Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:5]([OH:17])[CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+]>C(Cl)Cl.C(O)C.O>[CH2:1]([N:3]1[CH2:4][C@@H:5]([OH:17])[C@H:6]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1C[C@@H](O)[C@H](NCCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](N(CCc2ccccc2)C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirring slurry of 3.5 g (0.15 mole) of trans-1-ethyl-4-[(2-phenylethyl)amino]-3-pyrrolidinol and 5 g potassium carbonate in 75 ml of methylene chloride at ice bath temperature was added dropwise a solution of 3.2 g (0.023 mole) of benzoyl chloride in 25 ml of methylene chloride. After addition was complete, the mixture was stirred at ambient temperature overnight. The mixture was filtered through Celite and the filtrate was concentrated to give a yellow gum as residue. An NMR analysis of this gum indicated that it was a mixture of desired amide and the di-substituted amide-ester. The gum was dissolved in 50 ml ethanol and a solution of 0.5 g (0.08 mole) potassium hydroxide in 10 ml of water was added. The mixture was heated at reflux for 3 hr. The solution was concentrated and water was added to the residue. The mixture was extracted with methylene chloride and the combined extracts were dried over anhydrous sodium sulfate and concentrated to give 4.9 g (98%) of gum as residue. The gum crystallized upon standing and the solid was recrystallized from cyclohexane to yield white solid, m.p. 71°-75° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19].C(NCC)C.[CH3:25][N:26]([CH:28]=O)[CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:18][C:15]1[CH:16]=[CH:17][N:12]=[C:13]([CH3:19])[CH:14]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(C=CN(C)C)ccn1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
n-Butyl lithium in hexane (1.6 M, 35 ml, 56 mmol) was added dropwise to a solution of 2,4-lutidine (5.0 g, 46 mmol) in tetrahydrofuran (50 ml) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, diethylamine (5.1 g, 69 mmol) was added to the mixture, and the mixture was stirred at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Furthermore, DMF (6.8 g, 93 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was combined with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (7.5 g, 99%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[C:36]2([CH3:43])[CH3:42]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[C:36]4([CH3:42])[CH3:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1C(=O)c2c(N)cccc2C1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4(C)C)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 148A). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.00 (br s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.38-7.45 (m, 1H), 7.32 (br s, 1H), 7.07-7.16 (m, 2H), 6.84 (s, 1H), 6.31 (br s, 1H), 3.91 (quin, J=7.3 Hz, 4H), 3.77 (s, 3H), 3.13 (s, 3H), 3.06 (d, J=21.2 Hz, 2H), 1.27 (s, 6H), 1.16 (t, J=7.1 Hz, 6H). MS (ES+): m/z 608.24 [MH+] HPLC: tR=1.31 min (UPLC, analytical).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23].O>CC(N(C)C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1-c1cnn(C)c1
Temperature: 150 °C
Reaction time: 12 h
Yield: 10.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (82.9 mg, 0.300 mmol) and (R)-2-amino-4-methylpentanamide (39.0 mg, 0.300 mmol) in DMA (2 mL) was stirred at 150° C. for 12 h. Water was subsequently added and the mixture was extracted with EtOAc. The organic layers were washed with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc) to give the title compound as a yellow oil (11.7 mg, 11%).
