Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O.C[N:22]([CH:24]=[O:25])C>>[CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].[CH2:15]([C:24]([NH2:22])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCCCCN=C=O
Agent: CCCCN1CC(=O)NC1=O
Product: CCCCCCC(N)=O

Procedure:
1-Butylimidazolidine-2,4-dione (100 mg, 0.64 mmol) and 1-isocyanatohexane (97.7 mg, 0.768 mmol) were reacted in DMF in analogy to example 1. Yield: 9 mg (5%), M+H+: 284.50.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>ClCCl>[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:20]([F:23])([F:21])[F:22])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:35]([F:34])([F:45])[F:46])[CH2:16][CH2:15]2)=[N:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1cnc(N2CCNCC2)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To an ice-cold solution of 2-piperazin-1-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid (3-methylbutyl)amide (0.323 g, 0.935 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (0.242 mL, 1.40 mmol). The mixture was stirred for 10 minutes before 2-trifluoromethylbenzoyl chloride (0.175 g, 0.842 mmol) in 5 mL dichloromethane was added. The stirring was continued for another 15 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate solution, followed by water. The mixture was extracted with dichloromethane, and the organic layer was separated, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in yield 76% (0.225 g, 0.435 mmol). 1H NMR (CDCl3) δ 8.59, 7.73-7.71, 7.64-7.51, 7.35-7.33, 5.76, 4.09-3.74, 3.44-3.37, 3.26-3.22, 1.68-1.59, 1.48-1.41, 0.09. MS (ES+) m/z 518.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=O)=[CH:7]2.CC1C=CC=C2C=1N=C(C1C=CC=CC=1C(F)(F)F)C(CO)=C2.O=S(Cl)[Cl:49]>C1COCC1.C(Cl)(Cl)Cl>[Cl:49][CH2:22][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1]
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12
Reactant: O=S(Cl)Cl
Agent: Cc1cccc2cc(CO)c(-c3ccccc3C(F)(F)F)nc12
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc2cc(CCl)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure B using 8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde (1.6541 g, 5.25 mmol) and solid NaBH (0.2977 g, 7.87 mmol, 1.5 eq) in THF (26 mL) followed by Procedure C using the crude (8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol and SOCl2 (1.9 mL, 26.23 mmol, 5 eq) in CHCl3 (26 mL). After purification, 3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline was obtained as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.60 (1 H, s), 7.92 (2 H, dd, J=11.5, 8.0 Hz), 7.72-7.85 (2 H, m), 7.67 (2 H, dd, J=14.3, 7.2 Hz), 7.54-7.62 (1 H, m), 4.71 (2 H, dd, J=89.8, 11.9 Hz), 2.62 (3 H, s). Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][O:6][P:5]([CH2:9][C:10]([OH:12])=[O:11])(=[O:8])[O:4][CH2:3]1.O.[OH-].[Al+3:16].[OH-].[OH-]>O>[CH3:1][C:2]1([CH3:13])[CH2:7][O:6][P:5]([CH2:9][C:10]([O-:12])=[O:11])(=[O:8])[O:4][CH2:3]1.[CH3:1][C:2]1([CH3:13])[CH2:7][O:6][P:5]([CH2:9][C:10]([O-:12])=[O:11])(=[O:8])[O:4][CH2:3]1.[CH3:1][C:2]1([CH3:13])[CH2:7][O:6][P:5]([CH2:9][C:10]([O-:12])=[O:11])(=[O:8])[O:4][CH2:3]1.[Al+3:16]
Reactant: CC1(C)COP(=O)(CC(=O)O)OC1
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: CC1(C)COP(=O)(CC(=O)[O-])OC1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Prepare a reaction vessel from a 1000 mL single neck round bottom flask by fitting with a condenser with a nitrogen inlet. Charge the vessel with 31.55 g 2-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)acetic acid followed by 100 mL water and 4.38 g aluminum hydroxide monohydrate. Heat the resulting solution to 90° C. and hold at that temperature for 24 hours. Isolate the solid by vacuum filtration using a fritted funnel and wash with 400 mL acetone. Transfer the solid product to a glass bottle and place in a vacuum oven to dry overnight. The yield of the solid product of Aluminum tris(2-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2yl)acetate) is 31.25 g.
