg, 0.30 mmol) and cyclopentylamine (0.059 mL, 0.6 mmol) were dissolved in acetonitrile (2 mL) and stirred overnight. The product was purified by reverse phase HPLC eluting with 0% to 70% acetonitrile/0.1% aqueous trifluoroacetic acid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.36 (d, J=6.44 Hz, 3H), 1.68 (m, 5H), 1.85 (m, 3H), 2.16 (m, 3H), 2.38 (m, 3H), 3.60 (m, 1H), 4.20 (m, 1H), 4.77 (m, 1H). MS (ESI) m/z 236 (M+H)+.