Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[C:18]([N:26]=[C:27]=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:26]1[C:27](=[O:28])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:12])[S:10]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: S=C=NCc1ccccc1
Agent: Cl
Agent: [K+]
Product: O=C(c1ccccc1)n1sc(=O)n(Cc2ccccc2)c1=O

Procedure:
Reagents: Benzyl isothiocyanate (0.86 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), benzoyl isocyanate (0.81 ml, 6.5 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH2:5][CH:4]([NH2:9])[CH2:3]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>C(O)(C)C.C(#N)C>[Cl:10][C:11]1[N:16]=[C:15]([NH:8][CH:6]2[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([NH2:9])[CH2:5]2)[C:14]([F:18])=[CH:13][N:12]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC1CC(N)CC(N)C1
Solvent: CC(C)O
Solvent: CC#N
Product: CC1CC(N)CC(Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylcyclohexane-1,3-diamine, 76a, (2.2 g, 17.2 mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added 2,4-dichloro-5-fluoropyrimidine (1.4 g, 8.6 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified on silica gel eluted with 1-20% methanol/dichloromethane, to give 0.6 g of racemic N1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine: 1H NMR (300 MHz, MeOD) δ 7.85 (d, J=3.5 Hz, 1H), 4.07 (ddd, J=11.9, 7.9, 4.1 Hz, 1H), 3.54 (qd, J=11.3, 4.2 Hz, 1H), 2.82 (tt, J=11.4, 3.7 Hz, 1H), 2.16 (dd, J=15.0, 13.0 Hz, 1H), 1.89 (t, J=13.4 Hz, 2H), 1.50 (dd, J=76.0, 21.9 Hz, 2H), 1.10 (dt, J=17.9, 9.0 Hz, 1H), 0.99 (dd, J=8.5, 5.0 Hz, 3H), 0.81 (ddd, J=23.8, 12.0, 8.2 Hz, 1H); LCMS RT=1.24 (M+1) 259.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[NH4+:14].[OH-]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH2:14])=[N:7]2
Reactant: [NH4+]
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2cccc(Br)c2nc1Cl
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 5-bromo-2,3-dichloroquinoxaline (Leadgen Labs, Orange, Conn.; 2.00 g, 7.20 mmol) in 50 mL DMF at 0° C. was added NH4OH (30% NH3 in water; 18.68 ml, 144 mmol) dropwise via syringe. A thick solid formed. 2 mL DMF was added to promote stirring. The thick reaction was sealed and stirred for 2 h at RT. The reaction was diluted with 250 mL water and let stand overnight. In the morning, it was filtered and the solid was air dried, treated with silica gel and DCM, and concentrated in vacuo. The material was purified by silica gel chromatography using 0-50% EtOAc/hexane to separately provide 5-bromo-3-chloroquinoxalin-2-amine (0.510 g, 1.973 mmol, 27% yield) as a peach-colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69-7.76 (1H, m), 7.43-7.61 (4H, m). m/z (ESI, +ve) 259.9 (M+H)+ and 8-bromo-3-chloroquinoxalin-2-amine (0.78 g, 3.02 mmol, 42% yield) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (1H, dd, J=7.6, 1.4 Hz), 7.73-7.79 (1H, m), 7.61 (2H, br. s.), 7.30 (1H, t, J=7.9 Hz). m/z (ESI, +ve) 259.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH:20]=[O:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophene (1.06 g, 5.28 mmol) in 12 mL of THF at −78° C. is added n-BuLi (4.4 mL of a 1.6M solution in hexanes, 6.99 mmol). After 15 minutes, DMF (0.97 mL, 14 mmol) is added and the resulting solution is allowed to warm to 0° C. After 15 min, the solution diluted with EtOAc and quenched with saturated NaHCO3 solution. The organic solution is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product is purified by flash column chromatography eluting with a gradient of 10% Et2O/hexanes to 20% Et2O/hexanes to yield the title compound (0.89 g, 3.89 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ9.87 (s, 1H), 7.70 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 6.91 (d, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1F.C([Mg]Cl)(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:22](C)=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])([O-:16])=[O:15]
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: Fc1ccccc1I
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(C)[Mg]Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
2-Iodofluorobenzene (2.0 mL, 17 mmol) was dissolved in anhydrous THF (20 mL) under an argon atmosphere and cooled to −20° C. A solution of isopropyl magnesium chloride (8.5 mL, 17.0 mmol) was slowly added, and the solution was stirred for 20 min. 2-Nitro-5-methylbenzaldehyde (2.7 g, 16.5 mmol) in THF (20 mL) was then added, and the mixture was stirred for 20 min at −20° C. and then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic portion was collected, dried over MgSO4, filtered and evaporated in vacuo. This material was dissolved in anhydrous CH2Cl2 (80 mL). Silica gel (20.3 g) and pyridinium chlorochromate (5.4 g, 25 mmol) were then added and the suspension was stirred at room temperature for 3 h. The mixture was then filtered through silica gel. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 3:2) to provide the 2-nitro-benzophenone (3.7 g, 14 mmol). The benzophenone was dissolved in glacial acetic acid (50 mL), MeOH (50 mL) and deionized H2O (10 mL). Iron powder (<10 micron, 1.0 g) was added with vigorous stirring and the suspension heated to 60° C. After 20 min, additional iron powder (2.0 g) was added and the mixture was stirred at 60° C. for 3 h. After cooling, silica gel (12.5 g) was added and the volatile components were removed in vacuo. The resulting powder was suspended in EtOAc (100 mL) and carefully treated with 1N NaOH until basic to litmus. The suspension was filtered and the organic portion was separated, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 1:3) to provide 1af (3.1 g, 94%) MS m/z=230 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:20])=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=O)=[CH:4][CH:3]=1.[CH2:21]1COCC1.C[Mg]Cl>CC(=O)OCC>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:20])=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[CH2:21])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(=O)c3cc(Br)ccc3oc2c(F)c1F
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Product: C=C1c2cc(Br)ccc2Oc2c1cc(OC)c(F)c2F
Temperature: -10 °C