Reaction SMILES: [Na].Br[CH:3]([CH3:9])[C:4]([O:6]CC)=[O:5].O.[OH-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH3:14][CH:13]([O:16][CH:3]([CH3:9])[C:4]([OH:6])=[O:5])[CH3:15]
Reactant: CC(C)O
Reactant: CCOC(=O)C(C)Br
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(C)OC(C)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, addition funnel, condenser and nitrogen bubbler was charged with 250 milliliters of dry isopropyl alcohol. Sodium metal (7.1 grams, 0.31 mole) in small pieces was added and the solution was heated to reflux to complete the reaction. After cooling to 60° C., 54.3 grams (0.30 mole) of ethyl 2-bromopropionate in 50 milliliters of isopropanol was added dropwise over a 20 minute period, and then the solution was refluxed for 2 hours, and left standing overnight. One hundred fifty (150) milliliters of water and 13.0 grams of sodium hydroxide pellets were added and then the mixture was distilled at 90° C., then cooled in an ice bath and acidified to pH2 with concentrated hydrochloric acid. The oil phase which formed was extracted with 150 milliliters of dichloromethane, CH2Cl2, and the extract was dried over anhydrous magnesium sulfate, filtered and topped on a roto-vac at 70° C. to yield 27.8 grams of a pale yellow viscous liquid of 2-(1-methylethoxy)propanoic acid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.C(O)(=[O:24])C.OO.[OH2:28]>>[CH3:1][S:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([N+:12]([O-:14])=[O:13])=[C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1)(=[O:24])=[O:28]
Reactant: CSCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: CS(=O)(=O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 2.8 g. (0.009 mole) of 5-methylthiomethyl-2-nitro-3-phenylbenzofuran and 160 ml. of acetic acid is heated to 40° C., and 2.0 g. (0.018 mole) of hydrogen peroxide in 30 ml. of acetic acid is added dropwise as the temperature rises to 50° C. The solution is stirred for about six hours at 50° C. and for about 16 hours at 20° C., then poured into cold water. The precipitate is collected by filtration, rinsed with water and dissolved in dichloromethane. The solution is washed with water and saturated sodium chloride solution, then dried. Evaporation provides yellow solid which is recrystallized from a benzene-hexane mixture to give 5-methylsulfonylmethyl-2-nitro-3-phenylbenzofuran, m.p. 178°-181° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1COCC1.O.CC(OC)(C)C>[C:24]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:23])=[CH:5][CH:6]=3)(=[O:11])=[O:12])[CH:14]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1

Procedure:
Add to a 2 L 3-neck flask equipped with reflux condenser, thermometer and nitrogen inlet, 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (0.1 mol, 44.1 g), phenylboronic acid (0.12 mol, 22.35 g), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.0025 mol, 2.04 g), 2M sodium carbonate (140 ml) and 0.5 L THF. Heat the mixture to reflux under nitrogen for 2 hours. Remove THF under vacuum, and add MTBE (500 ml) and DI water (200 ml) to the residue. Filter the solution through a pad of Celite, and wash with MTBE (500 ml). Separate the organic layer and concentrate under vacuum to give a brown solid. Dissolve the solid in THF (250 ml). Add to this solution 5N NaOH (35 ml) dropwise over a 30 minute period. Stir the reaction at ambient temperature for 3 hours, and quench with DI water (250 ml) and MTBE (250 ml). Separate the water layer and back extract the organic layer with DI water (250 ml). Combine the aqueous layers and wash with MTBE (500 ml). Stir the aqueous layer at ambient temperature and adjust the pH is to 1 with concentrated HCl. Stir the slurry at ambient temperature for 2 hours, filter and wash with DI water (500 ml). Dry the off-white, gray solid in vacuum oven at 65° C. for 16 hours to obtain 25.44 g. 1H NMR (DMSO) 8.2 (d, 2H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (d, 2H), 7.4 (m, 5H). MS (ES−)=376.2 (M−1). Anal. Calcd. For C21H15NO4S: C, 66.8308; H, 4.0060; N, 3.7112. found C, 66.54; H, 4.07; N, 3.20.
