Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([O:41]C)=[O:40])[CH:36]=[C:35]([F:43])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[K+].CC(O)=O>C(OCC)(=O)C.CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([OH:41])=[O:40])[CH:36]=[C:35]([F:43])[C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a 25-mL round-bottom flask equipped with a stir bar was added sequentially methyl 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (0.55 g, 0.89 mmol), 4.0 mL of THF, 2.0 mL of MeOH, and 3 N aqueous KOH solution (1 mL, 3 mmol). The resulting homogenous solution was stirred for 1 hour at 70° C., cooled to RT, and then quenched with AcOH (roughly 0.2 mL of glacial acetic, 3 mmoles) until pH=6 was achieved (Whatman class pH strip paper). At this time the reaction was diluted with ethyl acetate (40 mL) and washed with water (3×5 mL). The ethyl acetate fraction was concentrated under vacuum to give to an oily residue. To the resulting oil was then added 6 mL of MeOH. The oil quickly dissolved, then immediately began to crystallize. Upon standing for 2.5 hrs the mother liquor was withdrawn and crystals washed (3×2 mL of ice cold MeOH). The crystals were dried via vacuum (10 mm Hg pressure at 45° C. overnight) and then recrystallized from acetonitrile, filtered, and dried under vacuum to give the desired product 2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCC(N1CC(CC2OC=CC=2)(O)C[C@H]1C(O)=O)=O)(=O)C>>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:20][C:17]1([OH:19])[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SCC(=O)N1CC(O)(Cc2ccco2)C[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1

Procedure:
The N-carbobenzyloxy-4-[(2-furyl)methyl]-4-hydroxy-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-[(2-furyl)methyl]-4-hydroxy-L-proline. This amino acid is reacted with 2-acetylthioacetyl chloride according to the procedure of Example 1 (c) to yield 1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-4-hydroxy-L-proline.
Reaction SMILES: C[C@@H:2]1[CH:6]([NH:7][CH3:8])[CH2:5][CH2:4][N:3]1[C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:3]2[CH2:4][CH2:5][C@@H:6]([N:7]([CH3:8])[C:21]3[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=3)[CH2:2]2)=[N:14][CH:13]=1
Reactant: CNC1CCN(c2ncnc3[nH]ccc23)[C@@H]1C
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of methyl (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.20 g, 0.92 mmol), 2,4-dichloropyrimidine (0.18 g, 1.21 mmol) and DIPEA (0.25 g, 1.94 mmol) in DMF (6 mL) was stirred at 110° C. for 16 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (2×8 mL). The combined extracts was washed with brine (2×30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (v. DCM/MeOH=12/1) to give the title compound. MS (m/z): 330 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: N#Cc1cnc(Br)s1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-5-carbonitrile (Tetrahedron Lett. 1977, 21, 1813).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]3[NH:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:32]NN>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@H:15]([NH:19][C:20]3[N:24]([CH3:32])[N:23]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]=3)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CNN
Reactant: CC(C)[C@@H](Nc1nc(-c2ccccc2)n[nH]1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1nc(-c2ccccc2)nn1C)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
(R)-1-(4-(4-Chlorophenyl)piperidin-1-yl)-3-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (40 mg, 0.09 mmol) was dissolved in THF (0.5 mL) and then treated with MeNHNH2 (10 μL, excess). The reaction was stirred at rt. overnight. After this time, the THF was removed in vacuo and the remains were taken up in MeOH and then purified by preparative HPLC to give (R)-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(1-methyl-3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (18 mg, 47%) as a 90/10 mixture of N1—CH3/N2—CH3 isomers. MS found: 452 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH:14]=1)([O-:3])=[O:2].Cl>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH:14]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 99.7 %

Procedure:
A solution of compound 78 (4.7 g, 15.650 mmol) in acetone (50 mL) was treated with 10% aq. HCl (50 mL) at room temperature and stirred for over night (14 h). Acetone was evaporated and crude was basified using 10% aq. NH4OH solution (100 mL). The precipitate was filtered off, washed with 10% NH4OH solution (2 10 mL) and water (2 10 mL). The product was dried under vacuum to obtain compound 79 (4.0 g, quantitative) as a solid. For spectral data, please see Example 23.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1.[CH3:16][O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21].C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=2)=[N:2][O:1][C:20]=1[NH2:21])=[O:22]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1N
Yield: 83.5 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.31 g, 43.41 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (8.42 g, 27.87 mmol, 83%) was obtained.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C:26]#[N:27])[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[CH:22][C:23]([Br:25])=[CH:24][C:9]1=2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+]>CN(C)C=O.O.[OH-].[Na+]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C:26]1[N:37]=[N:38][NH:39][N:27]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[CH:22][C:23]([Br:25])=[CH:24][C:9]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc(Br)ccc21
Temperature: 110 °C

