Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:13][C:12](=O)[NH:11][C:10](=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH2:17].C>CO>[CH3:16][N:17]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:9][C:10](=[O:15])[NH:11][C:12]1=[O:13]
Reactant: O=c1cc(-c2cccc(F)c2)oc(=O)[nH]1
Reactant: CN
Agent: C
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)cc(=O)[nH]c1=O
Yield: 54 %

Procedure:
To 490 mg (2.36 mM) of 6-m-fluorophenyl-1,3-oxazine-2,4-dione of Preparation IIa(1) is added 30.0 ml of a 40 percent aq. CH3NH2 solution. The reaction solution is heated at reflux for 18 hours. The solution is cooled and evaporated to dryness, under vacuum, to yield an amber solid. The solid is dissolved in CH3OH (hot), treated with darco, filtered and the CH3OH filtrate is evaporated to a white solid. The solid is recrystallized from H2O to yield 280 mg (54 percent) (m.p.: 192-194) of 1-N-methyl-6-m-fluorophenyl-2,4-pyrimidine-dione.
Reaction SMILES: Cl[C:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.CC1C=CC(C2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)=CC=1>>[NH:24]1[C:25]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:2]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[N:23]1
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(-c2n[nH]c3ccccc23)cc1
Product: CCOC(=O)c1ccc(-c2n[nH]c3ccccc23)cc1
Yield: 88.9 %

Procedure:
Ethyl 4-(chlorocarbonyl)benzoate was treated as in the preparation of 10 to afford 11 (0.94 g, 88.9%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9](F)=[N:10][CH:11]=1)[CH3:5])=[N+:2]=[N-:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21](C3C=CN=CC=3C(O)C)[C:14]1=2>>[N:1]([CH:4]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][C:7]=1[C:21]1[C:14]2[S:13][CH:17]=[CH:16][C:15]=2[CH:18]=[CH:19][CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(O)c1cnccc1-c1cccc2ccsc12
Reactant: CC(N=[N+]=[N-])c1ccc(F)nc1
Product: CC(N=[N+]=[N-])c1cnccc1-c1cccc2ccsc12

Procedure:
Using a procedure similar to the one used for 5-(1-azido-ethyl)-2-fluoro-pyridine above, prepare the title intermediate from 1-(4-(benzo[b]thiophen-7-yl)pyridin-3-yl)ethanol as a brown oil (0.66 g, 93%). MS (ES) m/z 280 [M+1]+.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:35])[C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C)C=O>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][C:16]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:15]2[CH2:14][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1)=[O:35]
Reactant: Sc1ncc[nH]1
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CSc1ncc[nH]1
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To a solution of 2-mercaptoimidazole (27.4 mg) in dimethylformamide (1.5 ml) was added potassium carbonate (51.6 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. To the mixture was added 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (120 mg) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added water under ice-cooling, and the resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-[(imidazol-2-yl)thiomethyl]quinoline (115 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)=[O:27])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: N#Cc1cc(Br)ccc1N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)ccc1NC(=O)c1ccccn1
Yield: 70.9 %

Procedure:
To a stirred solution of 2-amino-5-bromobenzonitrile 2-1 (2.8 g, 0.014 moles) in toluene was added (4.95 mL, 0.028 moles) of N,N-diisopropylethylamine, followed by slow addition of (2.74 g, 0.015 moles) picolinoyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 3 grams of 2-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 95% pure, M+1 peak m/e 301.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O-:12][CH2:13][CH3:14].[Na+].C(O)C>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:12][CH2:13][CH3:14])[N:10]=1
Reactant: CC[O-]
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1nc(Cl)ccc1C(N)=O
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of 2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1(5.01 g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bath was used to maintain reaction temperature around 14-16° C.; sodium ethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) with anhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition, the reaction was stirred for 40 min at 14-16° C. [Note: An aliquot (0.3 mL) of reaction was concentrated. A 1H NMR of aliquot recorded in d6-DMSO showed ˜98% conversion to desired 2]. The reaction was poured into water (500 mL) and extracted with EtOAc (3×400 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light gray solid (5.20 g, 95% purity as established by 1H NMR). The title compound was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ8.16 (d, J=8.2 Hz, 1H), 7.76 (br s, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:6])[CH3:2].[CH2:27](O)[CH:28]=[O:29]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:6])=[CH:27][CH2:28][OH:29])[CH3:2]
Reactant: O=CCO
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(C)=CCO
Yield: 90 %

