Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][C:20]=3[C:28]3[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([CH:37]=3)[C:33](OC)=[O:34])[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH:44][C:33](=[O:34])[C:32]1[CH:37]=[C:28]([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:19]=2[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:40])[CH3:1])[CH:7]=3)[N:18]=2)[CH:29]=[CH:30][C:31]=1[O:38][CH3:39]
Reactant: COC(=O)c1cc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)ccc1OC
Reactant: Nc1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)cc1C(=O)Nc1c(F)cccc1F
Yield: 74.1 %

Procedure:
To methyl 5-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzoate (2.35 g, 4.36 mmol) and 2,6-difluoroaniline (2.35 mL, 21.8 mmol) in THF (30 mL) was added sodium bis(trimethylsilyl)amide (26.0 mL, 1M in THF, 26.0 mmol) in one portion. Upon completion by MS, the reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography and trituration with diethyl ether provided the title compound (2.05 g, 3.23 mmol, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 6H), 2.56 (br. s., 2H), 3.98 (br. s., 5H), 6.55 (d, J=7.7 Hz, 1H), 6.69 (d, J=4.4 Hz, 1H), 7.01-7.11 (m, 1H), 7.17 (d, J=7.3 Hz, 3H), 7.27 (s, 2H), 7.32-7.42 (m, 1H), 7.42-7.54 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 9.49 (br. s., 1H), 9.78 (d, J=12.5 Hz, 2H). MS (M+H, ES+) 636.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[OH:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1
Reactant: CCOC(=O)[C@@H](Cc1cccc(C#N)c1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CO)Cc1cccc(C#N)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
The process is performed as in Example 2, starting with 3.3 g of ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)propanoate and 1.23 g of sodium borohydride in 50 cm3 of ethanol and working at a temperature in the region of −30° C. After stirring for 16 hours at a temperature in the region of 20° C., the reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. and the residue obtained is then stirred in a mixture of 100 cm3 of water and 100 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place and the aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and then washed with twice 50 cm3 of water, dried over magnesium sulfate, filtered and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. 2.13 g of N-[(1R)-2-hydroxy-1-(3-cyanobenzyl)ethyl]acetamide are obtained in the form of a white solid. (αD20=+7.5±0.6 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.[C:23]1(=[O:37])[N:27]([CH2:28][C:29](Cl)=[O:30])[C:26](=[O:32])[C:25]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]12>CN(C)C1C=CN=CC=1.ClCCCl>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:29](=[O:30])[CH2:28][N:27]2[C:23](=[O:37])[C:24]3[C:25](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:26]2=[O:32])[C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)CCCN(C(=O)CN2C(=O)c3ccccc3C2=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 55 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.519 g, 2.36 mmol), Pyridine (0.420 mL, 5.19 mmol), 4-Dimethylaminopyridine (21 mg, 0.17 mmol) and anhydrous 1,2-Dichloroethane (8.5 mL) were combined in a round bottom flask. α-Phthalimidoacetyl Chloride (1.105 g, 4.942 mmol) was added to the mixture and it was stirred at room temperature for 16.5 hours. The reaction was concentrated under reduced pressure and purified by normal phase chromatography to yield a yellow solid, 2-[2-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-oxo-ethyl]-isoindole-1,3-dione (55%) LCMS: m/z=408.11 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 2H), 7.87 (m, 2H), 7.74 (m, 3H), 4.74 (m, 1H), 4.55 (d, 1H, J=16.9), 4.55 (d, 1H, J=16.7), 2.68 (m, 1H), 2.23 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.51 (m, 6H), 1.26 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C(O)CCC>[F:11][CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCC(F)COc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Then, 6.3 g of p-hydroxyacetophenone and 12.7 g of 2-fluorooctyl-p-toluenesulfonate were dissolved in ml of butanol. To the solution, a solution of 3.1 g of potassium hydroxide in 40 ml of butanol was added dropwise, followed by heat-refluxing for 6 hours. After the reaction, the reaction mixture was poured into 200 ml of ice water and extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to precipitate a crystal. The crystal was purified by silica gel column chromatography to obtain 4.7 g of p-(2-fluorooctyloxy)acetophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C)n1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
1-(2-Methoxy-4-nitro-phenyl)-3-methyl-1H-[1,2,4]triazole (77 mg, 0.33 mmol) was dissolved in methanol (5 mL). The flask was evacuated and flushed with nitrogen. This procedure was repeated two times. 10% Palladium on charcoal (8 mg) was added. The reaction was stirred at room temperature under an atmosphere of hydrogen over night, filtered and the filtrate was evaporated under reduced pressure to yield the title compound as a brown solid (67 mg, ca. 100%). MS ISP (m/e): 205.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.35 (s, 1H), 7.37 (d, 1H), 6.32-6.35 (m, 2H), 3.82 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([N+:20]([O-])=O)[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:23])=[CH:4][N:3]=1.NN.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:38].Cl.C(O)C>COCCO.[Pd]>[ClH:38].[ClH:38].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([NH2:20])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[CH3:23])=[CH:4][N:3]=1
Reactant: Cc1ccnc2c([N+](=O)[O-])cc(Cc3cnc(N)nc3N)cc12
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: COCCO
Product: Cc1ccnc2c(N)cc(Cc3cnc(N)nc3N)cc12
Yield: 69 %

