Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].O=S(Cl)[Cl:11].Cl.[CH3:14]O>>[ClH:11].[NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: NCC(F)(F)C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C(F)(F)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 3-amino-2,2-difluoropropanoic acid (500 mg, 4 mmol) was solubilized in MeOH (10 mL). At 0° C., SOCl2 (1 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. Evaporation of the reaction mixture gave a white solid to be the product as HCl salt (570 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (t, J=16 Hz, 2 H) 3.87 (s, 3 H) 9.07 (br. s., 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1.[CH2:23]([NH2:26])[CH2:24][NH2:25]>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:25][CH2:24][CH2:23][NH2:26])[CH2:14]1
Reactant: NCCN
Reactant: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Solvent: O
Product: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1

Procedure:
Methanesulfonic acid 1-(6-methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl ester (1.96 g, 6.1 mmol) was heated to 100° C. in ethylene diamine (10 mL, 150 mmol) overnight. The reaction mixture was cooled, diluted with water and extracted 4× with a solution of 10% isopropanol in chloroform. The combined organic layers were washed with brine, dried over magnesium sulfate, and purified by column chromatography (silica, 10% MeOH in chloroform) to afford the title coompound as a white solid (1.3 g, quantitative yield as an adduct of two moles of water): LC/MS m/z 288 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:15])[NH:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[CH3:16].C(ON[C:23]([C:25]1[CH:34]=C2[C:28](C(C)=CC(C)(C)N2)=[CH:27][CH:26]=1)=O)(C)(C)C>>[C:11]([O:10][NH:9][C:8]([C:4]1[C:3]([CH3:16])=[C:2]2[C:7]([C:27]([CH3:28])=[CH:26][C:25]([CH3:34])([CH3:23])[NH:1]2)=[CH:6][CH:5]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1c(N)cccc1C(=O)NOC(C)(C)C
Reactant: CC1=CC(C)(C)Nc2cc(C(=O)NOC(C)(C)C)ccc21
Product: CC1=CC(C)(C)Nc2c1ccc(C(=O)NOC(C)(C)C)c2C
Yield: 84 %

Procedure:
This compound was prepared from 2-amino-6-tert-butyloxycarbamoyltoluene (4.00 g, 18.0 mmol) in a manner similar to that described for 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 13), affording 4.56 g (84%) of the desired dihydroquinoline as a white solid. Data for 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline: 1H NMR (400 MHz, CDCl3) 6.94 and 6.88 (br ABq, 2H, JAB·8.3 Hz, 6,5-H), 6.16 (br s, 1H, HNBoc), 5.27 (s, 1H, 3-H), 3.61 [br s, 1H, (CH3)2CNH], 2.04 (s, 3H, 8-CH3), 1.97 (s, 3H, 4-CH3), 1.50 [s, 9H, (CH3)3CO)], 1.28 [s, 6H, 2-(CH3)2].
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:36]=1.CO>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:9][C:8]=2[CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 60 °C
Yield: 81.4 %

Procedure:
A solution of 1 N aqueous sodium hydroxide solution (1 mL) was added to trans-methyl 2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylate (55 mg, 0.12 mmol) in THF (2 mL). Methanol was added until the mixture became homogeneous, and the resulting solution was heated at 60° C. for 1 h. The reaction was concentrated under reduced pressure to remove excess solvents, and the residue was partitioned between water and chloroform/isopropanol (4:1). The aqueous layer was adjusted to pH 2 by addition of aqueous phosphoric acid solution, with stirring. The organic layer was then separated, dried (Na2SO4), and concentrated under reduced pressure. The residue was suspended in acetone, and the resulting solid was collected by filtration and dried in vacuo to provide the title compound (45 mg, 84%). 1H NMR (300 MHz, acetone-d6) δ 10.40–10.10 (br s, 1 H), 8.15 (d, 2 H), 8.01 (d, 2 H), 7.87–7.82 (m, 5 H), 7.41 (dd, 1 H), 7.05–6.95 (m, 1 H), 4.26–4.17 (m, 1 H), 3.43–3.34 (m, 1 H), 2.31–2.23 (m, 1 H), 1.98–1.70 (m, 5 H); LC-MS m/z 461.3 (MH+), retention time 3.56 minutes.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=1.[SH:14][C:15]1[NH:16][C:17]2[C:23]([S:24]([C:27]3[C:38]([CH3:39])=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:28]=3[CH3:40])(=[O:26])=[O:25])=[C:22]([O:41][CH3:42])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:42][O:41][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([S:14][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([CH3:13])=[CH:6][N:5]=3)[NH:16][C:17]=2[C:23]=1[S:24]([C:27]1[C:28]([CH3:40])=[CH:29][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:37][C:38]=1[CH3:39])(=[O:25])=[O:26]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(S)[nH]c23)c(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(C)c(S(=O)(=O)c2c(OC)ccc3nc(SCc4ncc(C)c(OC)c4C)[nH]c23)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-Chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (4.4 g, 0.020 mol) was added to a mixture of methyl {4-[(2-mercapto-5-methoxybenzimidazolyl)sulfonyl]-3,5-dimethylphenoxy}acetate (Intermediate A4, 8.2 g, 0.019 mol), potassium carbonate (5.7 g, 0.041 mol), and dimethylformamide (80 mL). The mixture was stirred for 1.5 hr and was then poured in 150 mL of rapidly stirring ice water containing 40 mL of 1.2 M hydrochloric acid. The resulting solid was collected and washed with several portions of water. After partial air-drying, the 10 g of solid was dissolved in 100 mL of dichloromethane. This solution was washed with saturated aqueous sodium bicarbonate, filtered through 1PS paper, and concentrated. The residue was mixed with boiling methanol and collected, yielding 8.9 g (80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[CH2:10][C:11](=O)[CH3:12]>[OH-].[Na+]>[Cl:1][C:2]1[C:3]2[S:8][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1ccccc1Cl
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc2c(Cl)cccc12
Temperature: 120 °C

