Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[C:20]=[O:21].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:21])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: COc1ccccc1N=C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 1-isocyanato-2-methoxy-benzene, and diisopropylethyl amine, are reacted to give the title product. LC-MS: 411 (M++1). 1H NMR (CDCl3) δ 3.15–3.25 (m, 4H), 3.7–3.85 (m, 4H), 3.9 (s, 3H), 4.6–4.8 (s, 2H), 6.2 (s, 1H), 6.86–6.9 (m, 1H), 6.94–7.02 (m, 2H), 7.16–7.21 (m, 2H), 7.62–7.65 (d, 1H), 7.74–7.78 (d, 1H), 8.14–8.19 (m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>C(Cl)Cl>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]3[C:42]4[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=4[C:36]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=4)=[N:35]3)[CH2:13][CH2:12]2)=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 82 mg (0.27 mmol) of 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in 2 mL of CH2Cl2 was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperazine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 105 mg (68%) of a white solid. MS (electrospray), exact mass calculated for C29H31F3N6O3, 568.24; m/z found, 569.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.41 Hz, 1H), 7.69 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m, 1H), 4.93 (br m, 1H), 4.87 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2.3H), 4.09-3.95 (m, 1.7H), 3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3.62-3.49 (m, 4H), 3.01-2.85 (m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m, 2H), 2.58-2.45 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[C:6]([O:13][CH3:14])[C:5]([O:15][CH:16]([F:18])[F:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.CCN=C=[N:30][CH2:31][CH2:32][CH2:33]N(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N)CC>ClCCl.O>[Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]([NH:30][CH2:31][CH2:32][CH3:33])=[O:12])=[C:6]([O:13][CH3:14])[C:5]([O:15][CH:16]([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1c(OC(F)F)ccc(Br)c1OCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCCN
Product: CCCNC(=O)COc1c(Br)ccc(OC(F)F)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a stirring solution of 2-(6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)acetic acid (420 mg, 1.284 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.54 mL, 5.20 mmol), EDC.HCl (369 mg, 1.921 mmol), HOBt (393 mg, 2.56 mmol) and propylamine (227 mg, 3.85 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)-N-propylacetamide as a liquid (300 mg, 63%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:8]=[C:9]([CH:13]([OH:19])[C:14](=[NH:18])[O:15]CC)[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:8]=[C:9]([CH:13]2[O:19][C:1](=[O:2])[NH:15][C:14]2=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1cccc(F)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(F)c2)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 16 hours at room temperature was employed following the cold perfusion with phosgene and the product was extracted into methylene chloride following quench over crushed ice, ethyl 1-(3-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (16 g., 0.068 mole) was converted to toluene recrystallized 5-(3-fluorophenyl)oxazolidine-2,4-dione (7.51 g., 56%; m.p. 147°-149° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CS(O[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=O)=O.C([O-])(O)=O.[Na+]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN1CCNC1=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCN1CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 300 mg; 0.88 mmol), 2-(2-oxoimidazolidin-1-yl)ethyl methanesulfonate (Intermediate 31; 274 mg; 1.32 mmol), NaHCO3 (403 mg; 4.80 mmol) in EtOH (10 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated, diluted with EtOAc (30 mL), washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 100 mg (25%) of the title compound as a yellow solid, which was used directly used without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]=1[CH2:17][O:18][CH3:19])=[CH:13][C:12]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=3)(=[O:3])[CH3:2].C(O[CH:31](OCC)[N:32](C)C)C>>[CH2:21]([O:20][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:6]=[N:5][C:4]([C:1]3[O:3][N:32]=[CH:31][CH:2]=3)=[C:16]([CH2:17][O:18][CH3:19])[C:15]2=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCc1c(C(C)=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: CCOC(OCC)N(C)C