Procedure:
A solution of 7-bromo-3,4-difluoro-2-methoxy-9H-xanthen-9-one (8.25 g, 24.19 mmol) in THF (242 mL, 24.19 mmol) was cooled to −40° C. To the resulting slurry was added methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (24.19 mL, 72.6 mmol), leading to the formation of a slightly darker mixture. After slowly warming to −10° C. over the course of 30 min TLC showed the clean conversion to a slightly more polar product (1:1 EA in hexanes). The reaction was removed from the cold bath and quenched with saturated ammonium chloride (500 mL). This mixture was poured into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with 200 mL of 10% citric acid then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 7-bromo-3,4-difluoro-2-methoxy-9-methylene-9H-xanthene as a bright yellow solid that was used immediately. To a solution of iodine (8.98 g, 35.4 mmol) in 150 mL of THF at −25° C. was added silver cyanate (15.91 g, 106 mmol). The reaction was maintained at this temperature for 15 min at which time a solution of 7-bromo-3,4-difluoro-2-methoxy-9-methylene-9H-xanthene (12.0 g, 35.4 mmol) in 3 mL of THF was added. The reaction temperature rose to −15° C. during this addition. The reaction was maintained at −25° C. for 45 min at which time ammonia, 2.0 M solution in 2-propanol (106 mL, 212 mmol) was added. The reaction was allowed to warm to rt and was maintained at that temperature overnight. The reaction was filtered through a pad of celite, washing well with ethyl acetate. This solution was diluted with 10% sodium thiosulfate (1000 mL) and poured into a separatory funnel containing ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a light yellow foam. This solid was suspended in 100 mL of CH2Cl2 and 100 mL of ether was added. The slurry was filtered to provide 6.0 g of a light yellow solid. The filtrate was concentrated and purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-100% CH2Cl2 to 10:1 methanol in CH2Cl2 with 0.1% ammonium hydroxide) to provide 7′-bromo-3′,4′-difluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an orange solid (7.85 g).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:13]([OH:16])(=[O:15])[CH3:14]>C(#N)C.[Zn]>[C:13]([OH:16])(=[O:15])[CH3:14].[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Zinc dust (6.5 g) was added to a solution of 3,3-dibromo-7-azaoxindole (2.9 g) in acetic acid (20 ml) and acetonitrile (30 ml). The mixture was stirred for 2 hours at room temperature. The solids were removed by filtration and the solvent evaporated. The residue was treated with ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel. The collected ethyl acetate solution was evaporated and the residue dried under vacuum to give 1.8 g (91% yield) of 7-aza-2-oxindole acetic acid salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.C=O.N1CCC[C@H:26]1C(O)=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:26][CH:18]1[C:19](=[O:20])[O:21][C:14]([CH3:22])([CH3:13])[O:15][C:16]1=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: C=O
Solvent: CC#N
Product: CC1(C)OC(=O)C(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)C(=O)O1
Yield: 81.1 %

