Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][C:42]=1[C:50]([F:53])([F:52])[F:51]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([O:40][CH3:39])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:43]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
To a solution of {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (200 mg, 0.456 mmol) in THF (2 mL) was added N,N-diisopropyl ethyl amine (117 μl, 0.684 mmol), 4-methoxy-3-(trifluoromethyl)benzoyl chloride (131 mg, 0.547 mmol) and stirred for 4 h at ambient temperature. The reaction mixture was diluted with ethzl acetatec (10 mL) and was washed with an aqueous solution of sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (230 mg, 79%) as a colorless oil. MS m/e: 640.3 [M]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[K].[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].[I-].[Na+].O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][O:17][C:18]3=[O:23])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: ClCCCCSc1cccc2nccn12
Reactant: O=C1COC(=O)N1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 6.30 g (26.2 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 3.64 g (26.2 mmol) of oxazolidine-2,4-dione potassium salt in 100 ml of N,N-dimethylformamide, 3.92 g (26.2 mmol) of sodium iodide was added, followed by stirring at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 5.70 g (71.4%, light orange crystal) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2C(=O)C3C(=CC=CC=3NC=O)N=C2C)[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[CH3:24][C:25]1O[C:27](=[O:38])[C:28]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.NC1CCC(=O)NC1=O>>[CH3:24][C:25]1[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]2=[O:1])[C:27](=[O:38])[C:28]2[C:29](=[CH:31][CH:32]=[CH:33][C:34]=2[N+:35]([O-:37])=[O:36])[N:30]=1
Reactant: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In one particular embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the present of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid via transfer hydrogenation to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (d) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a), (b), (c), and (d) are each as described herein elsewhere.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14](=[N:19][OH:20])[NH2:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCCCCc1ccc(OCC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCc1ccc(OCC(N)=NO)cc1
Yield: 99.8 %

Procedure:
30.6 g (0.13 mol) of 4-n-heptyl-phenoxy-acetonitrile, 18.1 g (0.26 mol) of hydroxylamine hydrochloride and 27.6 g (0.26 mol) of sodium carbonate are stirred at reflux temperature in 100 ml of ethanol and 200 ml of water until the reaction is complete (approximately 24 hours). The entire reaction batch is subsequently introduced into water, and the mixture is extracted using methylene chloride. 34.3 g (99.8% of theory) of 4-n-heptyl-phenoxy-acetamide oxime are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][N:18]=[C:19]=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(OCC)(=O)C>[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][NH:18][C:19]([NH:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cn1cccc1CN
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Solvent: CCOC(C)=O
Product: Cn1cccc1CNC(=S)NCc1ccc(C(C)(C)C)cc1
Reaction time: 12 h
Yield: 75.9 %

Procedure:
(1-methyl-1H-pyrrol-2-yl)methylamine (65 mg) and 4-t-butylbenzylisothiocyanate (120 mg) were dissolved in ethyl acetate (30 ml) and the solution was stirred for 12 hours. After the completion of the reaction, the resulting mixture was purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 17-2 (140 mg, 75%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([CH3:21])[C:18](=[O:20])[CH3:19]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:17]([CH3:21])[C:18](=[O:20])[CH3:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C(C)Cl
Product: CC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
The process as indicated in Example 1 was repeated a number of times, utilizing molar quantities each of 4-benzyloxyphenol and 3-chloro-2-butanone, and varying quantities of base, catalyst and solvent, as well as differing times and temperatures.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl[CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1>C(Cl)Cl>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[CH3:8]
Reactant: CCOC(=O)C(C)C
Reactant: ClCc1ccoc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccoc1
Yield: 82 %

