Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[CH:5][N:6]=1.[CH3:17][NH:18][CH3:19]>C(O)(C)(C)C>[Cl:15][C:10]1[CH:9]=[C:8]([C:7]2[C:4]([OH:3])=[CH:5][N:6]=[C:2]([N:18]([CH3:19])[CH3:17])[N:1]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Nc1ncc(C(=O)c2ccc(Cl)c(Cl)c2)o1
Reactant: CNC
Solvent: CC(C)(C)O
Product: CN(C)c1ncc(O)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5-(3', 4'-dichlorobenzoyl)oxazole (2 g, 7.8 mmol) was combined with aqueous dimethylamine (100 ml) in t-butyl alcohol and stirred at room temperature for 4 hours. The solvents were removed in vacuum and the residue was chromatographed on silica gel with hexane and ethylacetate (3:1) as the eluent to yield 1.5 g of the title compound as a crystalline solid, m.p. 188°-189° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:24]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N+:19]=3[O-:33])[C:7]=2[CH:24]=1)#[N:2]
Reactant: COC(=O)c1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
237 mg of methyl 6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylate were dissolved in 30 ml of dichloromethane and 180 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature overnight and then washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil was triturated with diethyl ether to give a solid which was recrystallized from t-butyl methyl ether. There were obtained 60 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-(methoxycarbonyl)pyridine N-oxide of melting point 135°-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:1]([C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Oc1ccc2c(c1)Cc1ccccc1O2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)Cc1ccccc1O2
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 2-hydroxy-9H-xanthene 3 (2.63 g, 13.28 mmole) in DMF (15 ml) was added imidazole (1.36 g, 19.9 mmole), t-butyldimethylsilyl chloride (2.4 g, 15.92 mmole) and DMAP (15 mg) successively at room temperature. The mixture was allowed to stir overnight (16 hrs) and quenched with saturated NaHCO3 solution. The aqueous layer was extracted two times with 10% EtOAc-hexanes. The combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated. The light orange oily residue was loaded onto a silica gel plug and eluted with hexanes and then 3% EtOAc-hexanes. The relatively clean fractions of the desired product were pooled and concentrated, yielding the slightly impure 2-tert-butyldimethylsiloxyl-9H-xanthene 4 (3.297 g, 79.5%) as an off-white solid: mp 67-69° C. 1H NMR (CDCl3): delta 7.12-7.19 (2H, m), 6.96-7.01 (2H, m), 6.89 (1H, d, J=8.5 Hz), 6.61-6.67 (2H, m), 3.98 (2H, s), 0.97 (9H, s) and 0.17 (6H, s); 1R (CHCl3): 2960, 2938, 1630, 1587, 1487, 1464, 1251, 1203, 1158, 1120, 976, 892, 868 and 843 cm-1.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:17][C:18]1[N:27]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:19]=1>>[NH2:27][C:18]1[N:19]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:6][C:5]=2[N:17]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2cccs2)CC1=O
Product: Cc1nc(N)nc2c1C(=O)CC(c1cccs1)C2

Procedure:
The title compound was prepared from 2-acetyl-5-thien-2-yl-cyclohexane-1,3-dione (430 mg, 1.82 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:14]([S@:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[C:11](=[N:20]/[S:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19])/[CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: C/C(=N\S(=O)C(C)(C)C)c1cc(Br)cc([N+](=O)[O-])c1

Procedure:
1-(3-Bromo-5-nitro-phenyl)-ethanone (11.6 g, 47.5 mmol), (R)-(+)-tert-butanesulfinamide (6.34 g, 52.3 mmol) and Ti(OEt)4 (24.64 ml, 119 mmol) were mixed in 62 ml THF and refluxed for 2.5 hrs. The reaction was cooled and carefully quenched by addition of ice and water. The white precipitate was filtered off and the aqueous mixture was extracted with ethyl acetate. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellow oil. 1H-NMR (500 MHz, DMSO-d6): 8.58 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 2.79 (s, 3H), 1.24 (s, 9H); MS: 347 [(M+H)+]; [α]D=+54.5° (c=0.481% in chloroform).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:12][C:10](=[O:11])[C@H:9]([NH2:8])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)CC(C)C
Temperature: 25 °C