Procedure:
Add a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethylbenzyl)-cyanoamino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in anhydrous N,N-dimethylformamide dropwise to a stirred suspension of sodium azide and ammonium chloride in anhydrous N,N-dimethylformamide and heat the resulting yellow mixture at 110° C. under nitrogen. Dilute the cooled mixture with water and 2 N NaOH and wash with diethyl ether. Acidify with 5 N HCl, collect the precipitate and wash with water to provide the title compound.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1.Cl>C(O)C>[CH3:1][S:2][CH:3]([C:9]1[CH:14]=[C:13]([CH:15]=[C:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)C(SC)c1cc(C=O)ccc1OC
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(SC)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Temperature: 0 °C
Yield: 60.1 %

Procedure:
Ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate (7.50 g, 28.0 mmol), thiazolidine-2,4-dione (3.94 g, 33.6 mmol), piperidine (2.80 mL, 28.3 mmol) and ethanol (100 mL) were mixed and refluxed for 14 hours. After allowed to stand for cooling, concentrated hydrochloric acid was added under cooling with ice and stirring to make the reaction mixture acidic. Ice water was added thereto and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with ethanol and water, and then dried to obtain 6.18 g (60%) of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[S:15]([CH3:18])(=[O:17])=[O:16].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:15]([N:14]([CH3:13])[CH:19]1[CH2:20][CH2:21][N:22]([C:2]([Cl:1])=[O:4])[CH2:23][CH2:24]1)(=[O:16])=[O:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C1CCN(C(=O)Cl)CC1)S(C)(=O)=O
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (0.61 g, 2.08 mmol) in CH2Cl2 (30 mL) at −78° C., was added a solution of N-Methyl-N-piperidin-4-yl-methanesulfonamide (preparation described in the patent GB2000136) (1.00 g, 5.20 mmol) and pyridine (0.92 mL, 11.4 mmol) in CH2Cl2 (20 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded 0.53 g (40%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20]CC)=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CC(C)=O>[Cl:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH3:23])/[C:18]([OH:20])=[O:19])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C(C)=C/c1c(Cl)c(OC)c2ccccc2c1OC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CC(C)=O
Product: COc1c(Cl)c(/C=C(\C)C(=O)O)c(OC)c2ccccc12

Procedure:
Compound 42a was prepared from 41a (0.959 g, 2.90 mmol) as described above for 29a to give 0.872 g (2.84 mmol, 98%) of the product as a tan solid following flash chromatography (3:17 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[NH4+:15].CO>[Ni].Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([NH2:15])[CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Agent: [Ni]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(N)c1ccc2c(c1)OCCO2
Yield: 66 %

Procedure:
A mixture of 1-(2,3-dihydro-1,4-benzodioxin-6-yl)acetaldehyde, oxime, (Preparation 5, 10.74 g, 0.0556 mole), and Raney nickel (1 mL) in ammonium hydroxide/methanol (20 mL/200 mL) was hydrogenated (H2, 50 psi) for 48 hours. The reaction mixture was filtered through Celite and the resultant filtrate was concentrated in vacuo. The residual oil obtained was diluted with HCl (1N). The aqueous layer was washed with EtOAc (1×250 mL). The aqueous layer was then made basic with NaOH (1N), and extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title product (7.1 g, 66%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]3[NH:12][N:11]=[C:10]([CH3:20])[C:9]=3[N:8]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: COc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
128 mg of 3-methoxy-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)benzamide (4) were suspended in 5 ml of xylene and the suspension was boiled at 160° C.; 119 mg of phosphorus pentoxide were then added and the mixture was subsequently stirred at 160° C. for 15 min. 27 μl of phosphorus oxychloride were added dropwise to the suspension, which was then stirred at 160° C. for 12 h; a saturated solution of sodium hydrogen carbonate was then added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 3. C18H15N3O (298.34); MS (ESI 290 (M+H)
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([OH:25])=[C:17]2[C:26](=[O:38])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:28](=[O:29])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:39])=[C:17]2[C:26](=[O:38])[N:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:28](=[O:29])[C:16]=12)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 245 (350 mg, 0.69 mmol, 1 equiv.) was added DMF (20 mL) followed by K2CO3 (478 mg, 3.46 mmol, 5 equiv.). To this was added MeI (983 μL, 6.93 mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours. To the reaction was then added water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed several times with water (3×30 mL), saturated NaHCO3 (40 mL), brine solution (30 mL). It was dried over Na2SO4, filtered and concentrated in vacuo before being purified by silica gel chromatography using 3/2 Hexanes/ethyl acetate to obtain 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (78%, 280 mg, 0.54 mmol) as a yellow solid. 1H NMR (300 MHz) CDCl3 δ 9.03 (d, J=1.5 Hz, 1 H), 8.97 (d, J=1.5 Hz, 1 H), 7.75 (s, 1 H), 7.60 (dd, J1=1.5 Hz, J2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H), 7.03-7.20 (m, 1H), 4.86 (s, 2 H), 4.37 (s, 3 H). MS: 542.0 (M+23). TLC Rf: 0.5 Hexanes/Ethyl acetate (1/1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(NN2CCN(Cc3ccccc3)CC2)cc1
Yield: 59.8 %