Procedure:
886 g (2.44 mol) of 2-(triphenyl-phosphanylidene)-propionic acid ethyl ester in methylene chloride (4 L) was added dropwise into a refluxing solution of glycoaldehyde dimer (140 g, 1.17 mol) in methylene chloride (6 L). After refluxing for 4 h, the solvent was evaporated. Resulting crude product was fractionated (bp 108-114° C. at 2 mmHg) to give 304 g (90%) pure product as an oil. 1H-NMR (300 Hz CDCl3) δ 6.88 (t, 1H, CH), 4.35 (d, 2H, CH2OH), 4.20 (q, 2H, OCH2), 1.85 (s, 3H, CH3), 1.30 (t, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]1([Si:16]2(CCCCC)[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:10]([Si@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=3)=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1ccc(Cl)c(F)c1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(Cl)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH:14]1([Ti+3:13])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: [Ti+3]C1C=Cc2ccccc21
Yield: 70 %

Procedure:
A 250 mL Schlenk flask is charged with toluene, 75 mL, and titanium tetrakis(dimethylamide), 2.35 g (10.48 mmole). The mixture is stirred magnetically throughout the procedure. Freshly degassed indene (nitrogen sparged) is added to the Schlenk flask at room temperature in excess, 2.44 mL (20.96 mmole). The mixture is refluxed at least 24 hours giving a blood red solution. All volatiles are removed under vacuum at room temperature leaving a deep red, oily residue. The residue is transferred in a minimum of hexane to a micro scale distillation apparatus and distilled under vacuum. A viscous red oil distills at 60° C. (0.025 mm Hg) which is identified by nuclear magnetic resonance (NMR) as indenyltitanium tris(dimethylamide). The yield is 70% by this method of preparation.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[C:32]([O:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2)(=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine -2,4-dione (prepared as described in Example 28), 0.31 g of succinic anhydride and 1 ml of pyridine was allowed to stand overnight at room temperature. The reaction mixture was then washed 3 times, each time with 10 ml of cyclohexane, and the insoluble residue obtained was purified by silica gel column chromatography (eluted by mixtures of benzene and ethyl acetate ranging from 5:1 to 1:1) to give the title compound melting at 197°-202° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17](=O)[CH3:18])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[CH3:20][C:21]([S@:24]([NH:26][CH:17]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[C:2]([CH3:1])[CH:3]=1)[CH3:18])=[O:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(-n2cc(C(F)(F)F)cn2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cc(C(F)(F)F)cn1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (2.16 g, yellows oil) from 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (2.00 g, 7.43 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.35 g, 11.1 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)=O.O1C2C(=CC=CC=2)C=CC1C(O)=O.C(N1CCNCC1)C1C=CC=CC=1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH2:11][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:18]1
Reactant: O=C(C1C=Cc2ccccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1C=Cc2ccccc2O1
Agent: c1ccc(CN2CCNCC2)cc1
Product: C1=CC(CN2CCN(Cc3ccccc3)CC2)Oc2ccccc21

Procedure:
By carrying out the preparation as in Example 1, but using, at the start, 1-[(chrom-3-en-2-yl) carbonyl]-4-benzylpiperazine resulting from the condensation of chrom-3-ene-2-carboxylic acid with N-benzylpiperazine, the title compound is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[C:33]#[CH:34].C1(C)C=CC=CC=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:34][C:33]#[CH:32])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1

Procedure:
A 100 mL round bottom flask containing the 2-(hydroxy-3-methyl-benzoyl)-indan-2-carboxylic acid ethyl ester (3) (0.29 g 0.855 mmol) is charged with DMF (4 mL) and a stirring bar is added. After dissolution of the starting material, K2SO4 (0.3 g, 2.17 mmol) is added followed by a solution of propargyl bromide in toluene (11.59 M, 240 μL, 2.78 mmol). After stirring for 62 h tlc analysis (silica, 1:1 EtOAc/heptanes) indicates that the starting material had been consumed. The material is cleanly converted to a UV positive spot with a slightly lower Rf. The reaction is diluted with EtOAc (80 mL) and filtered through a pad of Celite. The filtrate is transferred to a reparatory funnel. This is washed repeatedly with a saturated aqueous solution of NaHCO3 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and evaporated in vacuo to yield 2.09 g of a light brown oil. This is purified (silica, 40 g ISCO column 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% EtOAc in heptanes for 10 column volumes). 17 mL fractions of UV positive eluent are collected. Fractions 4 through 10 are combined, evaporated in vacuo and pumped to constant weight to give 0.21 g of white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][C:7]#N)[O:3]1.[H-].C([Al+]C(C)C)(C)C.S(=O)(=O)(O)[OH:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH:7]=[O:27])[O:3]1
Reactant: C=CC1OC(C)(C)OC1C(CC#N)OCOC
Reactant: O=S(=O)(O)O
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC1OC(C)(C)OC1C(CC=O)OCOC
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
4,5-(Dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenenitrile (159.8 mg) was dissolved in dry toluene, and 1.6 ml of 0.5N diisopropyl aluminum hydride was added at -78° C. The reaction mixture was stirred at -78° C. for 2 hours and at -40° C. for 30 minutes, and 5% dilute sulfuric acid was gradually added at 0° C. The reaction mixture was diluted with diethyl ether, and the organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to afford 91.1 mg of 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH3:2].C(NCCCCC1C=CC([N+]([O-])=O)=CC=1)CC(C)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(OCC)(=O)C>[S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=1)([O-:50])(=[O:49])=[O:48].[CH2:1]([NH+:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CCCCc1ccc([N+](=O)[O-])cc1)CCC(C)C
Agent: CC(C)CCNCCCCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CC[NH+](CCCCc1ccc([N+](=O)[O-])cc1)CCC(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Isopentylamine was reacted with 4-(4-nitrophenyl)butanoyl chloride to provide N-isopentyl-4-(4-nitrophenyl)butyramide, which when reduced by reaction with diborane afforded N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of the latter compound with acetyl chloride under the conditions of Example 22 gave N-acetyl-N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of 21.8 g. of N-acetyl-N-isopentyl-4-(4-nitrophenyl)butylamine with 220 ml. of 1 M diborane in tetrahydrofuran provided, after workup according to the method of Example 22, 19.8 g. of N-ethyl-N-isopentyl-4-(4-nitrophenyl)butylamine. Reaction of the amine with para-toluenesulfonic acid in ethyl acetate afforded N-ethyl-N-isopentyl-4-(4-nitrophenyl)butylaminium tosylate. M.P. 78°-80° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[CH3:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH3:5])=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(C(C)=O)cc1