Procedure:
The product of Example 12 (0.78 g, 2.5 mmol) was dissolved in 35 ml of β-methoxyethanol, and then 0.06 g of 5% Pd/C and 0.3 ml of 95% hydrazine were added, and the reation was refluxed for 1 hour. The Pd/C was filtered off, the solvent removed, and the product was purified on a silica gel column which was eluted with 7% methanol in methylene chloride. This gave 0.48 g (69% yield) of the free base which was recrystallised as the dihydrochloride salt from ethanol, mp 303°-305° dec. Anal. Calcd. for C15H16N6.2HCl.0.5H2O: C, 49.73; H, 5.29; N, 23.20; Cl, 19.57. Found: C, 49.71; H, 5.30; N, 23.18; Cl, 19.51.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:12]=[C:11]([NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>>[C:18]1([CH3:17])[CH:23]=[CH:22][C:21]([C:24](=[N:14][NH:13][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:12]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: NNc1nc(C(F)(F)F)nc2ccccc12
Reactant: CC(=O)c1ccc(C)cc1
Product: CC(=NNc1nc(C(F)(F)F)nc2ccccc12)c1ccc(C)cc1

Procedure:
The title compound was prepared from (2-trifluoromethyl-quinazolin-4-yl)-hydrazine (250 mg, 1.1 mmol) and 4′-methylacetophenone (0.22 mL, 1.6 mmol) by a procedure similar to Example 1, step 4 yielding 225 mg (60%) of a yellow solid. HPLC Purity: 95%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][NH:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][N:44]2[C:19]1[S:20][C:16](=[CH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:27][C:3]=2[C:2]([F:32])([F:33])[F:1])[N:7]=[CH:8]3)[C:17](=[O:23])[N:18]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Product: CC(C)(C)OC(=O)N1CC2CC1CN2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH3+:11])[CH3:10])=[C:5]([F:12])[CH:4]=1.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:21]([C:18]2([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]2)=[O:22])[CH3:10])=[C:5]([F:12])[CH:4]=1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: C[C@@H]([NH3+])c1ccc(Br)cc1F
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(Br)cc1F
Reaction time: 6 h