Product: COCc1c(-c2ccno2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At 100° C., 500 mg of 3-acetyl-6-benzyloxy-4-methoxymethyl-β-carboline is stirred overnight in 5 ml of N,N-dimethylformamide diethylacetal. After concentration by evaporation, the mixture, without further purification, is taken up in 20 ml of absolute ethanol, combined with 600 mg of hydroxylamine-O-sulfonic acid in 5 ml of methanol, and stirred for 5 hours at room temperature. After neutralization with triethylamine, the reaction mixture is stirred overnight, introduced into water, and extracted with ethyl acetate; the organic phase is dried over magnesium sulfate and concentrated under vacuum. After chromatography over silica gel with acetone:triethylamine in a ratio of 10:1 as the eluent, 130 mg of 6-benzyloxy-4-methoxymethyl-3-(5-isoxazolyl)-β-carboline is obtained, melting point 125°-126° C.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]>>[CH3:18][C:16]([C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[OH:26])[CH:9]=[O:10])([CH3:19])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CC(C)(C)c1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 22.6 %

Procedure:
Into 101.5 g of N-methylformanilide was added dropwise with cooling 107 g of phosphoryl chloride over a period of 15 minutes. The mixture was allowed to warm to room temperature and stirred for 70 minutes. 67.5 g of ortho-t-butylphenol was added and stirred for about 45 minutes after which the mixture was heated to about 50°-60° C. and allowed to stir for 4.5 hours. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 ml of a 5% potassium hydroxide solution. The aqueous potassium hydroxide layer was separated and added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to 3 with concentrated hydrochloric acid with stirring. The resultant layers were separated and the aqueous layer was again extracted with chloroform and dried over sodium sulfate overnight to give 18.1 g of the desired subtitled intermediate.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17]C=O)[CH3:16])[C:9]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])(=[O:3])[CH3:2].[OH-].[Na+].C(OC(=O)C)C>O1CCOCC1>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([OH:17])[CH3:16])[C:9]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The formate ester (e4, 425 mg,0.89 mM) was dissolved in 20% aqueous 1,4-dioxan (80 ml) and cooled to 0° C. 0.1 N Sodium hydroxide solution (10.74 ml, 1.07 mM) was added and stirring continued for 5 minutes. Ethylacetate (150 ml) was then added and the organic solution washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration, the solvent was removed to yield a pale yellow solid. This solid was chromatographed over silica gel (15 gm). Elution with 10% ethanol/chloroform gave the pure p-nitrobenzyl (5R,6S)-3-(E-2-acetamidoethenylthio)-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (e5) as a white solid. This solid was digested in dry diethyl ether and collected by filtration (100 mg), λmax (EtOH) 325 nm (εm 16880), 263 nm (εm 17968), νmax (KBr) 3420, 3260, 1778, 1700, 1675, 1624, 1554, 1520, 1380, 1350, 1335 cm-1 ; δH (d7 -DMF) 10.50 (1H, d. J 10 Hz, NH), 8.30 (2H, d, aromatic protons), 7.85 (2H, d, aromatic protons), 7.22 (1H, dd, J 10 Hz and 14 Hz, NHCH=CH), 6.02 (1H, d, J 14 Hz), 5.47 (2H, q, CH2Ar), 4.28 (dt, 1H, J 3 Hz and 9 Hz, 5-CH), 4.08 (1H, dq, 8-CH), 3.43 (1H, dd, J 3 Hz and 6.3 Hz, 6-CH), 3.27 (2H, ABX, 4-CH2) 2.03 (3H, s, COCH3), 1.23 (3H, d, J 6 Hz, CH3CH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (15.0 g, 68.49 mmol, 1 eq) in MeOH (150 mL), SOCl2 (23.09 mL, 136.9 mmol, 2 eq) was added at 0° C. for 15 min and the mixture was stirred at RT for 12 h. The MeOH was evaporated and the residue was diluted with ethyl acetate (250 mL), washed with a saturated aqueous solution of NaHCO3, brine (150 mL) and water (150 mL). The ethyl acetate layer was dried over Na2SO4, evaporated under vacuum to get methyl 4-bromo-2-fluorobenzoate (15 g, 93%) as an off white solid (LC-MS purity, 99%; TLC system: EtOAc/PE (3:7), Rf: 0.8).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[OH:6][CH2:7][CH:8](S(C)(=O)=O)[C@@H:9](O)[C:10]([OH:12])=[O:11].O1C[C@H]1CC([O-])=O>>[O:6]1[CH2:7][C@H:8]1[CH2:9][C:10]([O-:12])=[O:11].[C:1]([NH3+:5])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)C(CO)[C@@H](O)C(=O)O
