Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([OH:10])=O)[O:6][CH2:5][CH2:4][O:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[F:61])[C:49]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[CH:48]2>CN(C=O)C>[F:61][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][N:50]1[C:51]2[C:47](=[CH:46][C:45]([NH:44][C:8](=[O:10])[CH2:7][C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)=[CH:53][CH:52]=2)[CH:48]=[C:49]1[C:62]([O:64][CH2:65][CH3:66])=[O:63]
Reactant: CC1(CC(=O)O)OCCO1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)CC3(C)OCCO3)ccc2n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
140 mg (0.96 mmol) of (2-methyl-1,3-dioxolan-2-yl)acetic acid are added to 5 ml of DMF, and 547 mg (1.44 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 186 mg (0.25 ml, 1.44 mmol) of N,N-diisopropylethylamine are added. 300 mg (0.96 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVI are added. The mixture is stirred at RT for 3 hours. For work-up the DMF is removed using a rotary evaporator. The residue is taken up in dichloromethane and extracted with aqueous hydrochloric acid. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]([C:8]1[NH:9][C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([Cl:23])[N:11]=2)[CH3:7])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]3[N:9]([C:10]=2[N:11]=1)[CH2:2][C:3](=[O:4])[NH:5][CH:6]3[CH3:7]
Reactant: CC(NC(=O)CBr)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)Cn2c1nc1c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 2-bromo-N-[1-(2-chloro-6-morpholin-4-yl-9H-purin-8-yl)-ethyl]-acetamide (275 mg, 0.68 mmol) and cesium carbonate (0.48 g, 1.36 mmol) in anhydrous DMF (10 mL) was stirred at RT for 2 h, then diluted with water and extracted five times with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2) gradient 0-5% methanol in DCM) to give 3-Chloro-8-methyl-1-morpholin-4-yl-7,8-dihydro-2,4,4b,7,9-pentaaza-fluoren-6-one (93 mg, 42%). LCMS RT=2.41 min, [M+H]+=323/325
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:10]([CH3:24])[C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].[Li+].[OH-].C(OCC)(=O)C>C(O)(C)C.O>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1c(C(=O)CCCC(=O)OC)n(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCCCc1c(C(=O)CCCC(=O)O)n(C)c2ccccc12
Reaction time: 3 h

Procedure:
To a solution of 5-(3-hexyl-1-methyl-1H-indol-2-yl)-5-oxo-pentanoic acid methyl ester in isopropanol and water was added LiOH and stirred for 3 hours. The reaction was treated with 1M HCL and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3([CH2:14][CH2:15][N:16]([CH2:30][CH2:29][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:18]3)[NH:10][C:9]2=[O:19])=[CH:20][CH:21]=1
Reactant: O=C1NC2(CCNCC2)C(=O)N1Cc1ccc(Br)cc1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC2(CCN(CCC(c3ccccc3)c3ccccc3)CC2)C(=O)N1Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 32.1 %

