Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:5][CH:4]=1)#[N:2].O.[NH2:18][NH2:19]>C(O)C>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]2[CH:9]3[CH:10]([C:12](=[O:13])[NH:18][N:19]=2)[CH2:11]3)=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 66.4 %

Procedure:
2.45 g (11.4 millimoles) of cis-2-(p-cyanobenzoyl)-cyclopropanecarboxylic acid, 0.57 g (11.4 millimoles) of hydrazine hydrate and 50 ml of ethanol are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 1.6 g (67% of theory) of 2-(p-cyanophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as ocher crystals which are identical with the compound from Example 39.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@H:26]1[CH2:31]CCC[C@@H:27]1N.Br[C:35]1[S:39][C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:37][CH:36]=1>CN(C)C(=O)C.[Cu](I)I.O>[CH3:14][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([C:35]2[S:39][C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:37][CH:36]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][CH:31]=[CH:26][CH:27]=1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: CN(C)[C@H]1CCCC[C@@H]1N
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(-n2nc(-c3ccccc3)c(C)c2-c2ccccc2)s1
Temperature: 25 °C
Yield: 366.1 %

Procedure:
To a solution of 3-phenyl-1H-indazole (50 mg) synthesized according to the literature (T. Edward C., et al., Tetrahedron, 1991, 47, 9599-9620) in N,N-dimethylacetamide (500 μL, manufactured by Kanto Chemical Co., Inc.), potassium phosphate (85 mg, manufactured by Wako Pure Chemical Industries, Ltd.), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (5 mg, manufactured by Tokyo Chemical Industry Co., Ltd.), copper iodide (4 mg, manufactured by Kanto Chemical Co., Inc.), and ethyl 5-bromothiophene-2-carboxylate (45 mg, manufactured by Alfa Aesar GmbH & Co. KG) were added, and the mixture was irradiated with microwave irradiation for 45 minutes at 185° C. The reaction solution was cooled to room temperature, and then water (1 mL) was added thereto. The mixture was extracted with ethyl acetate (3×2 mL), washed with brine (5 mL), and dried (MgSO4), and then the mixture was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate 85:15), to give 50 mg of the title compound. LC-MS: HPLC retention time 6.52 minutes, m/z 349 (M+H), condition A-1.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][CH:12]=2)[O:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:15][CH2:14]2
Reactant: CCOC(=O)C1CCc2cccc(OC)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2c1OC(C(=O)O)CC2
Reaction time: 24 h
Yield: 106.3 %

Procedure:
The mixture of 100.7 g (0.43 mol) 8-methoxy-2-chromancarboxylic acid ethyl ester and 20.1 g (0.50 mol) sodium hydroxide in 800 ml ethanol was stirred for 24 h at 20°. After evaporation, the residue was treated with water and extracted with diethyl ether. The aqueous phase was acidified and then extracted with diethylether. Usual work-up yielded 95.2 g of crystalline 8-methoxychroman-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccnc2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with imidazole (1.02 g, 15 mmol) to give the titled compound as an amorphous-like substance 239 mg, 18%).
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]([CH3:8])=[C:5]([CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C(I)=C([OH:39])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.C(=O)=O.CC(C)=O>C1COCC1>[C:11]([O:10][CH2:9][C:5]1[CH:6]([CH3:8])[O:7][C:3](=[O:39])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)OCc1c(C)oc([Si](C)(C)C)c1-c1ccccc1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C=O
Agent: O=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C
Yield: 27 %