Reactant: CC(C)(C)N
Agent: O=C([O-])C[C@@H]1CO1
Product: CC(C)(C)[NH3+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
t-butyl amine (571mg, 7.81mmol) was added to the reacting solution of D2O containing (S)-4-hydroxy-3-methanesulfonyl hydroxybutyric acid, so prepared from Example 3 and stirred at room temperature for 4 hours. The presence of the target t-butyl anmmonium (R)-3,4-epoxybutyrate in a layer of the reacting solution was confirmed by nuclear magnetic resonance.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]>C(O)(=O)C>[N:10]1([C:11]2[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH:12]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
2,5-dimethoxytetrahydrofuran (0.74 ml, 0.76 g, 5.74 mmol, 1.2 eq) was added to a stirred suspension of dimethyl 5-aminoisophthalate (1.0 g, 4.78 mmol, 1 eq) in 7 ml acetic acid under Ar. The mixture was heated to reflux at 135° C. After 45 min the reaction was cooled to RT, and the solvent was removed in vacuo. The residue was stirred in saturated aqueous NaHCO3/EtOAc overnight. The layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (×1), water (×2), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.288 g (1.11 mmol, 23% yield) of the product. A significant amount of crude product was also collected.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.BrBr.[CH:26]([NH2:28])=[S:27].C(N)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[S:27][CH:26]=[N:28][C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: NC=S
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Agent: BrBr
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: NC=O
Product: CCn1c(Cc2scnc2-c2cccc(F)c2)nc2cc(Br)ccc21

Procedure:
A mixture of 3-(5-bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.2 g, 0.53 mmol) and bromine (0.1 g, 0.62 mmol) is refluxed in 1,4-dioxane for 2 hours. Thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (1.3 mmol) are added to the solution. The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (15 mL) and DCM (40 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×30 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% methanol in DCM) to give 5-bromo-1-ethyl-2-[4-(3-fluoro-phenyl)-thiazol-5-ylmethyl]-1H-benzoimidazole. 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.91 (s, 1H), 7.38-7.48 (m, 4H), 7.11-7.19 (m, 2H), 4.59 (s, 2H), 3.90 (q, 2H), 1.12 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:24]>CN(C=O)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]([OH:30])=[O:29])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1C(=O)O)=C1SC=CS1
Temperature: 60 °C

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (15.9 g) and anthranilic acid (14 dissolved in DMF (100 ml). The mixture was stirred at 60° C. for hrs. The reaction mixture was poured into ice-water. The solid formed was filtered and recrystallized from ethyl acetate to give the titled compound. (5.6 g, 30.7%)
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].CCN(CC)CC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:34](=[O:35])[O:36][CH2:37][CH3:38])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(C(=O)Nc2ccc(N(CC)CC)cc2)CCc2ccccc2C1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