Reaction SMILES: [N:1]12[CH2:14][CH2:13][N:7]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2.[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>>[OH:17][CH:16]([CH2:18][OH:19])[CH2:15][N:10]1[CH2:9][CH2:8][N:7]2[CH2:13][CH2:14][N:1]([CH2:2][CH2:3][N:4]([CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH2:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: C1CN2CCNCCN(CCN1)CC2
Reactant: OCC1CO1
Product: OCC(O)CN1CCN2CCN(CC1)CCN(CC(O)CO)CC2

Procedure:
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and glycidol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[O:7]([CH2:15][CH3:16])[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9]>CCCCCC>[F:12][C:11]([F:14])([F:13])[S:8]([O-:10])(=[O:9])=[O:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: CCOS(=O)(=O)C(F)(F)F
Solvent: CCCCCC
Product: CCn1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 72.5 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
6.31 g (0.0768 mol) of 1-methylimidazole in 50 ml of dry hexane are introduced into a round-bottomed flask fitted with a reflux condenser. 13.75 g (0.0772 mol) of ethyl triflate are added over the course of 20 minutes with constant stirring and cooling with the aid of an ice bath. After a further 10 minutes, the ice bath is then replaced by an oil bath, and the reaction mixture is refluxed for one hour (oil-bath temperature 70-75° C.). After the hexane has been removed by distillation, the reaction mixture which remains is held at 80-90° C. in a 30-100 Pa vacuum for 5 hours, giving 19.80 g (yield: 99.1%) of 1-methyl-3-ethylimidazolium trifluoromethanesulfonate as a transparent, colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[C-]#N.[K+].O>CN(C)C=O>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:6]
Reactant: C=CC(=O)OC
Reactant: O=Cc1cccc(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mml) in 35 mL dimethylformamide (DMF) was added to a heated (48° C.) solution of methyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN under Argon. The reaction mixture was stirred at 40° C. for 2 hours and then poured into 500 mL of water. This aqueous phase was extracted twice with 500 mL of Et2O and once with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, and then dried over MgSO4. The solvent was evaporated under reduced pressure to give 50.89 g (242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester as an oil. MS: 211 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: COCCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methoxyethylamine (0.9 ml) in dichloromethane (20 ml) was added triethylamine (2.1 ml), and the mixture was cooled in an ice-cooling bath. A solution of 3-nitrobenzoyl chloride (1.8 g) in dichloromethane (10 ml) was dropwise added thereto and the resulting mixture was stirred for 1.5 hours at the same temperature. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to afford N-(2-methoxyethyl)-3-nitrobenzamide (2.7 g) as a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][S:25](Br)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:12]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCCO)c2ccccc21
Reactant: CS(=O)(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCOS(C)(=O)=O)c2ccccc21
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
To a solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propan-1-ol (Intermediate 41; 3.2 g, 0.009 mol) in CH2Cl2 (25 mL) was added at −40° C. methanesulfonyl bromide (0.93 mL, 0.011 mol) and triethylamine (1.74 mL, 0.012 mol). The reaction mixture was stirred for 5 minutes. More CH2Cl2 was added into the mixture and the organic layer was washed with water. The solvent was removed under reduced pressure giving the title compound (3.5 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH2:16](O)C>C(N)=O>[CH3:13][C:10]([CH3:11])([CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCO
Solvent: NC=O
Product: CC(C)(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
4.0 g of XXVIII was refluxed in 20 ml of formamide for 30 minutes. After cooling 30 ml of ethanol was added and the yellow crystals were filtered off and recrystallized from 15 ml of DMF. Yield 2.0 g (XXIX) NMR (see Table I). ##STR13##
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br>CN(C=O)C.C(OCC)C.O>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: COC(CBr)OC
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1ncc2ccc([N+](=O)[O-])cc21)OC
Temperature: 25 °C

Procedure:
To a mixture of 6-nitroindazole (10.0 g, 61 mmol) and K2CO3 (9.31 g, 67.5 mmol) in DMF (60 mL) at room temperature was added 2-bromoacetaldehyde dimethylacetal (7.98 mL, 67.5 mmol), after which the mixture was heated to 50 C for 18 hours. The mixture was cooled to room temperature, diluted with diethyl ether (60 mL) and H2O (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to an orange oil. The residue was purified by MPLC (SiO2, 9:1 Hexane:ethyl acetate to 4:1 Hexane:ethyl acetate) to provide 1-(2,2-dimethoxyethyl)-6-nitro-1H-indazole as an orange oil. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.27 (s, 6 H), 4.71 (d, J=4.75 Hz, 2 H), 4.79 (m, 1 H), 7.97 (m, 2 H), 8.34 (s, 1 H), and 8.76 (s, 1 H); MS (ESI) 252 (M+H)+.