Procedure:
Ethyl isobutyrate (10.7 mL, 80.1 mmol) is alkylated with 3-(chloromethyl)furan according to general procedure F to give the product as a yellow liquid (12.91 g, 82%) after FC (CH2Cl2) . 1H NMR (CDCl3) 7.32 (s, 1), 7.20 (s, 1), 6.20 (s, 1), 4.12 (t, 2, J=7.4), 2.66 (s, 2), 1.25 (t, 3, J=7.4), 1.18 (s, 6); 13C NMR (CDCl3) 177.56, 142.36, 140.54, 120.78, 112.76, 60.39, 42.85, 35.43, 24.96, 14.13; MS (MW=196.3, CI/CH4, eE=70 eV) m/z 197 (M+H)+, 195, 161, 151, 123 (base peak), 109, 81.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][OH:14]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Under N2 atmosphere, 3,4-dihydro-2H-pyran (6.39 g, 76.09 mmol) was added drop-wise to a stirred solution of 6-bromo-2-methyl-2-p-tolyl-hexan-1-ol (18.20 g, 63.86 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.26 mmol) in dichloromethane (300 mL) at −5° C. The reaction mixture was allowed to warm to rt and stirred for 3 h. The solution was filtered through aluminum oxide (160 g), which was washed with CH2Cl2 (500 mL). The filtrate was concentrated in vacuo to furnish 2-(6-bromo-2-methyl-2-p-tolyl-hexyloxy)-tetrahydropyran (22 g, 93.4%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.40-1.33 (s, 3H), 1.40-1.08 (m, 1H), 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 142.78, 135.22, 128.81, 126.39, 99.09, 61.99, 41.67, 38.12, 37.87, 33.68, 30.99, 25.96, 23.08, 22.89, 21.12, 20.97, 19.41. HRMS (LSIMS, nba): Calcd. for C19H30O2Br (MH+): 369.1429, found: 369.1451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[S:31]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 7.60 (s, 1H), 7.72-7.77 (m, 3H), 7.90 (s, 2H), 8.00 (s, 1H), 8.13-8.20 (m, 3H), 8.75 (s, 1H), 11.21 (s, 1H); MS (ES): 513.99 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: CB(O)O
Reactant: Fc1cnc(Br)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: C1COCCO1
Solvent: O
Product: Cc1ncc(F)cc1Br
Temperature: 110 °C
Yield: 32.2 %

Procedure:
2,3-Dibromo-5-fluoropyridine (5.0 g, 19.6 mmol), Pd(PPh3)4 (1.13 g, 0.98 mmol) and methyl boronic acid (3.52 g, 58.9 mmol) were combined in dioxane (50 mL) then treated with K2CO3 (8.13, 58.9 mmol) and water (10 mL). The mixture was purged with N2 then heated to 110° C. in a sealed vessel for 16 hours. The cooled mixture was partitioned between water (100 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1-3% EtOAc/hexanes to afford the product as a white solid (1.20 g, 32% yield). MS (apci) m/z=190.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][N:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2cn[nH]c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ncc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg, 1.01 mmol) in DMF (5 mL) was added cesium carbonate (494 mg, 1.515 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (215 mg, 1.515 mmol) was added. The reaction solution was stirred for 2 h and quenched with water. Volatiles were removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give crude product which was purified by chromatographic column to afford the desired product 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine. LCMS-ESI+: calc'd for C7H6BrN3: 211.98 (M+H+); Found: 212.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:10])=[O:9])=[CH:5][CH:4]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CN(C=O)C>[CH:24]1([NH:1][CH2:2][C:3]2[S:7][C:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])=[O:10])=[CH:5][CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CN)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNS(=O)(=O)c1ccc(CNC2CCCC2)s1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The resin-bound 5-(aminomethyl)-N-dodecylthiophene-2-sulfonamide (example 125, step c, 0.23 mmol) was swelled in a 1% HAc in DMF mixture for 15 min at rt Cyclopentanone (97 mg, 1.15 mmol) and sodium cyanoborohydride (144 mg, 2.3 mmol) were then added and the reaction mixture shaken 14 h at rt. The resin was washed successively with DMF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the title compound which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[CH2:14]O)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2)=[O:24]>>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:7][C:8]1[CH:9]=[C:10]([O:16][C:17]([F:18])([F:20])[F:19])[CH:11]=[C:12]3[C:13]=1[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:14]3)[N:29]=[CH:28]2)=[O:24]
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CC(C)Cn1ncc2cc(OC(F)(F)F)cc(CO)c21
Product: COC(=O)c1ccc2c(cnn2Cc2cc(OC(F)(F)F)cc3cnn(CC(C)C)c23)c1
Yield: 46 %