Procedure:
A mixture of 26.2 mg (70 μmol) of 3-(4-bromo-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride, 21.4 mg (70 μmol) of 3,3-diphenylpropyl bromide and 29 mg (210 μmol) of potassium carbonate in 1 mL of anhydrous DMF was heated overnight at 60° C. After cooling to room temperature, 0.5 mL of water was added and the solution was extracted with DCM (2×2 mL). The crude material was purified by semi-preparative HPLC (method A) yielding 12.8 mg (32.1%) of Compound 3 as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-phenyl-2-morpholinecarboxamide (340 mg, 0.61 mmol) and hydrazine monohydrate (0.39 mL, 12.54 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. in a sealed tube for 18 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by flash chromatography (60 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (243 mg) as a pale yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.24 (d, J=6.6 Hz, 3H), 2.86 (d, J=4.0 Hz, 3H), 2.97-3.15 (m, 1H), 3.83 (d, J=11.1 Hz, 1H), 3.94 (d, J=11.1 Hz, 1H), 4.16 (dd, J=11.2, 2.9 Hz, 1H), 4.33-4.88 (bs, 2H), 5.39 (s, 2H), 6.56-6.73 (m, 2H), 7.10 (t, J=7.3 Hz, 1H), 7.34 (t, J=7.9 Hz, 2H), 7.63 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.3 Hz, 3H), 8.01 (s, 1H), 9.88 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2O[C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[NH:35][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nnc(C(C)c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(C(C)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 2-[1-(4-fluorophenyl)ethyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (23 mg) and ammonium acetate (88 mg) in acetic acid (1 mL) was stirred at 150° C. for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: CO.O.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[CH2:18][N:17](C(=O)C(F)(F)F)[C:14]2=[CH:15][CH:16]=1>C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[CH2:18][NH:17][C:14]2=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CN1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1CCC2(CNc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
Methanol (10.7 mL), water (3.6 mL), and potassium carbonate (0.4 g, 2.86 mmol) were added to t-butyl 2-(5-chloro-1-(2,2,2-trifluoroacetyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate (0.6 g, 1.43 mmol), and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and brine. The organic layer was concentrated in vacuo to obtain t-butyl 2-(5-chlorospiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate (0.47 g, >100%) in the form of a light brown oily product.
Reaction SMILES: [CH2:1]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N+:28]([O-])=O)=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:28][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)=[CH:18][C:17]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1N
Yield: 88.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-benzylphenoxy)-2-nitrophenyl]-N-methylcarbamate (12.2 g), palladium on carbon (10%, 0.91 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (10.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](/[CH:14]=[CH:15]/[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)[CH2:19][CH2:18]3)[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:31])[N:3]=1.[CH3:32][NH2:33]>C(O)C>[ClH:31].[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11](/[CH:14]=[CH:15]/[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)[CH2:19][CH2:18]3)[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:33][CH3:32])[N:3]=1
Reactant: Cc1c(/C=C/CN2CCN(c3cc(F)cc(F)c3)CC2)cnn1-c1cc(Cl)nc(N)n1
Reactant: CN
Solvent: CCO
Product: CNc1cc(-n2ncc(/C=C/CN3CCN(c4cc(F)cc(F)c4)CC3)c2C)nc(N)n1
Product: Cl
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
A mixture consisting of 300 mg of 1-[1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-4-pyrazolyl]-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-trans-propene, 10.2 ml of a 40% methylamine aqueous solution, and 15 ml of ethanol was stirred at 60° C. for 4.5 hours. The reaction mixture was concentrated, and a saturated sodium hydrogencarbonate aqueous solution was added to the residue. The mixture was extracted three times with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 19:1 mixture of chloroform and methanol as a developing solvent. The fraction containing the desired product was concentrated, and a 1N ethanolic solution of hydrochloric acid was added to the residue. Concentration followed by recrystallization from ethanol gave 95 mg of the title compound as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7].C(N(CC)CC)C.[C:16]1([CH:26]=[C:27]2[CH2:32][C:31](=[O:33])[O:30][C:28]2=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>ClCCl>[C:16]1([CH:26]=[C:27]([CH2:32][C:31](=[O:33])[N:6]([CH3:7])[CH2:5][C:4]([O:3][CH3:2])=[O:8])[C:28]([OH:30])=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(=Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 1.40 g of sarcosine methyl ester hydrochloride in 50 ml of dichloromethane were added 1.54 ml of triethylamine and 1.70 g of the 2-(1-naphthylmethylene)succinic anhydride obtained, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed successively, with diluted hydrochloric acid, and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform) to obtain 2.37 g of 2-(1-naphthylmethylene)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]1[NH:31][CH2:30][CH2:29][N:28]2[CH2:32][CH2:33][CH2:34][C@H:27]12>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:31]4[CH2:30][CH2:29][N:28]5[CH2:32][CH2:33][CH2:34][C@@H:27]5[CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN5CCC[C@@H]5C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-octahydropyrrolo[1,2-a]pyrazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 4 H) 2.33 (d, J=2.53 Hz, 3 H) 2.81-4.24 (m, 9 H) 7.64 (br. s., 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.95-8.83 (m, 4 H). ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[O:10][C:9](=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[NH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[N:31][NH:32]2)=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]([NH:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][C:8]=2[C:9]([NH:25][C:26]2[CH:34]=[C:33]3[C:29]([CH:30]=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[O:23])=[O:10])=[CH:14][CH:15]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reaction time: 24 h
Yield: 42.2 %

Procedure:
To a stirring solution of 6-nitro-2-[4-t-butylphenyl]-4H-3,1-benzoxazin-4-one (1.5 g, 4.62 mmol) in toluene (25 mL) was added 6-aminoindazole (560 mg, 4.2 mmol) and the solution was heated to reflux. After about 24 h, the solution was cooled, filtered and the solid was washed with diethyl ether. The product was then chromatographed over silica gel, eluting with 25% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 810 mg (42%) of pale yellow solid.
Reaction SMILES: O.[O:2]=[CH:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12]>C1C=CC=CC=1>[CH2:8]([O:2][CH:3]([O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([Cl:7])([Cl:6])[Cl:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCO
Reactant: O=CC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCOC(OCCCCC)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral-hydrate, 10 ml of amyl-alcohol, 0.1 g of 4-methyl-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. After a reaction time of 9 hours the benzene is washed with a sodium hydrogen carbonate solution and water, dried on magnesium sulfate, then it is vacuum-distilled.
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5](OCC)=O.[H][H].BrC[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]=1>O1CCCC1.C(O)(=O)C>[C:28]1([C:20]2[N:19]=[C:18]([CH2:5][CH2:4][C:3]([OH:11])=[O:10])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: BrCc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)CCc1nc(-c2ccccc2)nc2ccccc12
Temperature: 5 °C
Reaction time: 15 h
Yield: 40.5 %

