Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH:65]1[CH2:70][CH2:69][N:68]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:67][CH2:66]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH:65]1[CH2:66][CH2:67][N:68]([C:71]([O:73][CH2:74][C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72])[CH2:69][CH2:70]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCC(CCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(2-bromoethyl)-1-piperidinecarboxylate.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CN(C=O)C>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][S:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCS
Reactant: Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of NaH (60% dispersed in oil, 0.731 g, 21.7 mmol) in dry DMF (15 ml) was added Ethyl 3-mercaptopropionate (2.66 g, 19.8 mmol). When the evolution of hydrogen ceased, 4-Hydroxybenzyl bromide from Step A was added. The reaction mixture was stirred for 16 hours at room temperature, quenched with sat. NH4Cl and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (dichloromethane: ethyl acetate, 95:5) to provide the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].CC(C[AlH]C[CH:21]([CH3:23])[CH3:22])C.[CH3:24][CH2:25][O:26]C(C)=O>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:3][OH:4])=[N:6][N:7]2[CH:22]2[CH2:21][CH2:23][CH2:24][CH2:25][O:26]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1n[nH]c2cc(Cl)ccc12
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: OCc1nn(C2CCCCO2)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-Chloro-1H-indazole-3-carboxylic acid methyl ester (2.94 g, 10.0 mmol) in dry CH2Cl2 (50 mL) cooled to −78 degrees Celsius was added DIBAL-H (3.56 mL, 20.0 mmol) slowly. After the addition was complete, the reaction was allowed to warm to room temperature, where HPLC showed that there was a remaining 10% starting material. Extra DIBAL-H (0.35 mL) was then added and stirred for 10 minutes. The reaction was diluted with EtOAc (1000 mL) and washed with 1 N HCl (2×100 mL). It was further washed with 1 N NaHCO3 (100 mL), and then with saturated NaCl (100 mL). The organic was dried over Mg SO4, filtered, and then concentrated to a white solid (2.65 g, 99.5%).
Reaction SMILES: N[C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](CSC1C=C(C)N3N=CC=C3N=1)=[C:7]2[C:11]([OH:13])=[O:12].O.C(N(CC)CC)C>C(#N)C>[O:10]=[C:9]1[N:8]2[CH:3]([S:4][CH2:5][CH:6]=[C:7]2[C:11]([OH:13])=[O:12])[CH2:2]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2ccnn12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)C1=CCSC2CC(=O)N12
Reaction time: 1 h

Procedure:
1.00 g of (6R,7R)-7-amino-3-[[(7-methylpyrazolo-[1,5-a]pyrimidin -5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was brought into solution in 5 ml of acetonitrile and 5 ml of water with 0.37 ml of triethylamine. The solution was treated with 1.0 g of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl) ester and stirred at 20° for 1 hour. The reaction mixture was partitioned between water and ethyl acetate and the aqueous phase was chromatographed on Optiup (C12) (Antec AG, CH-Bennwil) with a gradient of 0% to 10% acetonitrile in water. The product fractions Were concentrated to 10 ml and adjusted to pH 2.2 with HCl. The precipitate was filtered off under suction. There was obtained (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([O:24]C)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)sc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 60 °C
Yield: 97.8 %