Procedure:
An adaption of the procedure of Flaugh1 was used. Thus, a solution of 5-nitroindole (50.0 g, 0.31 mol), Meldrum's acid (46.0 g, 0.32 mol), 37% aqueous formaldehyde (26.0 mL, 0.32 mol) and proline (1.8 g, 0,016 mol) in 200 mL of acetonitrile was stirred at room temperature for 18 h. The resulting thick yellow slurry was filtered and the filtercake was washed with acetonitrile, then acetone and finally with ether. This material was dried in vacuo to give the title compound (80.0 g, 81%) as a bright yellow solid, m.p. 182° C. (dec). The mother liquor was concentrated and then diluted with H2O, and the resulting solid was collected and washed and dried as before. This gave a second crop of the product (7.0 g) as a darker yellow solid. Total yield=87.0 g (89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4](Br)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[NH:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: NCCCO
Reactant: COC(=O)C(Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NCCCO)c1ccc(F)cc1
Temperature: 45 °C
Yield: 95 %

Procedure:
To a solution of bromo-(4-fluoro-phenyl)-acetic acid methyl ester (16.0 g) in chloroform (100 mL) was added potassium carbonate (17.9 g, finely ground) followed by 3-amino-1-propanol (4.87 g). The reaction was heated to 45° C. for 18 hours. The reaction was filtered and the filtrate was diluted with water and the phases were separated. The aqueous phase was further extracted with chloroform (3×25 mL) and the combined organics were washed with brine. The chloroform phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the desired (4-fluoro-phenyl)-(3-hydroxy-propylamino)-acetic acid methyl ester (14.85 g, MS (ES+): 242.2 (MH+)) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:27][CH2:28]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) was added di-tert-butyl {[4-(aminooxy)piperidin-1-yl]methylylidene}biscarbamate 65 (0.389 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 66 (0.33 g, 74%) as a white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[NH4+:16]>>[NH2:16]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: C/C(N)=C/C(=O)OCCC#N

Procedure:
Namely, 2-cyanoethyl acetoacetate (11) is reacted with an amine or ammonium acetate to obtain 2-cyanoethyl 3-aminocrotonate (35).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]3=[N:9][C:10]3[N:11]2CO[CH:16]=3)[C:3](=O)[CH:2]=1.N.[ClH:19].[C:20](=[O:37])([O:22]CC1NC2C=CC=C3C=2C(N=1)=CC=C3)[NH2:21]>C(COC)OC>[ClH:19].[NH:11]1[C:12]2=[C:13]3[C:4](=[CH:3][CH:2]=[CH:1]2)[CH:5]=[CH:6][CH:7]=[C:8]3[N:9]=[C:10]1[CH2:16][NH:21][C:20](=[O:22])[OH:37]
Reactant: NC(=O)OCC1=Nc2cccc3cccc(c23)N1
Reactant: O=c1ccc2n3c(nc4cccc1c4=2)=COC3
Agent: Cl
Agent: N
Solvent: COCCOC
Product: O=C(O)NCC1=Nc2cccc3cccc(c23)N1

Procedure:
A sample of 1H, 3H-oxazolo[3,4-a]perimidine-3-one is dissolved in dimethoxyethane and is treated with excess conc. ammonia. The separated solid, (2-perimidyl)methyl carbamate, is filtered, dissolved in ethanol and treated with hydrochloric acid to give the acid addition salt, (2-perimidyl)methyl carbamate hydrochloride, m.p. 240° (dec.).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3](OC(C)(C)C)=[O:4].[CH3:45][N:46](C)[C:47](Cl)=O>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([N:46]([CH3:47])[CH3:45])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 29, Step H in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Thus 1 part of triphenylcarbinol is reacted with 2 parts of malonic acid at 170° for three hours to provide 3,3,3-triphenylpropionic acid and this acid is converted into the acid chloride by reaction with thionyl chloride. Reacting the acid chloride with 2 parts of 2-azabicyclo[2.2.2]octane provides the amide, 2-(3,3,3-triphenylpropionyl)-2-azabicyclo[2.2.2]octane and reduction of this amide with 1 part of LiAlH4 in tetrahydrofuran provides 2-(3,3,3-triphenylpropyl)-2-azabicyclo[2.2.2]= octane. The addition of concentrated hydrochloric acid to an ethereal solution of above amine provides 2-(3,3,3-triphenyl propyl)-2-azabicyclo[2.2.2]octane hydrochloride, melting at 221°-223° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:14])[CH2:12][CH3:13].[CH2:15]=O.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[ClH:22]>C(O)(C)C.CC(C)=O>[ClH:22].[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:14])[CH:12]([CH3:15])[CH2:13][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNC1
Reactant: C=O
Reactant: CCC(=O)c1ccc(OC)c(C)c1C
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1ccc(C(=O)C(C)CN2CCCC2)c(C)c1C
Temperature: 0 °C