Procedure:
(1R)-1-(4-Bromo-2-fluorophenyl)ethanaminium chloride (16.50 g, 64.83 mmol), 1-[(trifluoroacetyl)amino]cyclopropanecarboxylic acid (12.78 g, 64.83 mmol), EDC (12.43 g, 64.83 mmol), and HOAT (4.41 g, 32.41 mmol) were dissolved in dimethylformamide (100 mL). To this solution was added triethylamine (6.56 g, 64.83 mmol). After 6 hours, the reaction was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a solid. This solid was purified by silica gel chromatography and eluted with 5% methanol/CH2Cl2 to yield N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide as a white solid. Low resolution mass spectrometry: (M+H+)=399.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7]([C:9]2[N:13](CCOC[Si](C)(C)C)[N:12]=[CH:11][C:10]=2[NH:22][C:23]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=23)=[O:24])[CH:8]=1)#[N:2].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:34][CH3:35])=[C:7]([C:9]2[NH:13][N:12]=[CH:11][C:10]=2[NH:22][C:23]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=23)=[O:24])[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C#N)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a solution of N-(5-(5-cyano-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.04 mmol) in 20 mL ethanol was added HCl (2.0 mL of a 6 M solution in water, 12 mmol). The reaction mixture was then stirred at 70° C. for 4 hours. After cooling to room temperature, a light yellow precipitate formed, which was filtered off and rinsed with methanol and diethyl ether. The filtrate was reduced in volume to precipitate more solid product, which was filtered off. The combined collected solids were dried under vacuum to yield 530 mg (72%) of N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=360.1; 1H NMR (400 MHz, DMSO-d6) δ12.98 (s, 1H), 9.59 (s, 1H), 9.30 (dd, 1H), 8.73 (d, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 7.78 (s, 1H), 7.43 (d, 1H), 7.25 (s, 1H), 3.9 (s, 3H).
Reaction SMILES: C1(S)C=CC=CC=1.C[O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:22]=[N:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[N:23]=[N:22][C:21]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH:20]=[CH:19][CH:18]=[N:17]4)=[CH:15][C:10]=3[OH:9])=[CH:26][CH:25]=2)[CH2:29][CH2:30]1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNCC2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNCC2)nn1
Yield: 17.8 %

Procedure:
Following GENERAL METHOD 3-1 for methoxy deprotection with thiophenol, 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine (70 mg, 0.20 mmol) was treated with thiophenol (27 mg, 0.24 mmol) and K2CO3 (25 mg, 0.18 mmol) in NMP (1.3 mL) for 15 min at 190° C. HPLC purification (0.1% trifluoroacetic acid as modifier) afforded 2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol (12 mg, 18%) as a yellow solid. LCMS Rt=0.50 min (LCMS method Q); [M+H]: 338.16; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.46 (bs, 2H), 8.45 (d, J=9.5 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.47 (dd, J=8.5, 2.5 Hz, 2H), 7.44 (d, J=9.5 Hz, 1H), 6.51-6.62 (m, 1H), 5.51 (tt, J=7.5, 3.5 Hz, 1H), 3.33 (br. s, 2H), 3.20 (br. s, 2H), 2.18-2.31 (m, 2H), 2.01 (ddt, J=13.5, 8.5, 4.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[CH2:5][N:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][CH2:12][C:11]1[CH:10]=[C:9]([CH:23]=[CH:22][CH:21]=1)[C:7]([N:6]([CH2:5][C:4]1[CH:32]=[C:33]([Cl:35])[CH:34]=[C:2]([Cl:1])[CH:3]=1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(C(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichlorobenzyl)(4-fluorobenzyl)carbamoyl)benzylcarbamate (0.8 g, 1.55 mmol) in CH2Cl2 (8 mL) was added TFA (1.19 mL, 15.5 mmol). The reaction mixture was stirred at rt. for 4 h, concentrated and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give the product as a white solid (0.61 g, 95%). 1H NMR (DMSO-(d6): δ 7.52-7.06 (m, 11H), 4.65-4.40 (m, 4H), 3.72 (s, 2H); MS (ESI): [M+H]+=416.9.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]([C:15]1[O:16][C:17]([C:21]2[CH2:25][C:24]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)=[CH:18][C:19]=1[CH3:20])=O>C(OCC)C.C(OCC)(=O)C>[CH3:20][C:19]1[CH:18]=[C:17]([C:21]2[CH2:25][C:24]([C:30]3[CH:31]=[C:32]([Cl:38])[C:33]([Cl:37])=[C:34]([Cl:36])[CH:35]=3)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=2)[O:16][C:15]=1[CH2:13][OH:12]
Reactant: COC(=O)c1oc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CO
Reaction time: 0.33 h
Yield: 103.1 %