Procedure:
To a suspension of methyl 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate (6.99 g, 18.9 mmol) in MeOH (50.0 mL), lithium hydroxide monohydrate (5.24 g, 125 mmol) was added, followed by water (50.0 mL). The mixture was heated at 60° C. for 5 h. The reaction mixture was then cooled to 0° C., and 6 M HCl was added slowly until the pH reached 2. The resulting solid was collected by filtration and the filter cake was washed with water (50 mL) and MeOH/water (1:1, 50 mL) to provide the sub-title compound as a yellow solid (6.59 g, 98%). LCMS calc. for C15H15F2N2O4S (M+H)+: m/z=357.1. found 357.0.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: C=CCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[NH2:26][NH:27][C:28]([NH2:30])=[S:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 4-phenylbenzoic acid (10.0 g), 1-hydroxybenzotriazole (7.5 g) and thiosemicarbazide (5.1 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (14.45 g) and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried under reduced pressure to give 1-(4-phenylbenzoyl)-3-thiosemicarbazide (10.274 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=23)[N:8]=1>CN(C)C=O>[CH2:1]([NH:4][CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=23)[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(F)c2C1=O
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2c(F)cccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
1 ml (12.2 mmol) of propylamine was added to a suspension of 1.7 g (4.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo-[1,5-a][1,4]benzodiazepin-6-one in 40 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried with magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, ethyl acetate/methanol 9:1). There were obtained 1.21 g (67%) of 3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, Rf=0.22 (silica gel, ethyl acetate/methanol 4:1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][NH2:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:31])([F:30])[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24](O)=[O:25])[N:17]=1>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([C:18]4[N:17]=[C:16]([C:15]([F:31])([F:30])[F:14])[O:20][N:19]=4)[CH:22]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCc1nc(-c2ccccc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 38 %

Procedure:
This compound was synthesized from (4-phenylthiazol-2-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.59 (m, 1H), 8.31-8.29 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.12-8.10 (m, 1H), 7.91-7.89 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J=7.5 Hz, 2H), 7.38-7.34 (m, 1H), 7.23 (t, J=4.8 Hz, 1H), 5.04 (d, J=5.5 Hz, 2H). MS (ESI) m/z: Calculated for C20H13F3N4O2S: 430.07. found: 431.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C.CS(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Br:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Br)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a stirred mixture of 6-nitro-7-bromo-1,4-dihydro-2,3-quinoxalinedione (87 mg, 0.30 mMol) in ethanol (3 mL) and DMSO (0.5 mL) was added SnCl2.2H2O (343 mg, 1.50 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution which was refluxed for another 1 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 50 mg (67%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 21 mg of pure as bright yellow needles, mp: >300° C. (dec. from 315° C.), changed color from 300° C. NMR (1H, DMSO-d6): d 5.257 (s, 2H); 6.558 (s, 1H); 7.087 (s, 1H); 11.599 (s, 1H); 11.792 (s, 1H). HRMS: calcd for C8H6N3O2Br (M+) m/z: 254.9642; found 254.9630. Potency relative to DCK: 7.1%.
Reaction SMILES: COC1C=CC([N:9]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:11]([O:19][C:20](=[O:22])[CH3:21])[C:10]2=[O:23])=CC=1>C(#N)C.O>[C:20]([O:19][C@H:11]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:9][C:10]1=[O:23])(=[O:22])[CH3:21]
Reactant: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(=O)O[C@@H]1C(=O)N[C@@H]1c1ccccc1