Reaction SMILES: CN1CCOCC1.Cl[C:9]1[N:14]=[C:13](OC)[N:12]=[C:11](OC)[N:10]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:46])([CH3:45])[C:28]([NH:30][C@H:31]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:32]([OH:34])=O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.NC1N=C([CH:54]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)=[O:56])NC=1>O1CCCC1>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[C:27]([NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:25])([CH3:45])[CH3:46])[C:32](=[O:34])[NH:10][C:9]2[N:14]=[CH:13][N:12]([CH:54]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:55](=[O:56])[N:57]3[CH2:58][CH2:59][CH2:60][CH2:61]3)[CH:11]=2)=[CH:37]1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Nc1c[nH]c(C(C(=O)N2CCCC2)c2ccccc2)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)Nc1cn(C(C(=O)N2CCCC2)c2ccccc2)cn1
Reaction time: 1.5 h
Yield: 31.6 %

Procedure:
N-Methyl morpholine (0.28 mL, 8.32 mm, 1 eq) was added to a stirred slurry of 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.46 g, 2.57 mm, 1 eq) and (2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoic acid (1 g, 2.57 mm) in 10 mL of anhydrous tetrahydrofuran cooled to less than 0° C. After 1.5 hours, 2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one, hydrochloride (0.97 g, 2.82 mm, 1.1 eq) was added and stirring was continued at ice bath temperatures. The reaction was stirred for 4 hours and quenched by the addition of 15 mL of deionized water and ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and the volatiles were removed under vacuum to give the crude product as a light purple foam (1.4 g, 84%) The crude product was purified by preparative chromatography to provide 0.52 g (31.5%) of the product as a foam. 1H nmr (CDCl3): δ1.10-1.40 (m, 15H), 1.67-1.92 (m, 3H), 2.92-3.60 (m, % H), 4.90 (s, broad, 1H), 5.33 (s, broad, 1H), 5.85 (d, 1H), 6.80-7.05 (m, 3H), 7.13-7.39 (m, 10H), 7.44-7.80 (m, 2H), 8.96 (s, broad, 1H), 10.20 (s, broad, 1H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O>[CH2:26]([O:25][C:23]([CH2:22][O:21][N:20]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([OH:17])=[O:16])=[O:24])[CH3:27]
Reactant: CCOC(=O)CON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
Sodium bicarbonate (0.84 g.) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (2 g.) in water (120 ml.) to prepare a solution. Ethyl 2-aminooxyacetate hydrochloride (4.56 g.) was added to the solution and stirred at ambient temperature for 3 hours while adjusting a pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.44 g.), mp. 112° C. (dec.).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[K+].C(O[C:14]([S-:16])=[S:15])C.O.Cl>CN(C=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]2[S:16][C:14](=[S:15])[NH:9][C:3]=2[N:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ncc(Br)c(N)n1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
5-Bromo-pyrimidine-2,4-diamine (2.0 g, 10.58 mmol) [prepared in a manner similar to English et. al. J. Am. Chem. Soc. 1946, 68, 453-458] and O-ethylxanthic acid potassium salt (3.39 g, 21.16 mmol) was heated in DMF (25 mL) to 140° C. After 5 h the reaction was cooled to ambient temperature and 25 mL of water was added. The pH was then adjusted to 5.0 using I N HCl. A red precipitate formed and was collected by filtration, yielding 900 mg (30%) of a solid: 1H NMR (400 MHz, d6-DMSO) δ 13.85 (s, 1H), 8.33 (br s, 1H), 6.90 (s 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:9]2[CH:5]([N:6]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:7][CH2:8]2)[CH2:4][CH2:3]1.[C:17]([N:24]1[CH:28]=[CH:27]N=[CH:25]1)(N1C=CN=C1)=[O:18].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2CCNC[CH2:37]2)=[CH:32][CH:31]=1>>[CH3:1][N:2]1[CH:9]2[CH:5]([N:6]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:24]4[CH2:25][CH2:37][CH:36]([C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)[CH2:27][CH2:28]4)=[O:18])=[CH:12][CH:11]=3)[CH2:7][CH2:8]2)[CH2:4][CH2:3]1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCC2C1CCN2c1ccc(N)cc1
Product: CN1CCC2C1CCN2c1ccc(NC(=O)N2CCC(c3ccc(Cl)cc3)CC2)cc1

Procedure:
4-(4-Methylhexahydropyrrolo[3,2-b]pyrrol-1-yl)phenylamine was reacted by method A with carbonyldiimidazole and finally with 4-(4-chlorophenyl)-piperidine. The product with the molecular weight of 439.01 (C25H31ClN4O); MS (ESI): 439 (M+H+) was obtained in this way.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[O:23]([C:25]#[N:26])[K]>O.C(O)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:25]([NH2:26])=[O:23])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: N#CO[K]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6dihydro-1-pyrimidinyl]ethoxy]benzyl hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in a mixture of water (2 ml) and acetic acid (0.5 ml) was added a solution of KOCN (343 mg, 3.0 mmol) in water (1 ml) and stirred for 1 h at 30° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the compound (295 mg, 85%).