Procedure:
The solution of Compound 15 and Rose Bengal in THF was saturated with O2, then cooled to approximately -5° C. (dry ice/acetone bath) and irradiated with a 150 watt flood lamp (maintaining the temperature of the mixture at -5° to 0° C.) for 3 hours. The reaction mixture was then filtered and concentrated to a pink oil which was purified by column chromatography (eluent, EtOAc/hexanes, 1:20 to 1:4) to give 3.4 g (27%) of pure title compound as a colorless oil. An additional 3 g (approximately 25%) of a mixture of the title compound and the 5-desmethyl derivative (ratio 1:1 by proton NMR integration) was also obtained as a yellow oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][Cl:33])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:34]([F:37])([F:36])[F:35])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[Cl-:33].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH+:27]([CH2:30][CH2:31][CH2:32][N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][C:2]3=[O:11])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:34]([F:35])([F:36])[F:37])[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C(F)(F)F)n1
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CC[NH+](CCCN3C(=O)CCc4ccccc43)CC2)cc(C(F)(F)F)n1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
3,4-Dihydroquinolin-2(1H)-one (3.40 mmol, 0.50 g) in N,N-dimethylformamide (5 ml) was added dropwise to a suspension of NaH (3.74 mmol, 0.15 g, 60%, deoiled) in N,N-dimethylformamide (10 ml) at 10° C., followed by preactivation at room temperature for 1 hour. Then 2-tert-butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-(trifluoromethyl)-pyrimidine (3.57 mmol, 1.30 g; prepared as in DE 19728996) in N,N-dimethyl-formamide (5 ml) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After the reaction mixture had been concentrated to dryness, the remaining oil was taken up in 1:1 ethyl acetate/water mixture. The aqueous mixture was extracted with saturated brine. The organic phase was dried over Na2SO4, the desiccant was filtered off, and the organic phase was concentrated under reduced pressure. The residue obtained in this way was purified by chromatography on silica gel (eluent: heptane:diethyl ether 0-100%), resulting in 840 mg of the title compound.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].P(Cl)(Cl)(Cl)=O.[CH2:12]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[C:2]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:1]
Reactant: c1ccc(Cc2cc3ccccc3[nH]2)cc1
Reactant: CC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(Cc2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of 29.5 g (39 mmol) of dimethylacetamide was added dropwise under ice-cooling 7.00 g (76.9 mmol) of phosphorus oxychloride. After stirring for 30 min at room temperature, to the mixture was added 8.00 g (38.6 mmol) of 2-benzylindole (prepared in accordance with the literature (Khim.Geterotsikl.Soedin.1994,p133)). After stirring for 2 hours at 100° C., the mixture was poured to ice-water, neutralized with 2N NaOH, extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The obtained crystal was washed with n-hexane to give 5.1 g of the titled compound. Yield: 52%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH3:17])[C:5]([Cl:18])=[CH:4][N:3]=1.C(O[C:23](=[O:25])[CH3:24])(=O)C.N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]([CH3:17])[C:23](=[O:25])[CH3:24])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: CNCc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 24 %

Procedure:
A solution of (2,5-dichloro-pyrimidin-4-yl)-(2-methylaminomethyl-phenyl)-amine in THF (25 mL) was treated with acetic anhydride (60 mg, 0.59 mmol, 1.2 eq) and pyridine (50 mg, 0.63 mmol, 1.3 eq.) at 25° C. for 2 h. The solvent was evaporated and the residue was purified by semi-preparative HPLC to give N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-N-methyl-acetamide (40 mg, 0.12 mmol, 24%). 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 7.73 (d, 1H), 7.3 (m, 3H), 4.48 (s, 2H), 3.24 (s, 3H), 2.12 (s, 3H); MS (m/e) 325 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.CN(C)C=O>O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=[O:14])[CH2:17][CH2:16][C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:18])=[CH:7]2
Reactant: C=CC(=O)c1ccc(C(=O)OC)cc1
Reactant: Cc1ccc(C)c2cc(C=O)ccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(C)ccc(C)c3c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
A mixture of 1.0 g of 5,8-dimethyl-2-naphthaldehyde, 1.2 g of methyl 4-acryloyl-benzoate, 0.28 g of 3-benzyl-5-(2-hydroxymethyl)-4-methylthiazolium chloride, 0.88 ml triethylamine and 20 ml N,N-dimethylformamide was heated under stirring at 70° C. for 3 hours. After the reaction solution was left standing for cooling to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated and the resulting crude crystals were washed with a mixed solvent of n-hexane and ethyl acetate to give 0.82 g of the title compound as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.[H-].[Na+].S(F)(OC)(=O)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: COS(=O)(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes at room temperature. To this was added 2.3 g of methyl fluorosulfate, and the whole was reacted for one hour at room temperature. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.7 g of 1-(m-nitrophenyl)- 3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 241°-242° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([O:17][S:18]([OH:21])(=[O:20])=[O:19])[C:10]1=[O:22])=O)(C)(C)C.[K].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([O:17][S:18]([OH:21])(=[O:19])=[O:20])[C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(OS(=O)(=O)O)C12CCCC2
Agent: [K]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NC1C(=O)N(OS(=O)(=O)O)C12CCCC2
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
3[(t-Butoxycarbonyl)amino]-2-oxo-1-(sulfooxy)-1-azaspiro[3.4]octane, monopotassium salt (280 mg, 0.75 mmoles) was covered with 2 ml of dry dichloromethane, 0.8 ml of anisole was added, and the mixture cooled to -10° C. Trifluoroacetic acid (3 ml) was added, and the solution was stirred at -10 to -5° C. for 1.5 hours. After 0.75 hours a solid formed, becoming quite substantial by 1.5 hours. The volatiles were evaporated in vacuo and the solid residue triturated with ether to give 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.4]octane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>ClCCl>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 72 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and dichloromethane (60 ml) was heated to reflux while stirring for 72 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and then evaporated. The evaporation residue was purified by column chromatography to obtain a target substance (0.5 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH:16]([OH:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:38])[CH3:37])[CH3:36]
Reactant: Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C(O)c1ccccc1
Temperature: 55 °C
Yield: 65 %

