Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1>>[O:27]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)[C@@H](C)NC(=O)OCc1ccccc1
Product: CC([C@@H](C)NC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
Under argon, 0.82 g of benzyl [(2R)-3-hydroxybutan-2-yl]carbamate (Example 134A, 3.3 mmol, 1 equivalent) were reacted with 0.57 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 3.9 mmol, 1.1 equivalents) and worked up analogously to Example 137A. This gave 1.25 g (72% of theory; purity 75%) of the title compound (diastereomer ratio about 3:1).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (560 mg) and 1,2-dichloroethane (15 mL) was added morpholine (170 mg) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 15 hr. Morpholine (170 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (400 mg, yield 63%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:15][C:2]([F:1])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:18])=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc(OCC(F)(F)F)n1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane/EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 1.14 g (45% yield) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:24](=[O:25])[N:23]([CH:26]([CH3:33])[CH:27]([NH:29]C(=O)C)[CH3:28])[N:22]=[CH:21]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Cl>[NH2:29][CH:27]([CH3:28])[CH:26]([N:23]1[C:24](=[O:25])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[CH:21]=[N:22]1)[CH3:33]
Reactant: CC(=O)NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: Cl
Product: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 0.7 %

Procedure:
A mixture of intermediate (3d) (0.0069 mol) in HCl conc. (50 ml) was stirred and refluxed for 48 hours. The solvent was evaporated and the residue was dissolved in H2O (50ml). The mixture was alkalized with NH4OH and extracted with CH2Cl2/CH3OH 80/20 (500 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, filtered off and dried, yielding 2.6 g (92%) of [R(R*,S*)]-2-(2-amino-1-methylpropyl)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 4; mp. 237.2° C.; [α]20D=+1.010° @19.79 mg/2ml in DMF).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:24]#[N:25])(C)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:10][CH:9]=2)[C:24]#[N:25])=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 94%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH3:11])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:11][C:7]1[O:8][CH:9]=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1occc1C(=O)O
Temperature: 25 °C
Yield: 67.2 %

Procedure:
2-Methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (70 ml), and 1N aqueous sodium hydroxide (78 ml) was added. The mixture was stirred at room temperature and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration to give 2-methyl-3-furancarboxylic acid (5.5 g) as crystals.
Reaction SMILES: CC1(C)S(=O)(=[O:7])C2CC(=O)N2C1C([O-])=O.[Na+].[C:17]([O:28]CC1C=CC=CC=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CCl)=[O:23].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CC(C)=O.[Pd]>[OH2:7].[C:17]([OH:28])(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(CCCCC(=O)OCc1ccccc1)OCCl
Reactant: CC1(C)C(C(=O)[O-])N2C(=O)CC2S1(=O)=O
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)O
Reaction time: 1 h
Yield: 208.6 %

Procedure:
To 400 ml acetone is added 48.5 g (0.19 mole) sodium 1,1-dioxopenicillanate, 48.0 g (0.17 mole) benzyl chloromethyl adipate and 19.3 g (0.06 mole) tetrabutylammonium bromide. The mixture is heated at reflux under nitrogen overnight, filtered, washed with acetone and the filtrate evaporated. The residue is taken up in 500 ml ethyl acetate, washed alternately with brine and water, 250 ml portions, brine again and dried (MgSO4). Evaporation of solvent in vacuo afforded 89.6 g light yellow oil. The oil is taken up in 250 ml ethyl acetate, 20.0 g 10% Pd/C added and the mixture is hydrogenated at 3.52 kg/cm2 for one hour. After adding 15 g of fresh catalyst the hydrogenation is continued for 2.5 hours. The catalyst is removed by filtration, the cake washed with acetone (1500 ml) and the combined filtrate and washings evaporated in vacuo to obtain a viscous oil. The oil is taken up in 150 ml acetone and water added slowly to start crystallization, then continued until 800 ml water is added. After stirring 30 minutes, the crystalline product is recovered by filtration, washing with water and air dried to obtain 58.2 g of the title carboxylic acid. Recrystallization from ethyl acetate affords the crystalline monohydrate, m.p. 100°-102° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(C(=O)N2CCOC3(CCNCC3)C2)n1
Reaction time: 0.33 h