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[CH2:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)[CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1ccccc1B1OCCCO1
Reactant: CCCCc1ccc(N)c(Br)c1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCc1ccc2nc(N)c3ccccc3c2c1
Reaction time: 18 h
Yield: 65.6 %

Procedure:
20.0 g (87.7 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 13.7 g (73.1 mmol) 2-bromo-4-butylaniline, 1.70 g (1.46 mmol) tetrakis(triphenylphosphine)palladium(0), and 27.2 g (198 mmol) potassium carbonate where refluxed in 400 mL toluene and 200 mL ethanol under N2 atmosphere for 20 h. HPLC and TLC revealed almost complete consumption of the aniline. An additional 1.8 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile was added and refluxed continued for an additional 18 h. The reaction mixture was cooled and passed through a filter. The solids were washed with ethyl acetate to remove organics from the collected base. The filtrate was then evaporated down and dried on silica. The sample was purified using silica gel chromatography with 100% ethyl acetate as the eluent. The product fractions were then evaporated down to a minimal amount and the product recrystallized from EtOAc/hexanes to give 12.0 g of the title compound as light yellow solids (65.9% yield, GC-MS confirmed).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(=O)(O)[O-].[Na+].[N-:39]=[N+:40]=[N-:41].[Li+].N([C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(N)=NC1=O)=[N+]=[N-]>CC(C)=O.C(OCC)(=O)C.CO.C(Cl)(Cl)Cl.CN(C)P(=O)(N(C)C)N(C)C>[N:39]([C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
10 g. uridine were stirred with 12 g. diphenyl carbonate in 80 ml. hexamethyl phosphoric acid triamide on an oil bath at a temperature of 140° C., thereafter 0.24 g. sodium bicarbonate was added thereto. When gas evolution ceased (after about 30 minutes), 8 g. lithium azide was added to the reaction mixture. After heating for about 2 hours, the thin layer chromatogram shows, in solvent system A (methanol/chloroform mixture (1/4 v/v)), that the 02,2'-cyclouridine had almost completely disappeared. The solution was then cooled, diluted with 160 ml. water and extracted twice with 160 ml. amounts of water. The combined aqueous solutions were then again extracted three times with 200 ml. amounts of chloroform. The aqueous solutions were evaporated in a vacuum and the residue was thoroughly stirred with a mixture of 160 ml. acetone and 60 ml. methanol and filtered. The filtrate was evaporated and the remaining oil was chromatographed on 700 g. silica gel which has been equilibrated with acetone, using acetone as elution agent. The fractions containing the desired product were applied to 6 plates coated with silica gel (2 mm. layer thickness, 20×40 cm.) for preparative thin layer chromatography, the plates being developed with an acetone/ethyl acetate mixture (1/1 v/v). The regions containing the product were scraped off and eluted with acetone. The acetone solution was evaporated and the residue was taken up with 45 ml. pyridine and filtered in order to remove traces of silica gel. The pyridine was then evaporated and traces of pyridine were removed by the addition of water and evaporation of the water. The product thus obtained is a viscous yellow oil which proved to be thin layer chromatographically pure (in the solvent system A and an acetone/ethyl acetate mixture (1/1 v/v)). The product is obtained in a yield of 5.49 g. (50% of theory). This compound can also be used for the preparation of 2'-azido-2'-desoxycytidine. When left to stand at ambient temperature, the oil crystallizes out spontaneously.
Reaction SMILES: [Br-].[CH3:2][Si:3]([CH3:13])([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][PH3+].[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.C[O-].[Na+].CO>CO>[CH3:2][Si:3]([CH3:13])([CH3:12])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)c1cccc(C[PH3+])c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C=Cc2cccc([Si](C)(C)C)c2)cc1
Reaction time: 17 h
Yield: 24.7 %

Procedure:
(m-Trimethylsilylbenzyl)phosphonium bromide (758 mg, 1.50 mmol) and methyl 4-formylbenzoate (258 mg, 1.57 mmol) were added to a NaOMe-methanol solution, which was prepared from 40 mg (1.74 mmol) of Na metal and 15 ml of dry methanol, and the mixture was stirred for 17 hours. The precipitate (trans form) was collected by filtration, washed with a cooled mixture of MeOH and n-hexane, and dried in vacuo to give 115 mg of white crystals. The mother liquors were evaporated and dissolved in CH2Cl2. The insoluble substance was filtered off and the filtrate was evaporated. The residue was purified by column chromatography to give 60 mg of colorless oil (cis form, yield 13%), 158 mg of white crystals (trans form, total yield 59%) and 110 mg of interfraction (yield 23%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]([C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1)=[C:11]=[O:12]>>[C:1]([NH:9][C:11]([NH:10][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: NC(=O)c1ccccc1