Procedure:
A mixture of 12.3 g. of 1-propyl bromide, 13.6 g. of 4-hydroxyacetophenone, 27.6 g. of potassium carbonate and 200 ml. of acetone was refluxed overnight. The mixture was then cooled, filtered, the filtrate concentrated and distilled in a Kugelrohr. The distillate was dissolved in ethyl acetate, treated with charcoal, filtered through diatomaceous earth, concentrated and dried, giving the desired intermediate as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: ClCCCBr
Reactant: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.5 %

Procedure:
A mixture of 5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep22, 1 g, 5.15 mmol), 1-bromo-3-chloropropane (0.81 g, 5.15 mmol) and potassium carbonate (0.71 g, 5.15 mmol) in DMF (10 ml) was stirred at room temperature for 7 hours, then the mixture was diluted with water and extracted with ethyl acetate. Organic phase was evaporated and the crude was purified by a FC (eluent P:E=3:1, 1:1) to afford the title compound (300 mg, y=21%)
Reaction SMILES: C([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH3:23])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:24])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:22]([NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:25]=[CH:26][C:27]([CH2:29][CH3:30])=[CH:28][C:9]=2[OH:8])=[C:13]([F:24])[CH:14]=1)(=[O:19])=[O:20])[CH3:23]
Reactant: CCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2O)c(F)c1
Yield: 43.9 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzene sulfonamide (402 mg; 0.94 mmol) and tetrahydrofurane for ethanol (4 mL), the title compound (140 mg; 44%) was obtained as a clear oil, after purification on preparative TLC (dichloromethane).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:31](OCC)C.[N+](=C)=[N-]>C(OCC)C.C(Cl)Cl>[CH3:31][O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH2:20][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:10]/[C:7]2[S:8][CH:9]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[N:6]=2)[CH:13]=1)=[O:30]
Reactant: CCOCC
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A suspension of 2.1 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid in 200 ml of ethyl ether/methylene chloride (1:3 v/v) was treated with an excess of an ethyl ether solution of diazomethane. After 10 min the excess of diazomethane was removed with a stream of nitrogen, the remaining solvents were removed in vacuo and the residual materials were taken up into methylene chloride. This solution was washed with water (2×15 ml) and dried (MgSO4). Removal of the volatiles in vacuo and recrystallization from ethyl acetate yielded 2.2 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester as an off-white solid, m.p. 143°-144° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.96 (dd, J=9.0, 4.8, 1H), 7.80-7.66 (m, 2H), 7.25-7.18 (m, 1H), 7.16-7.10 (m, 1H), 5.22-5.11 (m, 1H), 3.90-3.30 (m, 8H), 3.13-3.06 (m, 7H), 3.00 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:25][CH2:24]1
Reactant: O=CCCc1cc(-c2cccs2)no1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3cccs3)no2)CC1
Yield: 78.2 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(2-methoxyphenyl)piperazine (9.2 mg, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 10 hr and followed the same processes as in Example 1 to obtain 15 mg (81.5%) of the target compound.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C2C(=CC=CC=2)C=CC=1CN1CCC[C@H]1CO>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: OC[C@@H]1CCCN1Cc1ccc2ccccc2c1
Solvent: CO
Solvent: C1CCOC1
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmnol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3 ·THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(β-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.