Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[CH2:14][CH2:15]Cl)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:15][CH2:14][C:13]2=[O:17])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CCN1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3-nitrophenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3-nitrophenyl)-2-azetidinone as the residue.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[C:1]([C:5](=[N:15][OH:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CC
Yield: 69.4 %

Procedure:
Ethyl propionylacetate (14.4 g.) was added to acetic acid (19 ml.) and stirred at 5° to 10° C. To the solution was added dropwise over 40 minutes about 2/3 volume of an aqueous solution (30 ml.) of sodium nitrite (15 g.), and further water (50 ml.) was added to the solution and stirred at 25° C. for 1.5 hrs. The remaining aqueous solution of sodium nitrite was added dropwise over 10 minutes to the solution and stirred at room temperature for 2 hrs. The reaction mixture was extracted with diethyl ether (50 ml.) twice, and the extract was washed with saturated aqueous sodium bicarbonate (30 ml.) three times and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give ethyl 2-propionyl-2-hydroxyiminoacetate (12 g.).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O[C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:19][C:18]1[C:9]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1cccc(C)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(C)c1C(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
Pivaloyl chloride is added dropwise at 10°-15° C. to a stirred mixture of methyl 2-hydroxy-3-methylbenzoate and 4-dimethylaminopyridine in 25 ml of dichloromethane. After 2 hours at room temperature, the reaction is quenched with 200 ml of water. The organic layer is washed with 5% sodium bicarbonate, dried on anhydrous sodium sulfate and evaporated in vacuo. The product is purified by flash chromatography on silica gel.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:37])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].[Li+].[OH-].Cl>CO.O>[C:33]([O:32][C:30]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21](/[CH:20]=[CH:19]/[C:16]1[CH:15]=[CH:14][C:13]([CH:4]([CH2:5][CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])[C:3]([OH:38])=[O:2])=[CH:18][CH:17]=1)=[O:37])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(CCC1CCCN1C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCCC1CCC(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(1-methyl-pyrrolidin-2-yl)-butyric acid methyl ester (52.1 mg, 10 mmol) in MeOH/H2O (4:1) (2 mL), LiOH (24 mg, 100 mmol.) was added. After the solution was stirred at room temperature for 5 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (10 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid product without further purification. MS: calc'd 508 (MH+), exp 508 (MH+).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=1)[C:3]([C:5]1[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=1)=O.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29].O>CC(N(C)C)=O>[Cl:25][C:21]1[N:20]=[C:19]([C:2]2[O:29][C:28]([C:27]([CH3:32])([CH3:31])[CH3:26])=[N:30][C:3]=2[C:5]2[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)C(N)=O
Reactant: C=CCOC(=O)Nc1cccc(C(=O)C(Br)c2ccnc(Cl)n2)c1F
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)oc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Yield: 19.7 %

Procedure:
A stirring mixture of 2-propen-1-yl {3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (6.1 g, 14.23 mmol) and 2,2-dimethylpropanamide (2.16 g, 21.35 mmol) in DMA (200 ml) was heated to 80° C. for 2 days. Upon cooling, the reaction mixture was poured into water (500 ml) and extracted with EtOAc (100 ml×5). The combined organic layers were washed with brine, separated, dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with petroleum ether with EtOAc (10% to 16%) and collected fractions to obtain title compound as yellow solid (1.21 g, 19%). MS (ES): 431 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(4-chlorophenyl)-4-hydroxypiperidine (12.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.2 mg). Calcd for C22H21ClN2O3: 396.1241, found 396.1239.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Under stirring in an ice bath, 2.5 g of N-iodosuccinimide was added little by little to a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine and 10 ml of N,N-dimethylformamide, followed by stirring as it was overnight. Sodium sulfite was added thereto and the mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 4.19 g of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])[C:5]([F:21])=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][NH:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.[F-].[K+]>CS(C)=O>[C:22]([C:3]1[CH:4]=[C:5]([F:21])[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:12]([NH:14][O:15][CH3:16])=[O:13])=[N:7][C:2]=1[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:24])#[N:23]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(C#N)cc2F)c1
Reactant: CNCC(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)c(C#N)cc2F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
A mixture of 3-(6-chloro-5-cyano-3-fluoro-pyridin-2-ylamino)-N-methoxy-4-methyl-benzamide (55.6 mg, 0.166 mmol), N-methyl-neopentylamine (70 mg, 0.511 mmol), diisopropylethylamine (0.1 mL) and potassium fluoride (12 mg) in DMSO (1 mL) was heated to 150° C. overnight. The product (3.9 mg, 5.9%) was isolated after purification by HPLC. C21H26FN5O2 MS m/e=400 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[Br:17]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:17])=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(OC)c1-c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(Br)c(OC)c1-c1cccnc1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 2 using 1,3-Dimethoxy-2-(Pyrid-3-yl)benzene 29 and N-bromosuccinimide to yield 30.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4([C:29]([O:31]C)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[F:34][C:2]([F:1])([F:33])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20][CH2:21]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (89 mg, 0.18 mmol, EXAMPLE 1, Step 5) in tetrahydrofuran (1 mL), methanol (1 mL) and 2 N aq. sodium hydroxide (1 mL) was stirred at 70° C. for 17 h. The mixture was neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate was filtered.