Procedure:
1-(2,3-Dimethyl-4-methoxyphenyl)-1-propanone (20.0 g), paraformaldehyde (6.2 g) and pyrrolidine (8.9 g) are combined in isopropanol (30 ml) and 35% ethanolic hydrogen chloride (16 ml) is added to adjust the solution to an acidic pH. The mixture is then stirred and heated at reflux for 20 hours. After cooling, acetone (300 ml) is added to the reaction mixture and the resulting solution is cooled in ice water. Crystalline product is filtered and recrystallized twice from ethanol (50 ml)-acetone (50 ml) to give the analytically pure title compound (10.0 g), m.p. 169°-172° C.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]2[N:26]=[C:25]3[N:17]([C:18](=[O:31])[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20]4[N:21]=[CH:22][NH:23][C:24]=43)[N:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]2[N:26]=[C:25]3[N:17]([C:18](=[O:31])[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:20]4[N:21]=[C:22]([Br:32])[NH:23][C:24]=43)[N:16]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c(=O)n2nc(CCc3nc(Cc4ccccc4)no3)nc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCn1c(=O)n2nc(CCc3nc(Cc4ccccc4)no3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-[2-(3-benzyl-1,2,4-oxadiazol-5-yl)ethyl]-4-butyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (40 mg, 0.096 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature overnight, the reaction was quenched with phenol. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method A) to give desired product as white powder. LCMS calculated for C21H22BrN8O2 (M+H): 497.1. found: 497.0, 499.0.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][O:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH:21]([CH3:34])[C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1.CCCCCC>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[O:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[C:21]=1[CH3:34]
Reactant: O=[N+]([O-])C=C1NCCO1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: 125 °C
Yield: 30.7 %

Procedure:
2-Nitromethylene-oxazolidine (3 g, 23.0 mmol) was added portion wise to a stirred solution of 2-methyl-malonic acid bis-(2,4,6-trichloro-phenyl) ester (12 g, 25.15 mmol) in Xylene (50 mL) under nitrogen atmosphere over a period of 1 hour at 125° C. The resulting mixture was heated to 125° C. for 5 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was concentrated and the concentrate was purified by column chromatography on silica gel (60% ethylacetate in hexane) to afford 1.5 g of the product (30% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[OH-].[Na+].[CH3:17][C:18](=[O:21])[CH:19]=[CH2:20].[ClH:22]>O.CC(C)=O>[Cl:22][CH:19]([CH2:20][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:18](=[O:21])[CH3:17]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cl
Reactant: C=CC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1

Procedure:
27.6 g of 4-nitroaniline are dissolved in 180 ml of 20% hydrochloric acid. The solution is cooled to 0°-5° C. and a solution of 12.7 g of sodium nitrite in 30 ml of water is then added slowly, with cooling. The pH is then raised to 3 with a 25% solution of sodium hydroxide, the temperature being kept at 5°-10° C. A solution of 4.7 g of CuCl2 in 25 ml of water is added, followed by a solution of 17.3 ml of but-3-en-2-one in 180 ml of acetone. The reaction mixture is allowed to return to room temperature. After one night, it is decanted and the organic phase is concentrated. The residue is taken up with water and extracted with chloroform. After drying, the filtrate is concentrated to give a red oil, which is purified by chromatography on a silica column (eluent: 50/50 chloroform/petroleum ether) to give 15.4 g of 3-Chloro-4 -(4-nitrophenyl)-butan-2-one in the form of an orange solid melting at 86° C.