Procedure:
4-Benzyloxy-2-(hydroxy-phenyl-methyl)-phenol (690 mg, 2.25 mmol) and Cs2CO3 (734 mg, 2.25 mmol) in DMF (7 mL) was treated with ethyl bromoisobutyrate (0.66 mL, 4.5 mmol) and heated at 55° C. for 16 h. Additional bromo ester (0.40 mL, 1.23 mmol) and Cs2CO3 (400 mg, 1.23 mmol) were added and the reaction mixture was heated for 40 h. The mixture was cooled and partitioned between EtOAc (30 mL) and H2O (10 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate to give a pale yellow oil (615 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.39 (s, 3H), 1.43 (s, 3H), 4.19 (q, 2H, J=7.3 Hz), 4.97 (s 2H), 6.00 (s, 1H), 6.61 (d, 1H, J=8.8 Hz), 6.74 (dd, 2H, J=3.2, 9.0 Hz), 6.96 (d, 1H, J=2.9 Hz), 7.22-7.39 (m, 10).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1([CH2:17][CH3:18])[CH3:16])=[O:8].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[C:25]=1[Cl:33]>C1COCC1>[C:19]([C:4]1[S:3][C:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=2[Cl:33])=[O:32])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]2([CH2:17][CH3:18])[CH3:16])=[O:8])[CH:5]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CCC1(C)C(=O)NCCN1C(=O)c1cc(C(C)(C)C)sc1N
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CCC1(C)C(=O)NCCN1C(=O)c1cc(C(C)(C)C)sc1NC(=O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-3-ethyl-3-methylpiperazin-2-one (72.0 mg, 0.22 mmol) in THF (2 mL) was added 1,2-dichloro-3-isocyanatobenzene (50.0 mg, 0.27 mmol). The resulting reaction mixture was stirred at room temperature and the reaction progress monitored by SFC-MS. When the reaction was completed, solvent was removed under reduced pressure and the crude product purified by preparative TLC to afford 1-(5-tert-butyl-3-(2-ethyl-2-methyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(2,3-dichlorophenyl)urea (50 mg, 44%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 9.93 (s, 1H), 9.52 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.26-7.22 (m, 2H), 6.46 (s, 1H), 3.62-3.58 (m, 1H), 3.40-3.35 (m, 1H), 3.30-3.23 (m, 1H), 3.19-3.13 (m, 1H), 2.65-2.61 (m, 1H), 1.89-1.85 (m, 1H), 1.58 (s, 3H), 1.22 (s, 9H), 0.69 (t, J=7.4 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])[C:22]=1[CH2:34][CH3:35])(=[O:20])=[O:19])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:16][C:13]1[S:12][C:11]([C:9]2[O:8][N:7]=[C:6]([CH2:5][C@H:4]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][C:28]4=[O:33])[C:22]=3[CH2:34][CH3:35])(=[O:20])=[O:19])[C:3]([OH:36])=[O:2])[CH:10]=2)=[CH:15][CH:14]=1
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 7 (1.5 g, 2.71 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was treated with LiOH (194 mg, 8.12 mmol) and stirred at RT overnight. The mixture was acidified with HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with MgSO4, filtered and evaporated to dryness. The crude product (1.3 g) was used without further purification in the next step.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>O>[CH2:2]([O:9][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 148 °C
Yield: 88.2 %

Procedure:
Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml, 96 mmol) and the mixture was heated at 148° C. for 30 minutes, 7-fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J. Chem. Soc. section B 1967,449), was added and the mixture maintained at 148° C. for 24 hours. The reaction mixture was allowed to cool, the solution was poured on to water (1 70 ml) and the aqueous mixture adjusted to pH3 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, ether and dried under vacuum to give 7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](O)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:22])[NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN)OC
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1)OC
Reaction time: 24 h
Yield: 31.4 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (500 mg, 1.56 mmol) and 2,2-dimethoxy-ethylamine (163 mg, 1.56 mmol) in dichloromethane (5 mL) were added EDC-HCl (298 mg, 1.56 mmol), HOBt (210 mg, 1.56 mmol) and triethylamine (157 mg, 1.56 mmol). The mixture was stirred at room temp. for 24 h, diluted with water, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 15% EtOAc in hexane as eluent) to give (2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (200 mg, 31.6% yield) as a light brown liquid. MS calcd. for C21H33N2O6 [(M+H)+] 409.0, obsd. 409.0.
Reaction SMILES: [N:1]1[C:2]2[C:14](=O)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[OH:18][N:17]=[C:14]1[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: NO
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cnc2c([nH]1)-c1ccccc1C2=NO
Temperature: 80 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 g, 5.0 mmol), pyridine (40 ml) and hydroxylamine hydrochloride (0.42 g, 6.0 mmol) was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with water, acetic acid and water and dried. The crude material (0.81 g) was recrystallized from DMF to afford 0.52 g (49%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 7.49-7.62 (m, 2H), 7.88 (d, 1H), 7.95 (s, 1H), 8.36 (d, 1H), 12.5-13.2 (broad, 1H), 12.83 (s, 1H).