Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(/[CH:11]=[C:12](/[C:17]([F:20])([F:19])[F:18])\[CH:13]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)C>C(O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)/C=C(\C=[N+](C)C)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc2c(Br)cnn2c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
3-Amino-4-bromopyrazole (4.29, 26.5 mmol) and 2-(trifluoromethyl)-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (9.00 g, 26.5 mmol) were dissolved in ethanol (52.9 mL) and acetic acid (35.3 mL) and the reaction heated to 70° C. for 16 h. The solution was cooled to room temperature and concentrated. The residue was filtered through a fritted funnel, the precipitate washed with water, and dried under reduced pressure to afford the title compound (6.22 g, 23.4 mmol). LRMS (APCI) calc'd for (C7H3BrF3N3) [M+H]+, 266.0; found 265.9. 1H NMR (CDCl3, 500 MHz) δ 8.96 (d, J=1.1, 2.1, 1H), 8.71 (d, J=2.1, 1H), 8.28 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]([O:18]C)=[O:17])(=[O:4])=[O:3].O.[OH-].[Li+]>C1COCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]([OH:18])=[O:17])(=[O:3])=[O:4]
Reactant: COC(=O)Cn1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc2c1ccn2CC(=O)O
Yield: 89.9 %

Procedure:
To a solution of methyl 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetate (620 mg, 2.196 mmol) in a 1:1 mixture of H2O and THF (10 ml), lithium hydroxide (526 mg, 21.96 mmol) was added, and the mixture was reacted for 1 hour at room temperature. The organic solvent was evaporated and 1N HCl was added to the aqueous residue (pH=2); the aqueous phase was extracted with ethyl acetate (3×20 ml), and the combined organic layers were dried over sodium sulfate. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=95:5) affording 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetic acid (530 mg, 1.975 mmol, 90% yield). MS/ESI+ 269.1 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].C(Cl)Cl.N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reaction time: 0.33 h

Procedure:
A mixture of 570 mg. of l-ethyl 6,7-dimethoxy-3-aminomethylene-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 1.78 ml. of 1N sodium hydroxide and 3 ml. of ethanol was heated under reflux for 24 hours and then stored at 25° C. for 3 days. The solvent was removed by evaporation in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and then it was concentrated to give 540 mg. of an oil. The oil was chromatographed using 30 g. of silica gel, and using 6:4 benzene-ethyl acetate as solvent, giving 6 fractions. Fractions 1 and 2 were combined and recrystallized from ethyl acetate-hexane to give 49 mg. of the title product, m.p. 92°-93° C. Fractions 3-6 were combined to give 152 mg. of 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. This latter material was dissolved in 3 ml. of methylene chloride, and 3 ml. of pyridine followed by 0.5 ml. of ethyl chloroformate was added. After 20 minutes, the reaction mixture was diluted with an excess of methylene chloride and water. The organic phase was separated and washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The methylene chloride solution was then dried, and evaporated in vacuo to give an oil. The oil was recrystallized from ethyl acetate-hexane to give 95 mg. of the title compound, m.p. 92°-93° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:16]([NH2:18])=[NH:17].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:17][CH:16]=[N:18]2
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: N=CN
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2cc(F)cc(F)c12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
2,4,6-Trifluoro-benzonitrile (3.59 mmol, 500 mg) is dissolved in DMA (5 mL) and then formamidine acetate is added (3.59 mmol, 373.75 mg) followed by DIEA (10.78 mmol, 1.39 g). The reaction is stirred for 16 hr at 100° C. A solid forms, is collected by filtration and the solid is washed with CH2Cl2. This gives desired product 5,7-Difluoro-quinazolin-4-ylamine (227 mg, LC/MS m/z=182 [M+H]+) as a white powder.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])CCC.C(Cl)(=O)CC(Cl)=[O:18].C(N(CC)CC)C.[OH2:29]>C(OCC)C>[CH2:13]([CH:14]1[C:1](=[O:29])[NH:5][C:6](=[O:7])[NH:8][C:9]1=[O:18])[CH2:12][CH2:11][CH3:10]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CCCCNC(=O)Nc1ccccc1
Reactant: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCC1C(=O)NC(=O)NC1=O
Temperature: 30 °C

Procedure:
A quantity of 3.85 g of 1-t.butyl-3-phenylurea is stirred at 0° C. in 50 ml of dry diethyl ether. 1.95 ml of malonylchloride are slowly added dropwise to this solution. After the addition of a little triethylamine the reaction mixture is slowly heated to approximately 30° C. After 2 hours 50 ml of water are added. The ether layer is separated, washed with water, dried and evaporated. After recrystallisation from ethanol, 1-phenyl-3-t.butyl-barbituric acid is obtained in a yield of 0.6 g; melting-point 118°-125° C. The resulting product is acetylated as described in Example III, the title compound (28) being obtained; melting-point 145°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]4[CH2:25][CH:24]([C:26]([OH:28])=O)[CH2:23]4)[CH:19]=3)[N:14]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[N:39]1([C:26]([CH:24]2[CH2:23][CH:22]([CH2:21][C:18]3[CH:19]=[C:20]4[C:10]5([CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]5)[CH2:13][N:14]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[C:15]4=[CH:16][CH:17]=3)[CH2:25]2)=[O:28])[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)O)C3)cc12
Reactant: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)N4CCC4)C3)cc12
Reaction time: 15 h
Yield: 59.6 %