Procedure:
To a solution of 11.8 g. 2-chlorothiophenol (Aldrich, 15566-7) dissolved in aqueous sodium hydroxide (4.0 g./50 ml water) is added chloracetone (9.3 g.). After heating for 1 hour the reaction is cooled and extracted with methylene chloride. The extract is dried (MgSO4) and concentrated to an oil. The oil is added to polyphosphoric acid (100 g.) and slowly heated to 120° C. The mixture is added to ice and extracted with ethyl ether. The ether extract is washed with water (twice); dried (MgSO4) and concentrated to an oil. The oil is purified by distillation.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1.O1CCOCC1.Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][S:1][C:2]1[O:3][C:4]([C:7]2[O:11][C:10]([CH3:12])=[N:9][N:8]=2)=[N:5][N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Cc1nnc(-c2nnc(S)o2)o1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nnc(-c2nnc(SCCC(F)=C(F)F)o2)o1
Yield: 54.5 %

Procedure:
3.7 g of 2-mercapto-5-(2-methyl-1,3,4-oxadiazol-5-yl)-1,3,4-oxadiazole according to Example H1 are initially introduced into a mixture of 36 ml of dioxane and 4 ml of dimethylformamide, and 2.24 g of potassium t-butylate are added, while stirring. 4.2 g of 4-bromo-1,1,2-trifluorobut-1-ene are added dropwise and the mixture is stirred overnight at room temperature. After the salts have been filtered off, the solvents are distilled off in vacuo, the residue is taken up in methylene chloride, the solution is washed with water and 1-normal sodium hydroxide solution in succession and the solvent is evaporated off in vacuo. 3.2 g of the desired compound of melting point 77°-79° C. are obtained as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([CH3:34])[CH3:33])[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(O)C.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([CH3:34])[CH3:33])[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Iron (68 mg, 1.22 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-N-methyl-6-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (112 mg, 0.203 mmol) in ethanol (2.3 mL) and AcOH (2.3 mL) at rt. It was placed in a reaction block set to 100° C. and allowed to stir for 1 hr. The mixture was allowed to cool and was diluted with EtOAc and washed with 1M HCl, followed by 1N NaOH and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et2O to give the titled compound (52 mg, 47%). 1H NMR (500 MHz, CD3OD) δ ppm 6.58-6.65 (3H, m), 6.52 (1H, d, J=7.63 Hz), 6.37 (1H, d, J=7.93 Hz), 6.30 (1H, t, J=7.63 Hz), 6.18 (2H, d, J=7.32 Hz), 6.08 (1H, s), 6.03 (2H, t, J=7.78 Hz), 5.88-5.97 (3H, m), 5.73 (1H, s), 1.65 (3H, s), 0.50 (6H, s). LC-MS retention time 1.54 min; m/z (MH−): 520. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.11 min, purity=95%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=11.11 min, purity=94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=O.P(Cl)(Cl)([Cl:14])=O.O=[C:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1>>[CH3:27][O:26][C:24]([CH:21]1[CH2:22][CH2:23][C:18]2[C:19](=[C:6]([Cl:14])[C:5]3[C:4]([N:11]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH2:20]1)=[O:25]
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: COC(=O)C1CCc2nc3cc(Cl)ccc3c(Cl)c2C1
Yield: 73 %