Reaction SMILES: [CH2:1]([C:3]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>O1CCOCC1>[C:17]([CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][C:13]([NH:12][C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][CH3:2])=[O:16])[CH:24]=1)#[N:18]
Reactant: C=CC(=O)NC(CC)(CC)c1ccccc1
Reactant: N#CCc1c[nH]cn1
Solvent: C1COCCO1
Product: CCC(CC)(NC(=O)CCn1cnc(CC#N)c1)c1ccccc1

Procedure:
In a similar manner to Example 24, N-(1-ethyl-1-phenylpropyl)acrylamide (6.1 g) and 4-cyanomethylimidazole (3.0 g, Sigma Chemicals) were reacted in 1,4-dioxane (60 ml) in the presence of Triton B (0.8 ml) to give 3-[4-(cyanomethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propionamide, m.p. 121-122° C.
Reaction SMILES: [N:1]([C@H:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@@H:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][C@H:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@@H:5]([NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:6]
Reactant: CCCCCCCCCCCCCCC[C@@H](N=[N+]=[N-])[C@H](C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCC[C@@H](N)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of azide 95 (25 mg, 0.06 mmol) in MeOH (1.5 mL) at room temperature, Pd—C (10% wt, 16 mg, 0.015 mmol) was added. The mixture was purged with a stream of dry Ar, and then H2. The reaction was stirred overnight under a H2 atmosphere (1 atm). The catalyst was filtered off through a 0.45 μm teflon filter in polypropylene housing, washing the filter with MeOH (15 mL) and the solvent was evaporated in vacuo to obtain amine 96 as a white solid (22 mg, 94% yield).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:29]([CH3:30])=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=3[CH3:31])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([CH3:31])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][C:29]=3[CH3:30])=[O:18])[C:14]([CH3:32])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCCC(CO)C3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCCC(CO)C2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-(6-(3-(hydroxymethyl)piperidin-1-yl)-3-methylpicolinamido)-3,5-dimethylbenzoate (0.06 g, 0.146 mmol) in THF:MeOH (4 ml:1 ml). After 12 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 3 with aqueous citric acid solution, and extracted with ethyl acetate (2×10 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and filtered to afford the title compound as an off-white solid (0.03 g, 48%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:12][C:3]1=2.P(Cl)(Cl)([Cl:21])=O>CCCCCC>[Cl:21][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:12][C:3]=12
Reactant: N#Cc1c[nH]c2cc(-c3ccccc3)sc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#Cc1cnc2cc(-c3ccccc3)sc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-oxo-2-phenyl-4,7-dihydrothieno[3,2-b]pyridine-6-carbonitrile (878 mg, 3.48 mmol) and 10 mL of phosphorous oxychloride is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and hexane is added. The solids are collected by filtration and stirred with saturated aqueous sodium bicarbonate. The solids are collected by filtration washing with water, ethyl acetate and methanol to provide 751 mg of 7-chloro-2-phenylthieno[3,2-b]pyridine-6-carbonitrile that is not purified.