Procedure:
Sodium hydride (5.4 g, 80% strength in oil) is placed under nitrogen with anhydrous tetrahydrofuran (250 cc) and then, with the mixture cooled to about 5° C., diethyl malonate (25.6 g) is added. When the evolution of hydrogen has ceased, a solution of 4-bromomethyl-2-phenylquinazoline (23.9 g) in anhydrous tetrahydrofuran (100 cc) is added. After 1 hour's stirring at room temperature (approximately 20° C.), acetic acid (25 cc) is added, the solvent evaporated under reduced pressure and the residue taken up in concentrated hydrochloric acid (150 cc) and acetic acid (150 cc). The mixture is brought to 120° C. for 15 hours and evaporated again, water (200 cc) and ethyl ether (150 cc) are added and the mixture is alkalinised to pH 11 with sodium hydroxide solution. The organic phase is decanted and the aqueous solution washed with ethyl ether (2×100 cc). The aqueous phase is adjusted to pH 4 and extracted with ethyl acetate (2×100 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is crystallized in ethyl acetate. 2-Phenyl-4-quinazolinepropanoic acid (9 g), m.p. 159° C., is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:4].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:12]=1)=[O:10])[CH3:4]
Reactant: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)=CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of 0.88 g (22 mmol) of sodium hydride (60% dispersion in mineral oil) in THF (50 ml) was added under ice-cooling, 2.94 g (10 mmol) of 4-(5-chloroindol-3-yl)-2-hydroxy-4-oxo-2-butenoic acid ethyl ester prepared in Example 1 (1). After stirring for 15 min at room temperature, to the mixture was added dropwise a solution of 2.12 g (12 mmol) of benzenesulfonyl chloride in THF (20 ml). After stirring for 2 hours at room temperature, to the mixture was added DMF (8 ml). After stirring for additional 30 min, the reaction mixture was poured into ice-water containing 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was concentrated and the residue was crystallized from ether to give crude crystal, which was washed with ether to give 3.75 of the titled compound. Yield: 87%. Subsequent recrystallization from ethyl acetate afforded the pure ester, melted at. 156-157° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]([C:11](=[O:13])[NH2:12])[CH2:9][CH3:10].C(N(CC)CC)C.OC1C=CC=CN=1>O1CCCC1.C1(C)C=CC=CC=1>[CH3:10][CH2:9][C@H:8]([N:7]1[C:3](=[O:2])[CH2:4][CH2:5][CH2:6]1)[C:11]([NH2:12])=[O:13]
Reactant: CCC(NCCCC(=O)OC)C(N)=O
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Temperature: 80 °C

Procedure:
Hydrochloride salt of methyl-4-(1-carbamoylpropylamino)butyrate (VId) (0.7 g, 2.9 mmol) is dissolved in a mixture of tetrahydrofuran (10 ml) and triethylamine (0.6 g, 2 equiv.). The suspension is filtered and filtrates are concentrated to dryness to afford an oil. The resulting residue is dissolved in toluene (15 ml) and 2-hydroxypyridine (53 mg, 0.56 mmol, 20 mol %) is added. The mixture is heated to 80° C. until complete conversion. After 3 days (GC: 100% conversion) the mixture is concentrated to dryness under reduced pressure.
Reaction SMILES: C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.[N+:19]([C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O)([O-:21])=[O:20].C(=O)(OC(=O)C1C=CC=CC=1[N+]([O-])=O)OCC.[C:48]1([CH2:58][NH2:59])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[C:48]1([CH2:58][NH:59][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N+:19]([O-:21])=[O:20])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: CCOC(=O)OC(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(NCc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
1-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (7.5 g), was added in portions to a solution of 2-nitrobenzoic acid (5.01 g) in methylene chloride (300 ml) cooled to 0° C. The mixture (containing ethyl 2-nitrobenzoyl carbonate) was stirred for 15 minutes and then 1-naphthylmethylamine (4.7 g) was added dropwise at 0-5° C. The mixture was then stirred for 1 hour at ambient temperature and then washed successively with M hydrochloric acid, M sodium hydroxide and then with water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with methylene chloride/ether (80/20 v/v) to give N-(1-naphthylmethyl)-2-nitrobenzamide as a white solid (7.9 g), of satisfactory purity.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc(OCC(=O)OC)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
In 10 ml of dimethylformamide were suspended 1 g of 2-(3,4-diethoxyphenyl)-4-(4-hydroxy-3-methoxycarbonylphenyl)thiazole and 0.35 g of potassium carbonate. The suspension was stirred at room temperature for 30 minutes. Thereto was added 0.46 g of methyl bromoacetate. The mixture was stirred at the same temperature for 4 hours. The solvent was removed by distillation. The residue was extracted with 40 ml of dichloromethane. The extract was washed with 10 ml of water and 10 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and subjected to distillation to remove the solvent. The residue was recrystallized from diisopropyl ether to obtain 1.1 g of 2-(3,4-diethoxyphenyl)-4-(4-methoxycarbonylmethoxy-3-methoxycarbonylphenyl)thiazole.