Procedure:
A solution of tert-butyl 4-(4-isopropylthiazole-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 66, step a) (0.54 g) in DCM (20 mL) was treated with trifluoroacetic acid (5 mL) and the reaction mixture allowed to stand at 20° C. for 20 minutes. Toluene (40 mL) was added and the solvents removed under reduced pressure. The residue was azeotroped twice with acetonitrile to afford the subtitled compound. Yield 0.56 g.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[S:25][C:24]([O:26][CH2:27][C@@H:28]([NH:40]C(=O)OC(C)(C)C)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[N:23][N:22]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[S:25][C:24]([O:26][CH2:27][C@@H:28]([NH2:40])[CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=4)=[N:23][N:22]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](COc1nnc(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A 50% TFA/DCM mixture (2 mL) was added to tert-butyl (S)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate. After 30 minutes, the reaction mixture was concentrated. The residue was purified by reverse phase C-18 HPLC chromatography to provide (2S)-1-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yloxy)-3-(4-(trifluoromethyl)phenyl)propan-2-amine (50 mg, 42% over two steps). LCMS 431 (M+H) calc. for C21H18F3N4OS 431.1. 1H NMR (400 MHz, CDCl3): δ ppm 3.14 (d, J=6.46 Hz, 2H) 3.81-3.88 (m, 2H) 3.95-4.00 (m, 1H) 7.43 (d, J=8.02 Hz, 2H) 7.60 (d, J=8.22 Hz, 2H) 8.03 (d, J=6.26 Hz, 1H) 8.17 (s, 1H) 8.22-8.28 (m, 2H) 8.62 (d, J=6.26 Hz, 1H) 9.58 (s, 1H). 2H not detected.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:14]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OCc2ccccc2)ccc1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 5-(benzyloxy)-2-methylbenzaldehyde (250 mg) in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (379 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, diethyl ether was added, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg) as a yellow oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][CH2:33][O:34][C:35]([CH2:37]O)=[O:36].[C:39]1(=[O:45])[NH:43][C:42](=[O:44])[CH:41]=[CH:40]1>>[CH2:33]([O:34][C:35]([CH2:37][N:43]1[C:39](=[O:45])[CH:40]=[CH:41][C:42]1=[O:44])=[O:36])[CH3:32]
Reactant: CCOC(=O)CO
Reactant: O=C1C=CC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CN1C(=O)C=CC1=O

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), ethyl glycollate (0.71 ml, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: [C:1]([C:3]1[C:8](Cl)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[F-:10].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]([F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: [F-]
Reactant: N#Cc1ncccc1Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ncccc1F
Yield: 50.1 %