The amine from Example 8A (34 mg, 0.1 mmol) was dissolved in THF (0.5 mL) and Et3N (15 mg, 0.1 mmol) and ethyl chloroformate (13 mg, 0.12 mmol) were added at 0° C. after which the mixture was allowed to stir overnight. HPLC purification gave the titled compound (10 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ 9.14 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.08 (m, 4H), 7.08 (s, 1H), 6.61 (d, J=9.0 Hz, 2H), 3.96 (m, 2H), 3.28 (q, J=6.6 Hz, 4H), 3.02 (d, J=16.5 Hz, 1H), 2.73 (m, 2H), 2.36 (m, 1H), 2.05 (m, 1H), 1.13 (t, J=6.9 Hz, 3H), and 1.05 (t, J=7.2 Hz, 6H). (one proton (ArCHnHbC(C═O)) overlapped with water)). MS (ESI) positive ion 410 (M+H)+; negative ion 408 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3cn[nH]c3c2)CC1
Temperature: 110 °C

Procedure:
To a mixture of 6-bromoindazole (2.0 g, 10.2 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g, 11.2 mmol) and Pd(PPh3)4 (1.2 g, 1.0 mmol) under N2 were added 1,4-dioxane (80 mL), followed by addition of K2CO3 (2 M in H2O, 20 mL, 40 mmol). The resulting mixture was heated at 110° C. for 16 h, then cooled to room temperature. The resulting mixture was then treated with saturated Na2CO3 aqueous solution. The resulting mixture was extracted with EtOAc (3×). The combined extracts were washed with brine and then dried over Na2SO4. The resulting mixture was filtered, concentrated under reduced pressure, and the residue purified by flash chromatography on silica-gel (gradient eluent heptane to 60% EtOAc in heptane) to yield 4-(1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as brownish foam solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2.[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([N:15]=1)[C:13](=[O:16])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=2
Reactant: C[O-]
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc3ccccc3c(=O)n2n1
Yield: 70.9 %

Procedure:
2-Chloro-10H-pyridazino[3,2-b]quinazolin-10-one (2.3 g) and sodium methoxide (1.1 g) in 100 ml of methanol was heated at 60° C. for 5 hours. After completion of the reaction, the solvent was removed by distillation, followed by addition of an aqueous solution of acetic acid. The precipitates were collected by filtration and recrystallized from methanol to give 1.6 g of 2-methoxy-10H-pyridazino[3,2-b]-quinazolin-10-one (Compound No. 1). M.P., 222.5°-223.0° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Br:11])[CH:3]=1.[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH2:21][N:15]3[CH:14]=[CH:13][CH:12]=[C:16]3[CH2:17]2)=[O:7])=[C:4]([Br:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1Br
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccn2Cc2ccccc21
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Step b) (4-Fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzo-diazepin-10-yl)-methanone: A solution of 4-fluoro-2-bromobenzoyl chloride (5.32 g) from step a), in dichloromethane (35 ml), was added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (3.44 g) and triethylamine (2.27 g) in dichloromethane (80 ml) and cooled in an ice bath. The cooling bath was removed and after stirring for 16 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale purple foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in the intermediate (4-fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone as a tan foam (6.91 g), MS m/z: 384 (M)+. This material was used without further purification in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:52])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:18][C:17]=1[CH2:41][O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)(C)(C)C>C(Cl)Cl>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:52])=[O:12])=[C:17]([CH2:41][O:42][C:43](=[O:51])[NH:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:18]=2)=[CH:32][CH:31]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.031 mL, 0.4 mmol) was added to a solution of 3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-2-cyclohexylcarbamoyloxymethyl-phenyl}-propionic acid tert-butyl ester (50 mg, 0.08 mmol) in CH2Cl2 (5 mL) at room temperature. The reaction mixture was stirred overnight and concentrated under vacuum to give the title compound. (39 mg, 88%). 1H-NMR (200 MHz, CDCl3): δ 7.83-7.72 (m, 4H), 7.57-7.43 (m, 3H), 7.12 (d, 1H, J=8.6), 6.98-82 (m, 4H), 5.10 (s, 2H), 4.82 (br s, 1H), 4.23 (t, 2H, J=5.9), 4.15 (t, 2H, J=5.9), 3.57-3.36 (m, 1H), 2.94 (m, 2H), 2.62 (m, 2H), 2.28 (qn, 2H, J=5.9), 1.98-1.02 (m, 10H).