Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[Li+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[N:17]=[C:18]([I:19])[C:5]=12
Reactant: O=C(CCl)N1CCCC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Reaction time: 2 h
Yield: 47 %

Procedure:
Sodium hydride (60% in mineral oil, 32 mg, 1.75 mmol) was added to a solution of 4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (400 mg, 1.12 mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (54 mg, 1.8 mmol) in dry DMF (7.5 mL) at room temperature. After 1.5 h at room temperature further sodium hydride (60% in mineral oil, 27 mg) was added and the suspension stirred for 2 h. 4% LiCl aq. solution and ethyl acetate was added. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica gel, isohexane/ethyl acetate 1:0 to 0:1). The resulting solid was dissolved in minimum CH2Cl2 and diethyl ether was added until a solid precipitated. The solid was collected by filtration to provide 2-(4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (246 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]([CH2:24]Cl)=[CH2:23]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([O:12][CH2:24][C:22]([Cl:21])=[CH2:23])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C
Yield: 77 %

Procedure:
A mixture of 4,8-dimethyl-7-hydroxycoumarin (8.00 g., 42.1 m mole); anhydrous potassium carbonate (18.1 g., 130 m mole); 2,3-dichloropropene (33.6 g., 302 m mole); and acetone (600 ml.) was stirred and heated under reflux for twenty-four hours. The reaction mixture was concentrated to ca. 200 ml., filtered, and the inorganic salts were washed with acetone. Evaporation of the combined filtrate and washing under reduced pressure left a tan-colored residue (11.30 g.). Recrystallization from aqueous methanol gave a 77% yield of 4,8-dimethyl-7-(2'-chloroallyloxy)coumarin as small, off-white needles (8.55 g., m.p. 117.5°-120° C.). Another recrystallization did not change the m.p. but gave an analytical sample.
Reaction SMILES: [C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([OH:16])=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)O)C1
Reaction time: 0.5 h

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-isobutyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>>[N:17]1[CH:22]=[CH:21][CH:20]=[N:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:25][CH2:24]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.2 mol of 2-(4-bromobutyl)isoindole-1,3(2H)dione and 0.2 mol of 1-(2-pyrimidyl)piperazine are stirred with 0.2 mol of K2CO3 at 120°-130° C. under an atmosphere of N2 overnight. The mixture is then evaporated to dryness. Water is added and the residue is taken up in methylene chloride. After drying the organic solution, it is evaporated to obtain an oil which crystallises on trituration with cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH2:11]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([CH2:11][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(C=O)cc1CCl
Product: CCOP(=O)(Cc1cc(C=O)ccc1OC)OCC

Procedure:
In a ratio of 1:1 4-methoxy-3-chloromethylbenzaldehyde and triethyl phosphite were heated together until no more gas evolved. The reaction solution was then vacuum distilled to give the desired product. bp 172°-174° C. at 1 mm Hg.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:26]1[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C([O-])(=[O:44])C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21])[C:26]1[N:31]=[CH:30][C:29]([OH:44])=[CH:28][N:27]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromopyrimidin-2-yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amine (3.0 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (112 mg), potassium acetate (1.34 g) and bis(pinacolato)diboron (1.74 g) are dissolved in dimethylsulfoxide (20 ml) and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 1 hour. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (70 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (15 ml) under ice-cooling. One hour thereafter, thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:1) to give 2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (263 mg). MS (m/z): 595 [M+H]+
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].O>CCCCC>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([O:4][CH:1]([CH3:3])[CH3:2])=[S:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)O
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCC
Product: CC(C)OC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of isopropanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours at room temperature and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml of water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a semi-solid. The semi-solid was slurried in cold pentane and filtered. The filter cake was air dried and weighed 4.0 grams (20% crude yield) and melted at 62°-64° C. The product had a strong band at 1525 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]1(S(C=C)=O)C=CC=C[CH:22]=1>C1(C)C(C)=CC=CC=1>[C:15]1([C:4]2[C:3](=[O:2])[N:7]3[C:6](=[CH:21][CH:22]=2)[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH2:9][CH2:8]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Reactant: C=CS(=O)c1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=c1c(-c2ccccc2)ccc2n1CCc1ccsc1-2