Procedure:
A solution of 2-cyano-3-chloropyridine (1 g, 7.22 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50%) of 2-cyano-3-fluoropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=CN=[N:11]1.BrCC1C=CC([C:32]2OC3C=CC=CC=3[N:36]=2)=CC=1OC.N1C=NC=N1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[N:36][CH:32]=[N:11]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Agent: c1nc[nH]n1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cncn1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 1,2,4-triazole (70 mg, 1.0 mmol) afforded the desired 2-[3-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.13 (s, 1H), 7.92 (s, 1H), 7.71–7.78 (m, 2H), 7.51–7.54 (m, 1H), 7.29–7.34 (m, 2H), 7.24 (d, 2H), 5.34 (s, 2H), 3.92 (s, 3H). MS (ESI) 307 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][NH:24][C:25]([NH2:27])=[S:26].[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:27][C:25]([SH:26])=[N:24][N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NNC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(S)nnc1-c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.05 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 600.8 mg of thiosemicarbazide is stirred intensively at 90° for 30 minutes. The mixture is then cooled to 40° and treated with a solution of 870.1 mg of sodium hydroxide in 15 ml of water. The solution is subsequently heated to 90° for 30 minutes, cooled to room temperature and treated dropwise with 2 ml of conc. hydrochloric acid. The crystallized-out product is filtered under suction and then dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one of m.p. 282°-284° (from ethanol).
Reaction SMILES: [OH:1][C:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)([CH3:4])[CH3:3].C(OCC)(=O)C.[ClH:46]>C(OCC)(=O)C>[ClH:46].[ClH:46].[OH:1][C:2]([C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:10]1)([CH3:4])[CH3:3]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)(C)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(C)(C)O)C2)nc2ccccc21
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-(1-hydroxy-1-methylethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (180 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate (4 ml) was added, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure to give the object product (130 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1200 mg) in N,N-dimethylformamide (20 ml) were added potassium carbonate (1710 mg) and ethyl 2-bromopropionate (1.5 ml). The mixture was stirred at 100° C. for 12 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (882 mg, yield 60%) as a yellow oil.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Solvent: CO
Product: O=C1C=C(c2ccc(O)cc2O)CCC1
Reaction time: 2 h
Yield: 76 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (50 m g) was heated to 50° C. in methanol (4 ml) containing acidic ion exchange resin (500 mg). After 2 hr, the mixture was filtered and the filtrate was evaporated in vacuo and purified by flash column chromatography (SiO2, ether/petroleum ether, 9:1, v/v) to furnish the title compound as a yellow solid (31 mg, 76%). δH (DMSO) 1.95 (2H, quintet), 2.30 (2H, t), 2.69 (2H, t), 6.26 (2H, overlapping m), 6.35 (1H, m), 7.10 (1H, d), 9.67 (1H, bs), 9.86 (1H, bs); m/z (ES−) 407 (2M−H)−.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:44])[CH2:38][CH:39]=[CH:40]B(O)O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:40]=[CH:39][CH2:38][CH:37]([CH3:44])[CH3:36])=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC(C)CC=CB(O)O
Product: CC(C)CC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-methyl-1-pentenylboronic acid (39 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(4-methyl-pent-1-enyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[CH2:28](I)[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:28]([N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCI
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2sccc21
Yield: 56 %

Procedure:
The title compound was produced following the procedure of Example 13 using dimethylformamide as the solvent, the thienopyrimidine-2,4-dione (2.0 g, 5.17 mmol) from Example 19, and butyl iodide as the alkylating agent. The title compound was isolated in 56% yield (1.28 g) after recrystallization from EtOH, mp 139°-140° C.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([N+:13]([O-])=O)=[N:8][CH:9]=[C:10]([CH3:12])[CH:11]=1.Cl.O>[Fe].C(O)C>[NH2:13][C:7]1[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])=[CH:11][C:10]([CH3:12])=[CH:9][N:8]=1
Reactant: Cc1cnc([N+](=O)[O-])c(OCc2c(C)cccc2C)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cnc(N)c(OCc2c(C)cccc2C)c1
Yield: 92.1 %

Procedure:
A mixture of 3-(2,6-dimethylbenzyloxy)-5-methyl-2-nitropyridine (1.9 g, 6.99 mmol), iron powder (6.4 g), concentrated HCl (0.15 ml), water (1.5 ml) and 95% ethanol (35 ml) was refluxed for 1.0 h. The reaction mixture was filtered over celite and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, using methylene chloride:methanol (100:4) as eluent to give 1.56 g (92%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(#N)C>C(Cl)Cl>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NCc1ccccc1Cl
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-chlorobenzylamine and acetonitrile essentially as described above in example 48 except that the crude product is dissolve in DCM and purified by using a step gradient of 50% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=98%, [M+H]+=399.