Procedure:
To a slurry of 16.5 g (0.096 mol) of 4-chloroanthranilic acid and 166 ml of phosphorous oxychloride is added portionwise 15 g (0.096 mol) of methyl 4-ketocyclohexane carboxylate. The reaction mixture is refluxed for 3 h, cooled, and concentrated in vacuo. The residue is dissolved in methylene chloride and poured into an ice-NH4OH mixture. The aqueous phase is separated and extracted with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is triturated with ethyl ether to give 21.7 g (73%) of the title compound: IR (KBr) 1730, 1605, 1580, and 1550 cm-1 ; NMR (DMSO-d6) δ 8.14-8.08 (m, 1H), 8.0-7.96 (m, 1H), 7.70-7.64 (m, 1H), 3.70 (s, 3H), 3.30-3,16 (m, 1H), 3.12-2.96 (m, 4H), 2.32-2.20 (m, 1H), and 2.04-1.86 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1.[NH2:20][NH2:21]>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:20][NH2:21])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([NH2:19])[N:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Solvent: CO
Product: NNC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Reaction time: 48 h
Yield: 73.8 %

Procedure:
Methyl 4-[(2,6-diaminopyrimidin-4-yl)oxy]benzoate (2.74 g, 10.52 mmol) was suspended in ca. 180 mL of anhydrous methanol and anhydrous hydrazine (1.021 g, 1.0 mL, 31.85 mmol, 3.03 eq) was added to this suspension. The reaction mixture was refluxed for 3 hours, then MeOH was very slowly distilled off till the total volume reached ca. 30 mL. This solution was allowed to stand at ambient temperature for 48 hrs. A white precipitate slowly crystallized out. It was collected, washed with 40 mL of EtOAc, 40 mL of anhydrous Et2O and dried in vacuo to give the title product as a fine white powder (2.02 g). Yield 73.7%.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1.CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([NH:31][CH:32]6[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]6)=[N:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(NC6CCN(C(=O)OC(C)(C)C)C6)nc5)nn34)ccnc2c1
Reaction time: 1 h

Procedure:
A 0.5-2 mL microwave vial was charged with 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 100° C. and then 30 minutes at 120° C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate.
Reaction SMILES: N(C1C=CC(S(N[Si](C(C)(C)C)(C)C)(=O)=O)=CC=1)=[C:2]=S.COC1C=CC([C:29]2[C:34]3[S:35][CH:36]=[C:37]([C:38]4[NH:42][N:41]=[C:40]([NH:43][C:44]5[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=5)[CH:39]=4)[C:33]=3[CH:32]=[CH:31][CH:30]=2)=CC=1.[OH2:54]>>[CH3:2][O:54][C:30]1[CH:31]=[CH:32][C:33]2[C:37]([C:38]3[NH:42][N:41]=[C:40]([NH:43][C:44]4[CH:45]=[CH:46][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:48][CH:49]=4)[CH:39]=3)=[CH:36][S:35][C:34]=2[CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: O
Reactant: COc1ccc(-c2cccc3c(-c4cc(Nc5ccc(S(N)(=O)=O)cc5)n[nH]4)csc23)cc1
Product: COc1ccc2c(-c3cc(Nc4ccc(S(N)(=O)=O)cc4)n[nH]3)csc2c1
Yield: 34 %