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-4-methyl-pentanoic acid (2 g, 8.7 mmol) in methanol (20 mL) is added thionyl chloride (2.59 g, 21.7 mmol). The reaction mixture is refluxed for 2 h. The reaction mixture is cooled to room temperature and concentrated in vacuo. The crude product is carried on without any further purification. 1H NMR (400 MHz, MeOD): δ 1.00 (q, 6H, J=3 Hz), 1.7-1.9 (m, 3H, J=7.7 Hz), 3.85 (s, 3H), 4.0 (t, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:21])=[N:9]2)=[CH:4][C:3]=1[CH3:22].Cl[C:24]1C=CC(N2C(C3C=CC(SC)=CC=3)=CC(N)=N2)=C[C:25]=1C>>[CH:3]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([NH2:21])=[N:9]2)=[CH:25][CH:24]=1)([CH3:22])[CH3:4]
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(F)c(C)c2)cc1
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(Cl)c(C)c2)cc1
Product: CSc1ccc(-c2cc(N)nn2-c2ccc(C(C)C)cc2)cc1

Procedure:
The following compounds described in (1) to (2) were obtained according to a similar manner to that of Preparation 3.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([O:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=4[O:39][CH3:40])[C:24]=3[CH:41]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:11]1([O:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:38]=[CH:37][C:33]([C:34]([NH:10][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])=[O:35])=[CH:32][C:31]=4[O:39][CH3:40])[C:24]=3[CH:41]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cc(C(=O)O)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 21 h
Yield: 53.5 %

Procedure:
Benzenesulphonamide (0.037 g.) was added to a stirred solution of 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoic acid (0.1 g.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.046 g.) and 4-(dimethylamino)pyridine (0.029 g.) in dichloromethane (5 ml.), under an atmosphere of nitrogen. The mixture was stirred for 21 hours and then diluted with dichloromethane. This mixture was washed successively with 1M hydrochloric acid (2×10 ml.), 5% w/v sodium bicarbonate solution (2×10 ml.), and saturated brine (20 ml.). It was then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (3 cm. diameter column) eluting with 1:1 v/v ethyl acetate:hexane. The solid obtained was recrystallized from ethyl acetate to give the title compound as a white powder (0.071 g., 54%), m.p. 186°-187° C.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[C:15]([O:20][CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([O:20][CH3:21])[N:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1cccnc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(OC)nccc2c1=O
Temperature: 50 °C
Yield: 66.6 %

Procedure:
11.23 g of ethyl 2-butyryl-3-(2-methoxypyridine-3-yl)aminoacrylate prepared in the above (A) was dissolved in 60 ml so diphenyl ether, and the resulting solution was heated to reflux for 2 hours and cooled to about 50° C. Petroleum ether (200 ml) was added to give precipitates, which were filtered to give 6.3 g (76%) of the titled compound as brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Under argon, 8 (433.0 g, 1.37 mol) was dissolved in dry DMF (1.6 L) and to this sodium hydride (60.4 g, 1.51 mol) was added. To the resulting orange solution 4-fluorobenzaldehyde (185.0 mL, 1.71 mol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3.0 L) and extracted with water (3×1.0 L), then brine (1×1.0 L). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. The residue was suspended in methanol (3.0 L) and stirred overnight. Solid was filtered and dried under vacuum at 40° C. to yield 9 as pale yellow, solid (445 g, 77%): mp 108-110° C. 1HNMR (360 MHz, CDCl3) δ 9.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.11 (overlapped d, J=9.0 Hz, 2H), 7.08 (overlapped d, J=9.0 Hz, 2H), 6.36 (t, J=2.2 Hz, 1H), 6.25 (d, J=2.2 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 6H); Anal. (C25H22O6) C, H.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C@H:13]1[C@@H:17]([OH:18])[CH2:16][CH2:15][NH:14]1>CS(C)=O.C(=O)([O-])[O-].[Li+].[Li+]>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:14]2[CH2:15][CH2:16][C@H:17]([OH:18])[C@@H:13]2[CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(Cl)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)c(Cl)c1Cl