Procedure:
A mixture of 4-bromobenzotrifluoride (3.00 g, 13.3 mmol), 4-benzylpiperazin-1-yl-amine (3.06 g, 16.0 mmol), palladium acetate (60 mg, 0.267 mmol), (S)-(−)-BINAP (174 mg, 0.280 mmol) and sodium tert-butoxide (1.92 g, 20.0 mmol) in toluene (60 ml) was refluxed under a nitrogen atmosphere for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane/acetone=4/1) to afford (4-benzylpiperazin-1-yl)-(4-trifluoromethylphenyl)amine (2.666 g, yield 59%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH2:2][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CN(Cc3ccccc3)C(=O)O2)cc1OCC1CC1
Yield: 105.2 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first agitated with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes and, after adding 0.32 ml (2.7 mmol) of benzyl bromide,for 2 hours at room temperature. The procedure was continued analogously to Example 10, thus obtaining 348 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-benzyl-2-oxazolidinone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C@@:7]2([C:13]([O:15]C)=O)[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[C:30]([Cl:32])[CH:31]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]2[C:34](=[O:35])[N:33]([C:28]2[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=2)[C:13]3=[O:15])=[CH:17][CH:18]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@]1(Cc2ccc(Br)cc2)C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of methyl (4R)-2-(4-bromobenzyl)-4-hydroxy-L-prolinate (0.170 g) (Prep. 3) in 10 mL of DMF was added K2CO3 (0.15 g). The reaction mixture was cooled to 0° C., treated with 3,5-dichlorophenyl isocyanate (0.116 g), then allowed to warm to RT and stirred overnight. The insoluble material was removed by filtration, the DMF evaporated, and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting oily residue was purified over SiO2 isolute column (10 g) (eluent: DCM/acetone-95/5) to afford the above-titled compound (0.100 g) as a white solid. 1H NMR (CDCl3): 7.45 (2H,d), 7.30 (1H,m), 7.10 (2H,d), 6.85 (2H,d), 4.75 (1H,m), 4.10 (1H,dd), 3.45 (1H,d), 3.40 (1H,dd), 3.25 (1H,d), 2.35 (1H, dd), 2.20 (1H,dd).
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=O)(=O)C.Cl.[NH:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:25][C@H:22]1[CH2:23][CH2:24][N:20]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:21]1
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Temperature: 90 °C

Procedure:
4-Pyrrolidinophenethyl mesylate (13.45 g, 50.0 mmol), (S)-3-pyrrolidinol hydrochloride (5.56 g, 45.0 mmol) and potassium carbonate (18.63 g, 135 mmol) were added to acetonitrile (200 ml), and they were heated at 90° C. for 3 hours. The reaction mixture was cooled and then filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from the ethyl acetate layer with 1 M hydrochloric acid. The aqueous layer was neutralized and then the product was again extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow solid (6.30 g, 52%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:5][N:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:5][N:6]=1)(=[O:27])[CH3:26]
Reactant: Nc1nnc(SCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nnc(SCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)s1

Procedure:
1-[3-(2-Amino-1,3,4-thiadiazol-5-ylthio)-2-(2,4-dichlorophenyl)-2-hydroxy-propyl]-1,2,4-triazole (0.5 g, 0.00124 m) was stirred at room temperature with a mixture of acetic anhydride (0.5 ml) and pyridine (5 ml) for one hour. The resulting solid was collected by filtration, washed with water and dried to give the title compound, 0.44 g (80%); m.p. 132° C.
Reaction SMILES: [N:1]1[C:6](C=O)=[CH:5][CH:4]=[CH:3][C:2]=1C=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)=O>C(O)C>[C:12]1([N:11]=[C:6]2[CH2:5][CH:4]=[CH:3][C:2](=[N:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1cccc(C=O)n1
Solvent: CCO
Solvent: O=CO
Product: C1=CC(=Nc2ccccc2)NC(=Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
2,6-pyridine dicarboxaldehyde (0.3071 g, 2.3 mmol) was added to a solution of aniline (0.5292 g, 5.7 mmol) in absolute ethanol (20 mL) at room temperature. 0.5 mL of formic acid was then added to the above solution. The mixture was stirred at room temperature for 65 hours. The product was filtered, washed with cold ethanol and dried in a vacuum oven (50° C.) overnight. Yield 0.2245 g (34.2%).