Reaction SMILES: [CH3:1][N:2]([CH2:17][C:18]([NH2:20])=[O:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:5])=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:2]([CH3:1])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=1)(=[O:5])=[O:4])(=[O:23])[CH3:22]
Reactant: CN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)NC(=O)CN(C)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 138 °C
Yield: 85.6 %

Procedure:
In this example, a catalytic amount (about 4 drops) of concentrated sulfuric acid was added to a suspension of 3.5 g of (N-methyl-3-trifluoromethylbenzylsulfonamido)-acetamide in 7 mls (7.6 g) of acetic anhydride at room temperature. The mixture was heated for 2 hours at about 138° C. and then poured into ice water and extracted into methylene chloride. The methylene chloride extract was washed with aqueous 5 wt.% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness affording 3.4 g of a white solid. The solid was triturated with ethyl ether affording 2.17 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C@@H:5]([NH:17]C(OC(C)(C)C)=O)[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Cl.O1CCOCC1>ClCCl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C@@H:5]([NH2:17])[CH2:6][S:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COC(=O)C[C@H](CSCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(R)-3-t-butoxycarbonylamino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester (30 g, 81.3 mmol) prepared in Step D was dissolved in dichloromethane (70 mL). 4N hydrochloric acid/1,4-dioxane solution (71 mL) was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the residue were added dichloromethane (30 mL) and diethylether (150 mL). The resulting solid was filtered and dried to give the title compound (19.2 g, Yield 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([Cl:24])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (4.00 g, 19.7 mmol) in CH2Cl2 (90 mL) cooled at 0° C. was added DMF (76 μL, 0.98 mmol) and oxalyl chloride (2.15 mL, 24.6 mmol). The reaction was allowed to warm to ambient temperature and stirred for 3.5 h. The solution was concentrated in vacuo to provide 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 218.2. 1H NMR δ (ppm) (CDCl3): 7.89 (2H, s), 7.76 (1H, d, J=8.2 Hz), 7.59-7.60 (1H, m), 7.48-7.50 (1 H, m), 2.48 (3H, s).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:12][C:6]=2[CH:5]=1>C(O)(=O)C>[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH2:12][C:6]=2[CH:5]=1
Reactant: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(C2Cc3cc(F)ccc3Oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.15 G. of sodium borohydride are added in small portions over a period of 15 minutes to a solution of 12.3 g. of 1-[2-fluoro-dibenzo[b,f]oxepin-10-yl]-4-methyl-piperazine in 185 ml. of glacial acetic acid with cooling in such a manner that the temperature does not exceed 25° C. The mixture is stirred for an additional 1 hour at room temperature and the acetic acid is then evaporated in vacuo. The residue is partitioned between 3-N sodium hydroxide solution and chloroform. The aqueous phase is separated and extracted again with chloroform. The chloroform extracts are washed three times with water, dried over sodium sulfate, evaporated in vacuo, and there is obtained 1-[2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine as a crystalline residue. The dihydrochloride, prepared in ethanol, melts at 240°-241° C. (with decomposition).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Sodium azide (515 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-(p-toluenesulfonyloxy)-D-proline methyl ester (B, 1.65 g) in N,N-dimethylformamide (10 mL)-water (2 mL). After stirring at 80-90° C. for 1 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (1.04 g) as a colorless oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1.CCOCC>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol) in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which were then waashed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR40##
Reaction SMILES: [C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][SH:31])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].C[O-].[Na+].[CH2:35]1[O:37][CH:36]1[CH2:38][OH:39].Cl>O.CO>[C:1]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([CH2:29][CH2:30][S:31][CH2:35][CH:36]([CH2:38][OH:39])[OH:37])([F:27])[F:28])([F:24])[F:25])([F:21])[F:22])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2]
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: OCC1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC(O)CSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 ml reaction flask is charged with 50 g (0.094 mole) of (CF3)2CF(CF2)6C2H4SH, 5.1 g (0.094 mole) of sodium methoxide and 100 ml of methanol. To this is slowly added glycidol while maintaining the temperature at 25°C with an ice bath. After addition is completed, the reaction mixture is stirred for 3 hours, and then there is added 150 ml of water and enough concentrated hydrochloric acid to neutralize the base. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and evaporation of solvent affords 53 g of (CF3)2CF(CF2)6C2H4SCH2CH(OH)CH2OH, m.p. 92°-95°.