Procedure:
Prepared in 34% yield from 3-acetyl-6-methoxy-benzolblthiophene and 4-isothiocyanato-N-(TBDMS)-benzenesulfonamide analogous to the procedure for 4-{5-[7-(4-methoxy-phenyl)-benzo[b]thiophen-3-yl]-1H-pyrazol-3-ylamino]-benzenesulfonamide [Example 3(d)]. 1H NMR (300 MHz, DMSO-d6) 6 12.60 (s, 1H), 9.10 (s, 1H), 7.92 (d, 1H, J=8.7Hz), 7.80 (s, 1H), 7.65 (app d, 3H, J=8.7Hz), 7.48 (d, 2H, J=8.1Hz), 7.12 (d, 1H, J 8.7Hz), 7.05 (s, 2H), 6.28 (s, 1H), 3.85 (s, 3H). Anal. (C18H16N4O3S20.35 H2O) C. H, N, S. Calculated C=53.15, H=4.14, N=11.77, S=15.77; found C=53.50, H=4.14, N=13.77, S=15.77.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14].C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14]
Reactant: COC(CC#N)OC
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C#N)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Benzaldehyde (79.5 g, 0.75 mol) and 3,3-dimethoxypropionitrile (115.1 g, 1.0 mol) were mixed together and added to a solution of sodium methoxide (54.0 g, 1.0 mol) in methanol (400 mL) over a period of 15 minutes. The mixture was stirred at room temperature overnight. Most of the methanol was evaporated in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (450 mL). The organic layer was separated, washed with brine (400 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residual oil was distilled to give 103 g (68%) of the product as a colorless oil, bp 125-130° C. (2 mm Hg).
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=[O:6])[CH3:5].[C:8]1(=[O:15])[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)([O-:18])=[O:17]>C(O)C>[C:4]([C:3]1[CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)[C:13]2[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]=2[NH:1][C:2]=1[CH3:7])(=[O:6])[CH3:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(=O)C=C(C)N
Solvent: CCO
Product: CC(=O)C1=C(C)NC2=C(C(=O)CCC2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
4-Amino-3-penten-2-one (2.00 g), 1,3-cyclohexanedione (2.30 g), and 3-nitrobenzaldehyde (3.08 g) were combined in ethanol (180 mL) and heated at reflux for 5 hours. A yellow solid formed upon cooling to ambient temperature. The solid was purified by trituration with hot ethyl acetate/ethanol to yield the title compound (2.65 g) as a yellow solid; mp >250° C.; NMR: 1.67-1.97 (m,2, CH2), 2.13 (s,3, CH3), 2.22 (m,2, CH2), 2.35 (s,3, CH3), 2.47 (m,2, CH2), 5.11 (s,1, CH), 7.52 (m,1, Ar), 7.60 (d,1, J=7.7, Ar), 7.97 (m,2, Ar), 9.32 (s,1, NH); MS: m/z=326(M). Analysis for C18H18N2O4 : Calculated C, 66.25; H, 5.56; N, 8.58, Found: C, 65.99; H, 5.61; N, 8.40 .
Reaction SMILES: COC1C=CC([N:9]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)[C:10]([NH2:12])=[O:11])=CC=1.[CH3:21]S(O)(=O)=O>COCCOCCOC>[NH:9]1[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][NH:12][C:10]1=[O:11]
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(N(C(N)=O)c2ccc(OC)cc2)cc1
Solvent: COCCOCCOC
Product: O=C1NCc2ccccc2N1

Procedure:
A solution of 144 mg (0.53 mmol) 1,1-bis-(4-methoxy-phenyl)-urea, 160 μl (1.06 mmol) cumic aldehyde and 16 μl (0.27 mmol) methane sulfonic acid in 1 ml diglyme is heated for 4 d at 100°. The reaction mixture is extracted with water/dichloromethane and the intermediate dihydro-quinazolinone is isolated by preparative HPLC. Oxidation with ruthenium trichloride and sodium periodate, as described above, furnishes 4-(4-isospropyl-phenyl)-6-methoxy-1-(4-methoxy-phenyl)-1.H.-quinazolin-2-one.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:33]([NH:35][C@H:36]([C:48]([OH:50])=[O:49])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:34])[C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.N1C(C)=CC=CC=1C.FC(F)(F)S([O-])(=O)=O>ClCCl>[C:14]([S:13][C:10]([CH3:12])([CH3:11])[C@@H:9]([C:33]([NH:35][C@H:36]([C:48]([OH:50])=[O:49])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1)=[O:34])[NH2:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(S(=O)(=O)O)cc1)C(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](N)C(=O)N[C@@H](Cc1ccc(S(=O)(=O)O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
To the solution of tetrabutylammonium N-t-butoxycarbonyl-S-trityl-L-penicillamyl-p-sulfophenylalanine (B-23)(7.5 g) and 2,6-lutidine (3.8 ml) in dichloromethane (100 ml), was added dropwise at 0° C. the solution of trimethylsylyl trifluoromethanesulfonate (5.5 ml), and the mixture was stirred for 1 hour while the temperature was gradually returned to the room temperature. The solvent was evaporated off under reduced pressure and the residue was washed with diethyl ether and acetone, in this order, to give S-trityl-L-penicillamyl-p-sulfophenylalanine (3.lg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][S:10][C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>>[CH3:9][S:10][C:11]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:12]=1[C:13]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])=[O:14]
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: NC1CCCCC1=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)NC1CCCCC1=O

Procedure:
The title compound, off-white solid, MS: m/e=332.1 [(M+H)+], was prepared in accordance with the general method of intermediate B from 2-amino-cyclohexanone and 2-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:38][C:39]([O:41][CH3:42])=[O:40])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2nccc(-c3ccncc3)c2c1
Solvent: CO
Product: COC(=O)C=Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A mixture of 4-(4-pyridinyl)-6-quinolinecarbaldehyde (2.29 g, 9.78 mmol), methyl (triphenylphosphoranylidene)acetate (3.30 g, 9.78 mmol) in MeOH (75 mL) was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the resulting residue was purified by silica gel chromatography (1% MeOH in EtOAc) to give the title compound (2.71 g, 95%) as a white solid. MS(ES)+ m/e 291 [M+H]+.