Procedure:
3-((1′-(tert-Butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)methyl)cyclobutanecarboxylic acid (17.5 mg, 0.033 mmol) was dissolved in methylene chloride (1 mL) Thereafter, azetidine hydrochloride (6.0 mg, 0.064 mmol), triethylamine (9.0 μL, 0.065 mmol), and PyBOP (34.0 mg, 0.065 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 15 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-((3-(azetidine-1-carbonyl)cyclobutyl)methyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (11.2 mg, 60%) in the form of a light brown oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])(O)=O.[Na+].[Cl:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[Cl:45][CH2:46][C:47]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:48]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 2.21 mmol) in EtOAc:THF:sat'd NaHCO3 (110 mL: 30 mL: 50 mL) was added 2-chloroacetyl chloride (1 mL, 12.6 mmol) and stirred at RT for 2.5 hr. The reaction mixture was stirred at RT for 1.5 h. Another addition of 2-chloroacetyl chloride (0.5 mL) was added and continued to stir for 2 h. Concentrated in vacuo to remove volatiles and residue was washed with 5% citric acid (2×50 mL), water (2×100 mL), and sat'd NaCl (1×50 mL). The organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (1.02 g, 87%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36])=[O:24]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]3[CH:33]=[CH:34][C:25]([C:23]([O:22][CH3:21])=[O:24])=[C:26]([N+:35]([O-:37])=[O:36])[CH:27]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1[N+](=O)[O-]
Yield: 54.5 %

Procedure:
DMF solution (2.0 mL) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone (54.5 mg, 0.20 mmol) and 4-methoxycarbonyl-3-nitrobenzhydrazide (47.8 mg, 0.20 mmol) was heated at 110° C. for 6 hours After removing solvent, the residue was purified by column chromatography to give the title compound (53.8 mg, 55%) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Reactant: NCc1ccc(F)c(Cl)c1
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(F)c(Cl)c1)c(O)c2=O
Yield: 52.6 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.050 g, 0.197 mmol) with 3-chloro-4-fluorobenzylamine (0.10 g, 0.63 mmol) as described in the preparation of example 1 gave 0.038 g (52% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.48 (2H, s, CH2), 4.49 (2H, d, J=6.4 Hz, NCH2), 7.3–7.55 (3H, m, aromatics), 9.50 (1H, broad t, NH), 12.16 (1H, s, OH). MS (ESI+) m/z 367 [M+H+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].O[S:10]([OH:13])(=[O:12])=[O:11].[OH:14][S:15]([OH:18])(=O)=[O:16].O=S(=O)=O.[C:23](O)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:23]2[NH:7][C:2]3[C:3]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:4][C:5]([S:15]([OH:18])(=[O:16])=[O:14])=[CH:6][C:1]=3[N:8]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)=O
Solvent: O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2[nH]c(-c3ccccc3)nc2c1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
108 parts of o-phenylenediamine are introduced into 500 parts of H2SO4 (>96%) and then 800 parts of oleum (65%) are added dropwise, the temperature being maintained at a maximum of 120° C. After 15 min, the mixture is cooled to 70° C. and 120 parts of benzoic acid are added. The mixture is then heated for 2 h at 180° C. The mixture is then slowly hydrolysed with 2 500 parts of water, the temperature being maintained below 10° C. The precipitate (crystals) is filtered off with suction, suspended in 8 parts of water and dissolved with sodium hydroxide solution (32%) at pH =7. The solution is stirred with activated carbon until colorless, and then precipitation is induced using 96% H2SO4 at pH=1-2. 300 parts of 2-phenylbenzimidazole-4,6-disulfonic acid are obtained. The compound has an absorption maximum in the UV-B region at λmax=308 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O>>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(C=O)cc(Br)c1O
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extracted with an ethyl acetate-methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product which was used as is for the following step. It melted at 180° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]([OH:35])CO)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([OH:40])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:31][CH:30]([C:32]([OH:40])=[O:35])[O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16](=[O:17])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(O)CO)O3)ccc1OC(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To [8-benzyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (1.53 g, 3.17 mmol) in THF (28 mL) was added NaIO4 (1.36 g, 6.34 mmol) followed by the addition of water (10 mL). The reaction mixture was stirred at room temperature for 2 hours, then filtered through celite, and concentrated in vacuo. The residue was partitioned between sat. aq. sodium bicarbonate (50 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo. To the intermediate aldehyde (˜1.4 g) was added 2-methylpropan-2-ol (17 mL) and 2-methylbut-2-ene (9 mL, 85.08 mmol) and the reaction mixture was cooled to 0° C. A solution of NaClO2 (938 mg, 8.29 mmol) and NaH2PO4 (1.15 g, 8.31 mmol) in water (17 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, then extracted with ethyl acetate (4×50 mL) and the combined organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated in vacuo to give 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid as a white foam (1.48 g, 100%). ESI-MS m/z calc. 466.6. Found 467.5 (M+1)+; Retention time: 1.27 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([NH:11][CH2:12][CH2:13][NH:14][CH3:15])=[O:10])=[CH:7][C:6]=1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:3].[CH2:25](OC1(O[Si](C)(C)C)CC1)[CH3:26].[CH3:36]C(O)=O.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:15]1([N:14]([CH3:36])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[C:8]2[CH:16]=[CH:17][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:6]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:7]=2)[CH2:26][CH2:25]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CNCCNC(=O)c1ccc(CN(C)C)c(Oc2cccnc2)c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1ccc(C(=O)NCCN(C)C2CC2)cc1Oc1cccnc1
Temperature: 50 °C
Yield: 35.7 %