Procedure:
The above procedure may, in turn, be followed by modification of the lactam formed, should a different lactam starting material be desired. For example, a cis-1-p-methoxy-phenyl-3-acetoxy-4-phenylazetidin-2-one racemate prepared as above, in acetonitrile at a temperature such as -10° C. to -5° C., may be treated with a solution of ceric ammonium nitrate in water to yield a cis-3-acetoxy-4-phenylazetidin-2-one racemate. The latter compound may, for example, further be hydrolyzed, e.g., with aqueous potassium hydroxide, to yield cis-3-hydroxy-4-phenylazetidin-2-one.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=O)[CH:4]=[CH2:5].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33].N1C=CN=C1>C(OC)(C)(C)C.O.C(O)=O>[CH3:33][O:32][N:31]([CH3:30])[C:8](=[O:10])[CH2:7][O:6][CH:3]([CH:4]=[CH2:5])[C:2]([F:1])([F:15])[F:16]
Reactant: C=CC(OCC(=O)OC(C)(C)C)C(F)(F)F
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: O
Solvent: O=CO
Product: C=CC(OCC(=O)N(C)OC)C(F)(F)F
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a reactor containing tert-butyl 2-(1,1,1-trifluorobut-3-en-2-yloxy)acetate (1.150 kg, 4.788 mol) was added formic acid (6.2 kg) at rt. The reaction mixture was heated to 55-60° C. for 4-5 h. The formic acid was evaporated under vacuum (T=40-45° C.) and chased with toluene (2×3.0 L). To the residue was added CH2Cl2 (2.0 L) and further concentrated under vacuum. To the resulting residue was added CH2Cl2 (4.6 L) and the solution was cooled to 0° C., followed by N,N-carbonyldiimidazole (1.05 kg, 6.49 mol) in five portions. The mixture was stirred for 30 mins, and N,O-dimethylhydroxylamine hydrochloride (0.67 kg, 6.72 mol) was added in portions while maintaining temperature below 10° C. The reaction mixture was warmed to rt and stirred over 14 h. The reaction mixture was cooled to 3.2° C. and imidazole (100.7 g, 1.48 mol) was charged in two portions. The reaction mixture was warmed to rt and water (1.4 kg) was added, followed by methyl tert-butyl ether (14.0 L). The organic phase was washed with 2.0 N aq. HCl (1.0 L and 0.7 L), followed by sat. aq. NaHCO3 (1.2 L) and sat. aq. NaCl (1.20 L). The organics were concentrated to afford the title compound as an oil (0.95 kg, 87.2%). 1H NMR (500 MHz, CDCl3) δ ppm 5.85-5.76 (m, 1H), 5.62 (d, J=17.2 Hz, 1H), 5.56 (d, J=10.4 Hz, 1H), 4.49-4.34 (m, 3H), 3.68 (s, 3H), 3.67 (s, 1H), 3.18 (s, 3H), 3.08 (s, 1H); 13C NMR (126 MHz, cdcl3) δ ppm 169.9*, 163.4*, 128.61, 123.87 (d, J=282.0 Hz), 123.82, 78.54 (q, J=31.3 Hz), 66.12, 61.52, 60.56, 36.20, 32.24. Note: this compound is a 3:1 mixture of amide bond rotamers. *Carbonyl chemical shifts estimated indirectly through 1H-13C HMBC (heteronuclear multiple-bond correlation).
Reaction SMILES: [K].[Br:2][C:3]1[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]([NH:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:19]=1[C:20]([N:8]1[C:9](=[O:10])[C:4]2=[C:3]([Br:2])[C:13]([Br:14])=[C:12]([Br:15])[C:11]([Br:16])=[C:5]2[C:6]1=[O:7])=[O:21]
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: [K]
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)c2c(Br)c(Br)c(Br)c(Br)c2C1=O
Temperature: 25 °C

Procedure:
The potassium salt of 3,4,5,6-tetrabromophthalimide (0.10 mole) and dioxane (1200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise, with stirring, to the reaction mixture at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is stripped of solvent to yield the desired product N-(2,5-dichlorobenzoyl)-3,4,5,6-tetrabromophthalimide.
Reaction SMILES: [NH2:1][C:2](=[O:29])[CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]1=[O:28].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:1][C:2](=[O:29])[CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:24])[C:5]1=[O:28]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(N)=O)c1=O
Reactant: NCCN1CCOCC1
Product: NC(=O)Cn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-(2-amino-2-oxoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.36 (1H, m), 8.56 (1H, s), 7.61 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.01 (2H, t, J=8.5 Hz), 6.87 (1H, br s), 5.65 (1H, br s), 4.81 (2H, s), 4.12 (2H, s), 3.98 (4H, m), 3.91 (2H, q, J=6 Hz), 3.75 (2H, m), 3.37 (2H, t, J=6 Hz), 2.92 (2H, br); HRMS calcd for C24H26FN5O5+H+: 484.1996. Found: 484.1987.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH3:27])[N+:12]=2[O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH2:27][O:32][C:29](=[O:31])[CH3:30])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCc1c(C)[n+]([O-])c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Reactant: CC(=O)OC(C)=O
Product: CCc1c(COC(C)=O)nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12