Procedure:
2.85 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) was heated under reflux overnight in 100 ml of xylene together with 1.45 ml of phenylvinyl sulfoxide, whereupon the reaction mixture was evaporated in vacuo and the residue obtained was chromatographed on silica gel with toluene/ethyl acetate (9:1). There was obtained 4,5-dihydro-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 133°-134° (from ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][O:35][CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][O:35][CH2:36][CH2:37][NH:38][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCC1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCC3CCCO3)ccc21
Yield: 21.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(tetrahydro-furan-2-ylmethoxy)-ethyl]amide (21 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(tetrahydro-furan-2-ylmethoxy)-ethylamine (29 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 536.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.83-7.65 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 3.98-3.90 (m, 1H), 3.79-3.68 (m, 2H), 3.64 (bs, 3H), 3.61-3.52 (m, 2H), 3.49-3.38 (m, 5H), 1.94-1.68 (m, 2H), 1.60-1.47 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O>[CH2:22]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2)[C:10]([CH:11]=[O:12])=[C:2]1[CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a solution of 2-methyl-5-nitro-1H-indole-3-carboxaldehyde (500 mg, 2.45 mmol) in DMF (5 ml) was added potassium carbonate (1.0 g, 7.35 mmol) and benzyl bromide (0.44 ml, 3.68 mmol). The mixture was stirred at room temperature for 4 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was triturated with Et2O-hexane to yield 1-benzyl-2-methyl-5-nitro-1H-indole-3-carboxaldehyde (Compound 50) as a yellow solid (600 mg, 83%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:1]
Reactant: CCCOc1cc(C(N)=O)cc(C(=O)OC)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
A suspension of methyl 3-(aminocarbonyl)-5-propoxybenzoate (2.0 g, 8.2 mmol) in a dichloromethane (25 mL) at 0° C. was treated with pyridine (1.3 mL, 17 mmol) and then trifluoroacetic anhydride dropwise (1.4 mL, 9.9 mmol). The reaction was stirred at 0° C. for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a 40% dichloromethane/hexanes afforded 1.5 g (84%) of methyl 3-cyano-5-propoxybenzoate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>CN(C=O)C>[CH2:30]([O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Nitrosalicylaldehyde (1.7 g, 10 mm) was dissolved in 20 ml dry DMF and K2CO3 (2.2 g, 16 mm) was added cautiously. The reaction was stirred at room temperature for 20 minutes and 1-bromoundecane (2.6 g, 11 mm), in 20 ml dry DMF, was added dropwise to the mixture. The reaction was heated at 89° C. for 3 days, cooled and poured into 100 ml H2O. The product was extracted with diethyl ether, washed with 5% aqueous Na2CO3 and brine, and dried over MgSO4. Filtration and evaporation of the solvent yielded an oil which was chromatographed over silica gel using 10% ethylacetate/hexane. This yielded an oil which crystallized upon scratching. The resulting white solid melted at 47°-48° C.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:17])[C@@H:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3]1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41].CO>ClCCl>[OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:17])[C@@H:11]([NH:16][S:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)(=[O:42])=[O:41])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][N:4]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[CH2:3]1
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NS(=O)(=O)c1ccccn1)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Yield: 26.3 %

Procedure:
To a solution of (S)-2-amino-4-methyl-pentanoic acid [3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-yl]-amide of Example 28a (0.25 g) in dichloromethane was added triethylamine (0.27 mL) and 2-pyridinesulfonyl chloride (0.15 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.09 g): MS(EI) 525 (M+H+).
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>[Zn].C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2)cc1
Yield: 79.1 %

Procedure:
15 ml of water, 35 ml of concentrated hydrochloric acid, 50 ml of toluene and 10 gm of 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid were added to 20 gm of amalgamated zinc (Org. Synthesis, Coll. Vol. III, 786), and the mixture was refluxed for 6 hours while stirring, another 10 ml of concentrated hydrochloric acid being added after 3 hours. Subsequently, the mixture was vacuum-filtered to remove the unreacted zinc, and the filtrate was extracted with ether. The residue remaining after evaporation of the ether was recrystallized from cyclohexane, yielding 7.5 gm (79% of theory) of colorless 4-(4'-fluoro-4-biphenylyl)-butyric acid, m.p. 118°-120° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]O)[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:50][CH2:49][N:46]1[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:41])=[O:42])[CH2:44][CH2:45]1)[CH:5]=2
Reactant: CS(=O)(=O)N1CCN(CCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 96 h
Yield: 99 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(4-(methylsulfonyl)piperazin-1-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:2) to obtain the title compound (99%)
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:41]=[C:42]([NH:47][C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])[CH:43]=[CH:44][C:45]=2[CH3:46])[CH2:36][CH2:35]1>C(Cl)Cl>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:41]=[C:42]([NH:47][C:48](=[O:52])[CH:49]([CH3:50])[CH3:51])[CH:43]=[CH:44][C:45]=2[CH3:46])[CH2:36][CH2:35]1)=[O:5]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of hydroxy(diphenyl)acetic acid (100 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (78 mg, 0.48 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 3 h, then a solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide (140 mg, 0.44 mmol) in CH2Cl2 (5 mL) was added. The resulting mixture was stirred at room temperature for overnight, evaporated in vacuo, and dissolved in a mixture of EtOAc and 1N NaOH. The organic layer was separated, washed twice with water, dried over MgSO4 and concentrated. The residue was purified over preparative TLC (10% 2M NH3/MeOH in 50% EtOAc/hexane) to give 111 mg (0.21 mmol, 48%) of (N-{3-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 7.64–7.48 (m, 4 H), 7.32–7.16 (m, 6 H), 6.95 (d, 1 H, J=8.0 Hz), 6.64 (d, 1 H, J=8.0 Hz), 5.83–5.62 (br, 1 H), 3.54–3.38 (m, 2 H), 3.11–2.94 (m, 2 H), 2.79–2.59 (m, 1 H), 2.57–2.41 (m, 2 H), 2.26 (s, 3 H), 2.29–2.16 (m, 1 H), 2.16–1.91 (m, 4 H), 1.74–1.53 (m, 4 H), 0.86 (d, 6 H, J=6.8 Hz); ESMS m/e: 528.4 (M+H)+.