Procedure:
To a solution of 4-dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide (0.090 g, 0.274 mmol) in a 1:1 mixture of THF:MeOH (4 mL) was added [(1-ethoxycyclopropyl)-oxy]trimethylsilane (0.28 mL, 1.37 mmol), AcOH (0.08 mL, 1.37 mmol), and NaCNBH3 (0.088 g, 1.37 mmol). The reaction mixture was heated to 50° C. for 24 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL), washed with sat. NaHCO3 (5 mL), dried (Na2SO4), and concentrated. HPLC purification under basic conditions yielded the desired product (0.036 g, 38%). MS (ESI): m/z found, 369.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.CO.[Pd]>[O:2]=[C:3]1[CH:4]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:5][C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:12]1
Reactant: [H][H]
Reactant: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
tert-butyl 4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate (660 mg, 1.7 mmol) was dissolved in a mixture of ethyl acetate (15 mL) and methanol (15 mL). Acetic acid (250 μL, 4.4 mmol) was added to the mixture. A catalytic amount of 50% wet 10% palladium on carbon was added to the mixture. Reaction vessel was charged with 15 psi of hydrogen gas. Reaction shook on a Parr apparatus at room temperature for 2 hours. Reaction mixture was filtered to removed the catalyst. Filtrated was concentrated in vacuo. Silica gel chromatography gave the title compound as orange foam in 47% yield. MS m/e (M−H)−=329.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].F[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:31]2[CH:32]=[CH:27][C:28]([N+:36]([O-:38])=[O:37])=[CH:29][C:30]=2[N+:33]([O-:35])=[O:34])[S:7]1(=[O:13])=[O:12]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CN(c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (303 mg, 1.05 mmol) in dry 1,4-dioxane (5 mL) is treated with Cs2CO3 (342 mg, 1.05 mmol). 1-Fluoro-2,4-dinitrobenzene (197 mg, 1.05 mmol) is added and the mixture is stirred at RT for 16 h. The solvent is evaporated and the residue is partitioned between EtOAc and 1N aqueous HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated. The residue is chromatographed on silica gel using 10%→100% EtOAc in hexanes as the eluent to afford 2-(2,4-dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a yellow solid: [M−1]−=451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:21]([O:20][C:18]([C:17]1[N:16]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[N:14][C:13]=1[CH3:12])=[O:19])[CH3:22].[CH2:21]([O:20][C:18]([C:17]1[N:16]=[CH:15][N:14]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[CH3:12])=[O:19])[CH3:22]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)c1c(C)ncn1-c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ncn(-c2ccc(Cl)c(Cl)c2)c1C
Temperature: 20 °C
Reaction time: 48 h
Yield: 22 %
Yield: 8 %

Procedure:
A suspension of 3,4-dichlorophenylboronic acid (8.22 g, 43.1 mmol), ethyl 4-methyl-5-imidazolecarboxylate (6.64 g, 43.1 mmol) and copper(II) acetate (7.83 g, 43.1 mmol) in CH2Cl2 (86 ml) was stirred at 20° C. for 48 h. All solids were filtered, the organic phase diluted with AcOEt (500 ml) and stirred with saturated aqueous Seignette salt solution. After filtration and evaporation the residue was chromatographed (silica, eluation with gradient hexane to AcOEt) to obtain 2.8 g (22%) of 3-(3,4-dichloro-phenyl)-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester [Mp. 135-136° C. (AcOEt/hexane), MS: m/e=298 (M+)] and 1.0 g (8%) of 1-(3,4-dichloro-phenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester [Mp. 163-164° C. (AcOEt/hexane), MS: m/e=298 (M+)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1CO
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4C)c(C)c3C)c2cc1OC
Yield: 96.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (140 mg, yield 89%).