Procedure:
Diisobutylaluminium hydride (DIBAL-H, 12.1 ml, 1M in Toluene) is added to a solution of 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carboxylic acid methyl ester (1.84 g) in diethyl ether (30 ml) under nitrogen at −5° C. After 20 minutes at −5° C., the reaction mixture is diluted with ethyl acetate and is quenched with a saturated solution of NaHCO3. The resulted fine white precipitate is filtered and the aqueous phase is separated. The organic phase is washed with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-yl}-methanol (1.78 g) as a light yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccoc1CN1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (1.5 g, 8.57 mmol) and pyrrolidine (1.42 mL, 17.14 mmol) and CH2Cl2 (30 mL) was added sodium triacetoxyborohydride (3.63 g, 17.14 mmol). The mixture was stirred at room temperature for 5 hours. The resulting mixture was diluted with EtOAc (300 mL) and the organic layer was washed with saturated NaHCO3 and brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (1.26 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:11][C@@H:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)[C:9]1=[O:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3S,5R)-3-(4-benzyloxyphenyl)-5-(tert-butyldimethylsilanyloxymethyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 3.91 mmol) in tetrahydrofuran (45 mL) was cooled in an ice bath. Aqueous 0.5M HCl solution (7.8 mL, 3.9 mmol) was added and the resulting mixture was allowed to warm to room temperature while stirring overnight. After a total reaction time of 24 hours, saturated aqueous NaHCO3 solution was added. The mixture was extracted twice with diethyl ether and the combined organic phases were washed with brine, dried over MgSO4 and concentrated to an oil. The title compound, a colorless oil (1.02 g, 65%), was isolated by flash chromatography on silica gel eluting with 50% ethyl acetate in hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[BH4-].[Na+]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]([CH3:12])[OH:13]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cccc([N+](=O)[O-])c1Cl
Yield: 83.4 %

Procedure:
According to the procedure of Example 3, 1-(2-chloro-3-nitrophenyl)ethanone (9.0 g, 44.6 mmol) is reacted with sodium borohydride (0.84 g, 22.3 mmol) to give 2-chloro-α-methyl-3-nitrobenzenemethanol (7.5 g, 83%), mp=62-64° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:13]=O>CN(C=O)C.O=[Pt]=O>[NH2:13][C:3]1[C:4](=[O:12])[NH:5][C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[NH2:1]
Reactant: CCCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: CCCn1c(N)c(N)c(=O)[nH]c1=O

Procedure:
33.3 g of 6-amino-5-nitroso-1-propyl-2,4-(1H,3H)-pyrimidinedione (III) was catalytically hydrogenated in 800 ml of DMF in the presence of 0.1 g PtO2 for 3 hours at room temperature and at a pressure of 200 kPa. The catalyst and the crystals were filtered off and washed with ethanol. Yield 29 g (93%) (IV).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:20])[CH2:9][CH:8]([OH:10])[O:7][CH:6]1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:20])[CH2:9][CH:8]([O:10][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:4]
Reactant: COC(=O)C1(C)CC(O)OC1COCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CC(OC(C)=O)OC1COCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-Benzyloxymethyl-5-hydroxy-3-methyl-tetrahydro-furan-3-carboxylic acid methyl ester (0.48 g, 1.7 mmol) prepared as previously described, in pyridine (5 mL), Acetic Anhydride (0.32 mL, 3.4 mmol) and DMAP (5 mg) were added and the reaction was stirred at room temperature. After 3 h stirring, the reaction mixture was diluted with ethyl acetate, washed with 0.5N HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography (EA/Hexanes, 40:60). The product was isolated as a 2.8/1 anomeric mixture.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[S:16][NH:17][C:18](=[O:19])[C:10]=12.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([N:17]1[C:18](=[O:19])[C:10]2[C:11](=[N:12][C:13]([CH3:15])=[CH:14][C:9]=2[CH3:8])[S:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1cc(C)c2c(=O)n(Cc3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (approximately 3 ml) is added to a slurry of 5.0 g of 4,6-dimethylisothiazolo-(5,4-b)-pyridin-3(2H)-one in 120 ml reagent grade acetone until the mixture becomes homogeneous. A solution of 4.0 g (0.024 m) of benzyl bromide in 20 ml acetone is then added. The reaction mixture is stirred for 3 days at room temperature and is then stripped to dryness. The residue is washed once with deionized water, then with 95% 2B ethanol, then ether and dried to give the product.