Product: COc1cc(NC(=O)NC(=O)c2ccccc2)cc(OC)c1OC
Temperature: 140 °C
Yield: 76 %

Procedure:
A mixture of benzamide (0.5 g, 4.13 mmol, 1.0 equiv) and 5-isocyanato-1,2,3-trimethoxy-benzene (1.30 g, 6.19 mmol, 1.5 equiv; commercially available) was heated by microwave irradiation to 140° C. for 30 min. Recrystallization from ethanol provided 1.04 g (76%) of the title compound. MS (ISP): 331.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([O:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[N:19]=[CH:18][C:17]3[N:25]([CH3:36])[N:26]=[C:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)[C:16]=3[C:15]=2[CH:14]=1)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:27]2[C:16]3[C:15]4[CH:14]=[C:13]([O:12][CH:4]([C:5]5[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=5)[C:3]([OH:37])=[O:2])[C:22]([O:23][CH3:24])=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:25]([CH3:36])[N:26]=2)=[CH:29][CH:30]=1)#[N:35]
Reactant: COC(=O)C(Oc1cc2c(cc1OC)ncc1c2c(-c2ccc(C#N)cc2)nn1C)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
Methyl[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-(4-fluorophenyl)acetate (260 mg, 524 μmol) is dissolved in tetrahydrofuran and methanol (66 ml each). Sodium hydroxide solution (1.0 M, 1.58 ml, 1.58 mmol) is subsequently added dropwise. The reaction mixture is stirred at room temperature for 18 h. When the reaction is complete, the mixture is evaporated to dryness in vacuo, and the residue obtained is taken up in water (100 ml). The mixture is carefully acidified to pH 5 by addition of hydrochloric acid (1.0 M) and stirred for a further 30 min. The precipitate formed is filtered off with suction and rinsed with water. The filter cake is subsequently suspended in 2-propanol (5 ml), filtered off with suction again, and the residue is dried overnight in a high vacuum, giving [1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yl-oxy]-(4-fluorophenyl)acetic acid (235 mg, 488 μmol) as a solid having a melting point of 211.6° C. MS: 483.1 (M+H+), TLC (HPTLC): Rf=0.11 (ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:9](=[O:27])[C:8]=3[CH:7]=[CH:6][N:5]2[C:28]=1[CH3:29].[C:30](Cl)(=[O:32])[CH3:31]>C1(C)C=CC=CC=1>[C:30]([N:12]1[C:13]2[C:4]3=[N:3][C:2]([CH3:1])=[C:28]([CH3:29])[N:5]3[CH:6]=[CH:7][C:8]=2[C:9](=[O:27])[C@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](OC(=O)C(C)(C)C)[C@@H](c1ccccc1)N3
Solvent: Cc1ccccc1
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
175 g of (8R,9R)-2,3-dimethyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are dissolved in 2200 ml of toluene under argon and with exclusion of moisture with mechanical stirring. Half the amount of acetyl chloride (130 ml in total) is then added dropwise with ice cooling in the course of 30 min. After removing the ice bath, half the amount of triethylamine (250 ml in total) is then added dropwise at 10° C. in the course of 40 min (warming to 30° C.). After 15 min at this temperature, the procedure is repeated as described with the second half of the reagents indicated. The mixture is then added to 1 l of ice water with stirring. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2×200 ml). The combined organic phases are washed with water (3×400 ml), dried over sodium sulfate and evaporated. The yellow-brown residue is crystallized using 300 ml of tert-butyl methyl ether. After stirring in the cold for 1 h, it is filtered off, washed with 200 ml of tert-butyl methyl ether and the filter residue is dried to constant weight in a vacuum drying oven. 186 g (95%) of the title compound are isolated as a yellowish solid of m.p. 168-170° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1.N1C=CC=CC=1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl>[S:16]([O:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1)([CH3:19])(=[O:18])=[O:17]
Reactant: CC1CC(O)CC(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1CC(OS(C)(=O)=O)CC(=O)O1
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-6-methyltetrahydropyran-2-one (1.5 parts) in dichloromethane (40 parts) was added pyridine (1.1 parts) and then, over 15 minutes, mesyl chloride (1.65 parts). The reaction was set aside at ambient temperature under N2 for 18 hours at which point GLC analysis indicated less than 1.5% of the starting material remained. The reaction mixture was filtered and the organic phase then washed with water before evaporating to obtain 4-mesyloxy-6-methyl-tetrahydropyran-2-one (0.5 parts).