Procedure:
Using 2,3-dichloro-4-fluorobenzonitrile (400.5 mg), 0.9 mol/L solution (2.35 mL) of (2S,3S)-2-methylpyrrolidin-3-ol in dimethyl sulfoxide and lithium carbonate (78 mg), the title compound was obtained as yellow crystals (yield: 417 mg) by an operation similar to that in Example 3.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:23])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[OH-:26].[K+]>COCCOC>[Cl:23][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:26])=[O:4])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: CCOc1ccc(-c2cc3c(C(=O)C(Cl)(Cl)Cl)c[nH]c3cc2Cl)cc1
Agent: [K+]
Solvent: COCCOC
Product: CCOc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
To a solution of 2,2,2-trichloro-1-(6-chloro-5-(4-ethoxyphenyl)-1H-indol-3-yl)ethanone (70.0 mg, 0.17 mmol) in DME (1 mL) was added 1N KOH (0.71 mmol, 0.71 mL). The reaction mixture was stirred at room temperature for 12 hours, and concentrated in vacuo. The crude material was diluted with water (5 mL), and acidified to pH 2.5 with 1N HCl to form a white precipitate. The precipitate was filtered, washed with water (20 mL) and dried under vacuum to provide the title compound (37 mg, 70%) as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([Cl:24])[CH:23]=2)[C:20](=[O:25])[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:22]1[CH:23]=[C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]=[C:17]2[C:21]=1[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 109.2 %

Procedure:
4-[7-Chloro-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (54.90 mg, 0.102 mmol) was stirred in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) overnight. The reaction mixture was quenched with sodium carbonate to pH=8-9 and the free base was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (48.9 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.39 (d, 2H), 7.18 (d, 3H), 7.06 (s, 1H), 4.77 (s, 2H), 4.61 (broad s, 1H), 4.23 (s, 2H), 3.16 (d, 2H), 2.62 (m, 4H), 1.61 (d, 3H), 1.29 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)=[C:2]=[O:3].C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>CCOC(C)=O>[CH3:10][C:7]1[N:8]=[CH:9][C:4]([NH:1][C:2](=[O:3])[NH:16][C:17]2[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=2)[CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cccc(N)c2)CC1
Reactant: Cc1ccc(N=C=O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2cccc(CCN3CCN(C(=O)OC(C)(C)C)CC3)c2)cn1
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(3-aminophenethyl)piperazine-1-carboxylate (7D, 1.0 eq) in THF (about 0.3 M 7D in THF) was added 5-isocyanato-2-methylpyridine (1.0 eq) dropwise. The resulting reaction mixture was stirred for 2 h. To the reaction mixture was added saturated aq. NaHCO3. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed twice with saturated aq. NaHCO3 and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification over silica gel using 5-12% MeOH/CH2Cl2 as the gradient eluant provided tert-butyl 4-(3-(3-(6-methylpyridin-3-yl)ureido)phenethyl)piperazine-1-carboxylate (7E, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][C:7]1[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Agent: [Pd]
Product: Nc1ccc(OCCOCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a stirred solution of 35 (6.30 g, 12.9 mmol) in 1:1 THF/TEA (26 mL) in a Parr apparatus was added a catalytic amount of 20% Pd/C (0.05 g). The reaction vessel was purged with hydrogen then pressurized to 70 psi. After stirring for 16 h the reaction mixture was filtered through a 4 cm pad of celite and concentrated under reduced pressure to afford 36 as a brown oil (5.80 g, 98%): 1H NMR (300 MHz, CDCl3) δ 6.75 (d, J=8.9 Hz, 2H), 6.62 (d, J=8.9 Hz, 2H), 4.71-4.55 (m, 1H), 4.09-4.00 (m, 2H), 3.94-3.31 (m, 22H), 1.93-1.44 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:25]([O:27]C)=O)=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]3[N:23]=O)=[C:5]([CH3:29])[O:4][N:3]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO.[Zn]>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:11]=3[C:10]([C:25](=[O:27])[NH:23]4)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c2c1N(N=O)C(c1ccccc1)CO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccc1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A suspension of methyl 8-(3,5-dimethylisoxazol-4-yl)-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (0.228 g, 0.580 mmol) in ethyl acetate (4.04 mL) and methanol (4.04 mL) at 0° C. was treated with saturated aqueous ammonium chloride solution (2.02 mL, 30.2 mmol) and then zinc (0.303 g, 4.64 mmol) was added in three portions over 6 min. The cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through a Celite pad, and rinsed with ethyl acetate (2×10 mL). The filtrate was washed with water (20 mL), brine, (20 mL), dried over sodium sulfate, filtered, and concentrated to give a crude tan foam. Purification by flash column chromatography (100% dichloromethane to 10% methanol/dichloromethane) gave the desired product (0.14 g, 70%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ 10.98 (br s, 1H), 7.40-7.29 (m, 3H), 7.26 (d, J=8.3 Hz, 1H), 7.23-7.15 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 5.39 (br s, 1H), 4.74 (dd, J=11.5, 3.1 Hz, 1H), 4.61 (dd, J=11.5, 5.8 Hz, 1H), 2.31 (s, 3H), 2.15 (s, 3H). LCMS calculated for C20H18N3O3 (M+H)+: m/z=348.1. found: 348.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:35])[C:13]2[N:12]=[C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([C:29]4[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=4)[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=3)[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.Cl>CCO>[CH3:3][C:4]1([CH3:35])[C:13]2[N:12]=[C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([C:29]4[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=4)[CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)C[C@@H](c1ccc(OCc2ccc3c(n2)C(C)(C)CCC3)cc1)c1nccn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(n2)C(C)(C)CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10% NaOH (aq) (1 mL) is added to a solution of compound 54.1 (45 mg, 0.1 mmol) in EtOH (2 mL). The reaction mixture is stirred at room temperature for 4 hours. 1N HCl is added to neutralize the mixture to pH 6-7. The mixture is extracted with EtOAc (2×20 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is flash chromatographed (silica gel, 0-10% MeOH in DCM) to afford the compound 54.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:5]([CH2:4][C:2](=[CH2:3])[C:1]([OH:8])=[O:7])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: C=C1CC(=O)OC1=O
Solvent: Cc1ccccc1
Product: C=C(CC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of itaconic anhydride (33.6 g, 0.3 mol) in 100 ml of toluene is added benzyl alcohol (32.4 g, 0.3 mol). The resulting solution is heated to reflux for 3 hours. After cooling down to room temperature, hexanes (100 mL) are added to the above mixture and are continued to stir for 8 hours. A white solid is collected by filtration and washed with hexanes and dried in vacuum, giving rise to 55 g (83% yield) of the desired product: 2-(benzyloxycarbonylmethyl)acrylic acid monomer.
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(=O)c1cccs1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=O)c1cccs1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetic acid (8 g, 51.2 mmol), suspended in DCM (80 ml) and cooled to 5° C., is added oxalylchloride (5.3 ml, 61.5 mmol), followed by DMF (0.1 ml). Stirring is continued for 1 hour at 5° C. and 18 hours at room temperature. The reaction mixture is evaporated to dryness, toluene is then added and the mixture evaporated once more to give the title compound as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:10][CH2:9]C2)[CH:3]=1.ClC(Cl)(Cl)[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].C(N(CC)CC)C>C(#N)C>[CH:7]1([C:4]2[CH:3]=[C:2]([NH:1][C:13]([C:15]3[NH:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[NH:6][N:5]=2)[CH2:10][CH2:9]1
Reactant: Nc1cc(C2CCC2)n[nH]1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccc[nH]1
Yield: 45.8 %