Procedure:
421.5 g (1.1 M) of 1-(3,4-dimethoxyphenyl-3-methyl-4-ethyl-6,7-dimethoxy-isoquinoline N-oxide and 1.1 liters of acetic anhydride are refluxed for 2.5 hours, then the solution is evaporated at reduced pressure. The residue is recrystallized first from 1.2 liters of 99% ethanol, then the resulting product (414.5 g, m. p. 115° to 120° C.) is repeatedly recrystallized from one liter of 99% ethanol. Yield 393.7 g (84.1%), m.p. 129° to 131° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](Cl)=[O:23])[CH3:20].[OH-].[Na+]>C(Cl)Cl.O>[CH2:19]([O:21][C:22](=[O:23])[NH2:9])[CH3:20].[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Agent: NCCc1[nH]c2ccccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(N)=O
Reaction time: 0.17 h

Procedure:
To a solution of 18.9 g 3-phenyl-1H-indol-2-ethanamine in 220 ml methylene chloride are added 15.3 ml of chloroformic ethyl ester followed by 110 ml water. The mixture is stirred for 10 minutes. 6.4 g sodium hydroxide in 100 ml water are added and stirring is continued for further 20 minutes at room temperature. The organic phase is separated, washed once with 2N tartaric acid and water, dried and evaporated under reduced pressure. The oily residue of the heading compound is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[O:21].CC(=CC)C.C([OH:31])(C)(C)C>>[C:20]([C:3]1[CH:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])([OH:31])=[O:21]
Reactant: CC(C)(C)O
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Agent: CC=C(C)C
Product: COc1cccc2c1SC(c1ccccc1)C(C(=O)O)=C2Cl

Procedure:
As in example 13 but starting from 3.16 g of 4-chloro-3-formyl-8-methoxy-thioflav-3-ene, 250 ml tert-butanol and 60 ml 2-methyl-2-butene. After work up the crude oil is crystallised in a mixture of n-hexane and ethyl acetate. Pure 3-carboxy-4-chloro-8-methoxy-thioflav-3-ene is obtained as yellow crystals; m.p. 207°-210° C.-TLC (SiO2, CH2Cl2 /Acetone/HCOOH 18/1/1): Rf =0.45.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1.Cl.COCCO>O1CCOCC1>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 7-Amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mg, 0.00053 mol) Isopropyl alcohol, (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (170 mg, 0.00048 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and 2-Methoxyethanol (5.3 mL, 0.067 mol;) in a Radley tube, heat to 110° C. for about 4.5 h. Cool to RT and a solid came out of solution, stirred over night Filtration was followed by washing with 2-methoxyethanol to give a yellow powder. The powder was treated with saturated aq. bicarb, sonicated to break up solids and stirred for 1 h. The yellow solid was filtered and dried overnight. Isolated C as a yellow solid (131.16 mgs, 52%); MP: 248-249° C.; 1H-NMR (dmso, 400 MHz) δ 9.60 (s, 1H), 9.38 (br s, 1H), 9.15 (br s, 1H), 8.32 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 6.53-6.48 (m, 2H), 3.80-3.78 (m, 4H), 3.77 (s, 3H), 3.70 (s, 3H), 3.25-3.19 (m, 6H), 2.70-2.68 (m 2H), 2.14-2.10 (m, 2H); LC/MS: 525.36 (M+H).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:11]([NH:13][C:14]1[C:15](=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:16]([O:18]C)=[O:17])=[O:12].Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:11]([NH:13][C:14]1[C:15](=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)Nc2ccc(Cl)cc2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 20 ml of a 10% aqueous solution of sodium hydroxide and 10 ml of ethanol is added 0.95 g of methyl N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilate and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into 100 ml of water and after cooling, hydrochloric acid is added to make the mixture weakly acidic. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 0.7 g of N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid as colorless needles.