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16](=[O:29])[C:17]3[C:22]([N:23]4[N:27]=[CH:26][CH:25]=[N:24]4)=[CH:21][CH:20]=[CH:19][C:18]=3[F:28])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[C:17]=1[C:16]([N:12]1[CH2:13][CH:14]2[CH:10]([CH2:9][NH:8][CH2:15]2)[CH2:11]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.3 g, 3.21 mmol) was taken up in DCM (6.0 mL) and TFA (3.0 mL) was added. The mixture was allowed to stir at rt for 1 hr. Solvent was removed and then taken back up in DCM and basified with 1N aq. NaOH. The layers were separated. The aqueous was extracted 2 more time with DCM (and a small amount of MeOH). The organics were combined, dried (Na2SO4), filtered, and concentrated to provide the desired free base product, (2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone, as a viscous/foamy residue that was found to be very hydroscopic (950.6 mg, 93.3%). MS (ESI): mass calculated for C15H16FN5O, 301.32, m/z found 302.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.90-7.73 (m, 3H), 7.54-7.42 (m, 1H), 7.19-7.10 (m, 1H), 3.85-2.65 (m, 10H).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([OH:15])=O)[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].OC(C(F)(F)F)=O.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:45])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([N:29]2[CH2:30][CH2:31][CH:32]([N:35]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:45])[CH2:33][CH2:34]2)=[O:15])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCN1C(=O)C(=CC(=O)O)SC1c1ccccc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN1C(=O)C(=CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetic acid (11 mg, 0.036 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one TFA (18 mg, 0.054 mmol) and DiPEA (22 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (16 mg, 0.043 mmol) and the reaction mixture was stirred at RT for 16 hours. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][CH2:21][CH2:20][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A suspension of 2,3-Dihydroxy-benzoic acid methyl ester (336 mg, 2 mmol) and cesium carbonate (1.56 g, 4.8 mmol) in DMF was stirred at room temperature for 0.5 h. 1,2-Dibromoethane (0.224 ml, 2.6 mmol) was added to the DMF solution. The mixture was stirred at 80 C for 4 h, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product. It was chromatographed on silica gel with EtOAc/hexane (20%-40%) as eluent to afford 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester as a white solid. (223 mg, 1.14 mmol, 57.4% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)(=O)C>Cl>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])=[CH:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1ccc(C=C(C(=O)O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Phenyl acetic acid (489 mg, 3.59 mmol) and 4-t-butylbenzaldehyde (573 mmg, 3.53 mmol), TEA (5 ml) and acetic anhydride (5 ml) were added in round flask. A reaction mixture was heated and stirred overnight. The reaction mixture was poured into 5% HCl aqueous solution (30 ml). A aqueous solution was extracted with MC (30 ml×3). A combined organic layer was dried over MgSO4 and then concentrated in vacuo. The crude residue was column-chromatographed (hexane/ethylacetate=4/1) to yield a white solid (382 mg, 73%)
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13](O)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)#[N:30]>>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:29]#[N:30])[CH2:42][CH2:41]2)=[O:14])[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:27])([F:28])[F:26])(=[O:17])=[O:18]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Product: N#Cc1ccccc1N1CCN(C(=O)C2CN(S(=O)(=O)c3ccccc3C(F)(F)F)C(=O)N2c2ccccc2)CC1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11, step 4) was coupled with 1-(2-cyanophenyl)-piperazine to give the title compound as a colorless solid. MS: 583.5 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:15]2=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.C(=O)(O)[O-].[Na+]>[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](=[NH:33])[NH:25][C:22]1[CH:23]=[CH:24][C:15]2[N:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(N)ccc32)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(NC(=N)c4cccs4)ccc32)CC1
Reaction time: 3 h
Yield: 48.5 %

Procedure:
A solution of compound 4 (0.6586 g, 1.906 mmol) in dry ethanol (20 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (1.087 g, 3.812 mmol) at room temperature and was stirred for 3 hours. The mixture was diluted with saturated sodium bicarbonate solution (50 mL) and was extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL) and dried (Na2SO4). The concentrated crude product was subject to flash chromatography on silica gel using 2.5-5% MeOH/CH2Cl2, which resulted in a brown foam, compound 5 (0.42 g, 48%). 1H NMR (CDCl3) δ 7.42-7.40 (m, 2H), 7.08-7.05 (t, J=9.0 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.77-6.73 (m, 2H), 4.13-4.09 (m, 2H), 3.37 (tt, J=7.2, 21.9 Hz, 1H), 2.95-2.71 (m, 6H), 1.87 (d, J=12.9 Hz, 2H), 1.77-1.53 (m, 7H), 1.47 (s, 9H); MS-ESI (m/z, %): 457 (MH+, 14), 455 (M+, 100), 219 (18).