Procedure:
To 260 mg (1.9 mmol) of 5-amino-3-cyclobutylpyrazole in 7 mL of acetonitrile was added 407 mg (1.9 mmol) of 2-trichloroacetylpyrrole and 220 μL of triethylamine. The mixture was stirred and heated at reflux, under nitrogen, for 12 hours. TLC analysis showed some starting material still remained. The mixture was concentrated and chromatographed over silica gel, eluting with 5% methanol in chloroform. The fractions containing the product were concentrated to an oil, which crystallized upon concentration from ether and methanol, to afford 200 mg (0.87 mmol, 46%) of a beige solid, m.p. 207–209° C., 1H NMR (DMSO-d6) δ 12.1 (s, 1H), 11.5 (s, 1H), 10.2 (s, 1H), 7.08 (s, 1H), 6.89 (s, 1H), 6.41 (s, 1H), 6.09 (s, 1H), 3.46 (m, 1H), 2.24 (m, 2H), 2.11 (m, 2H), 2.0–1.8 (m, 2H); IR (drift) 3329, 3294, 3257, 3225 (b), 2460 (w), 2351 (w), 2318 (w), 2257 (w), 1643 (s), 1588 (s), 1541, 1487 (s), 1416, 757, 747, cm−1 Anal. Calcd for C12H14N4O: C, 62.59; H, 6.13; N, 24.33. Found: C, 62.37; H, 6.22; N, 24.13.