Procedure:
Compound 29 was prepared following general method 3A, using compound 21 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 46%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][N:5]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:4]2[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[C:4]2[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[CH2:6][N:5]2[N:9]=1
Reactant: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1Cc2cc(N)nn2CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 313c (450 mg, 2.3 mmol) in ethanol (30 mL) was added Pd/C (10%, 400 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 313d as a yellow solid (320 mg, 84%), which was used without further purification in the next step. MS-ESI: [M+H]+ 167.1
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][N:3]1[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][N:3]1[CH:4]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1cc(-c2cccs2)ccc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1cc(-c2cccs2)ccc1=O
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(2-oxo-5-(thiophen-2-yl)pyridin-1(2H)-yl)ethylcarbamate (125 mg, 390 μmol) in CH2Cl2 (1 mL) was added TFA (5 mL) and stirred for 30 min at 23° C. Solvents removed under reduced pressure and residue partioned between CH2Cl2 (10 mL) and 1M NaOH (5 mL). The organic layer was dried over MgSO4 and reduced to a brown oil under reduced pressure. MS (ESI pos. ion) m/z (MH+): 221 (MH+). Calc'd exact mass for C11H12N2OS: 220.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[CH2:12][OH:13].[OH-].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.O>[Cl:29][CH2:30][C:31]([N:14]([CH:11]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:12][OH:13])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=1)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(OC)c1C(CO)NCc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(OC)c1C(CO)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CCl
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A cooled (−10° C.) mixture of 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)-amino)ethanol (32 mg; 0.08 mmol) and NaOH (7 mg; 0.17 mmol) in DCM (1 ml) and water (0.5 ml) was treated with 2-chloroacetyl chloride (12 mg; 0.10 mmol). The resulting mixture was further stirred at −10° C., under nitrogen, for 15 min. Water and DCM were added, and the separated aq. layer was further extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-N-(1-(2,6-dimethoxyphenyl)-2-hydroxyethyl)-N-(4-(trifluoromethoxy)benzyl)-acetamide as a yellow oil. LC-MS (conditions E): tR=0.75 min.; [M+H]+: 447.98 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:35]C(C)=O>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][CH:24]=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C=CCCCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccccc2c1I
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCC=O)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of 81 (44 mg, 81 μmol) in THF (3 mL) was treated sequentially with a solution of NaIO4 (35 mg, 162 μmol, 2 equiv) in 0.5 mL H2O and a solution of OSO4 (7.5 mM in THF, 0.53 mL, 4 μmol, 0.05 equiv). The reaction mixture was stirred for 6 h at 25° C. EtOAc (20 mL) was added and the organic layer was dried (Na2SO4), filtered through Celite, and the solvent removed under vacuum. Chromatography (SiO2, 1×15 cm, 15% EtOAc-hexane) afforded 110 (35 mg, 80%) as an oil: 1H NMR (CDCl3, 400 MHz) δ 9.73 (t, J=1.3 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.61-7.49 (m, 4H), 7.42-7.32 (m, 3H), 6.77 and 6.72 (two s, 1H), 5.32-5.25 (m, 2H), 3.86 (ddd, J=14.0, 8.6 Hz, 6.7 Hz, 1H), 3.47 (m, 1H), 2.48 (m, 2H), 1.93-1.75 (m, 2H), 1.29 and 1.23 (two s, 9H); IR (film) νmax 3064, 3032, 2975, 2930, 2722, 1638, 1616, 1590, 1407, 1160 cm31 1; FABHRMS (NBA-CsI) m/z 678.0095 (M+Cs+, C26H28INO4 requires 678.0117).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][C@H:2]([C@H:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)c1ccccc1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with benzaldehyde; mp 155–158° C. 1H NMR (CDCl3): δ 8.10 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.26 (m, 4H), 5.30 (d, 1H), 4.26 (dq, J=3, 6 Hz, 1H), 1.26 (d, 3H). 13C NMR (CDCl3): δ 175.6, 151.0, 142.2, 141.0, 128.4, 127.7, 126.0, 125.5, 124.9, 116.3, 110.0, 73.2, 46.0, 10.3.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[CH2:10][CH2:9]1)C.C([NH2:41])=O.C[O-].[Na+]>>[F:25][C:24]([F:27])([F:26])[C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=1)[CH2:17][O:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][C:4]([NH2:41])=[O:3])[CH2:9][CH2:10]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC=O
Reactant: CCOC(=O)CCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)CCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser are introduced 493 mg (0.9 mmoles) of 4-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-butyric acid ethyl ester (compound 138 prepared at example 1.4.1 above), 15 ml of formamide and 97 mg (1.8 mmoles) of sodium methoxide. The mixture is heated to 95° C. for 4 hours, then 48 mg (0.9 mmole) of sodium methoxide are added and the mixture is kept overnight at 85° C. The mixture is cooled and partitioned between diethyl ether (100 ml) and brine (100 ml). The organic phase is dried and volatile substances are removed under reduced pressure, affording 400 mg of 4-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-butyramide as a yellow oil (yield 86%). The dimaleate salt of compound 288 is prepared in 2-butanone (yield: 4.32 g as a white solid).