Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:40]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[NH2:42]>CN(C=O)C.O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[N:40]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: CC(C)OC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(c3nc(OC(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.222 mmol) of the carboxylic acid from Example 21A in 0.89 ml of DMF and 1.78 ml of 1,4-dioxane were added, at 60° C., 108 mg (0.666 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 52.4 mg (0.333 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 22.6 mg (22% of theory)
Reaction SMILES: [O:1]=[C:2]1[CH2:14][CH2:13][C:5]2[S:6][C:7]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1.[BH4-].[Na+].O.Cl>C(O)C>[OH:1][CH:2]1[CH2:14][CH2:13][C:5]2[S:6][C:7]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: NS(=O)(=O)c1cc2c(s1)CCC(=O)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1cc2c(s1)CCC(O)C2
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of 5-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-sulfonamide (1.0 g, 0.0043 mole) in ethanol (30 ml) was added sodium borohydride (160 mg, 0.004 mole). The suspended solid dissolved within 10 minutes in a slightly exothermic reaction. Stirring was continued overnight at room temperature. After dilution with water (15 ml), the ethanol was stripped in vacuo. The residual aqueous solution was cooled in an ice bath and acidified with 6N HCl. The precipitate was collected, washed with water, and dried to yield 0.7 g (70%) of product as an off-white crystalline solid, mp 176°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:24])([F:23])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]([C:34]1[C:38]([NH2:39])=[CH:37][S:36][CH:35]=1)=[O:33].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:39][C:38]1[C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][S:36][CH:37]=1)=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:23])([F:22])[F:24])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1N
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(-c2ccsc2)c2ccc(C(F)(F)F)c(C)c12
Temperature: 150 °C
Yield: 59 %

Procedure:
To a solution of 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F (˜4.39 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 1G (1.38 g, 8.79 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-[3-(4-methoxycarbonyl-thiophen-3-yl)-ureido]-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1H (1.50 g, 2.59 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:21])[CH2:19]Br>CN(C=O)C>[CH3:16][O:17][C:18](=[O:21])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxybenzaldehyde (100 g, 0.818 mol) in dry DMF (1 L) was added potassium carbonate (260 g, 1.88 mol) and KI (10 g) with stirring at rt. The reaction mixture was slowly heated to 40° C. and added methylbromoacetate (104 g, 0.67 mol) with stirring and heated to 70° C. for 4 h. The reaction mixture was cooled to rt, filtered off the solid and filtrate was diluted with water (1.5 L). The aqueous mixture was extracted with EtOAc (3×750 mL), washed with 2.5% aqueous NaOH solution (2×400 mL), water and dried. The solvent was removed under vacuum to give the title compound a slight yellow solid (112 g).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[C:16]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])#[N:17]>>[C:16]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])=[O:22])#[N:17]
Reactant: CC(C)(CCC#N)C(=O)O
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)C(C)(C)CCC#N
Yield: 17 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 4-cyano-2,2-dimethylbutanoic acid as described for example 37 step 3 (400 mg, yield 17%) as yellow viscous liquid. 1H NMR (300 MHz, MeOD) δ 8.40-8.39 (dd, J=2.2 Hz, 0.7 Hz, 1H), 7.76-7.72 (dd, J=9.1 Hz, 2.3 Hz, 1H), 6.86-6.83 (d, J=9.0 Hz, 1H), 4.69-4.65 (m, 1H), 4.32-4.22 (m, 3H), 3.41-3.35 (m, 2H), 3.20-3.14 (m, 1H), 2.50-2.45 (m, 2H), 2.04-1.95 (m, 2H), 1.33 (s, 6H), 1.20-1.18 (m, 3H). MS (ESI) m/z: Calculated for C18H23N5O: 325.19. found: 326.1 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1.O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: N#CCc1ccc(N)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CCc1ccc(NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
2-Chloroacetyl chloride (3.3 ml, 5.0 g, 44 mmol) was added dropwise at 10°-15° C. to a solution of 4-aminobenzylcyanide (5.3 g, 40 mmol) in dimethyl acetamide (20 ml) and the mixture was stirred at room temperature for one hour. After pouring into water the precipitate was collected, washed with water and dried over P2O5 under reduced pressure to give the title compound (7.33 g) as nearly colorless crystals, yield: 87.8%, mp 124°-125° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:35]3[N:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2cccnn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.017, 0.095 mmol, 1 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.029 g (57%). 1H NMR (400 MHz, CD3OD): δ 9.14 (d, J=3.6 Hz, 1H), 7.97-7.85 (m, 6H), 7.56 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.89-1.86 (m, 2H), 1.62-1.59 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.63 (TFA), −112.22, −112.77 LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[I:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(I)cnc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-iodopyrimidin-2-one (556 mg) and α-bromoacetophenone (533 mg) in triethylamine (0.5 ml) and ethanol (50 ml) was stirred at ambient temperature for 71/2 hours. The resulting solution was evaporated and the residue triturated with water. This product was purified by preparative thin-layer chromatography on silica before crystallisation from ethyl acetate to give the title pyrimidinone: yield 253 mg: m.p. 155°-157°: λmaxEtOH 238.5 nm (ε 23070), 340 nm (ε 2400), λinf 250 nm (ε 17160), 275 nm (ε 1780).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=1)=O)C.[CH3:18][NH:19][NH2:20]>C1(C)C=CC=CC=1>[OH:3][C:4]1[N:19]([CH3:18])[N:20]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH3:16])[CH:9]=2)[CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(C)c1
Reactant: CNN
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(O)n(C)n2)cc1C
Yield: 68 %

Procedure:
At room temperature, to a mixture of 3-(4-methoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester (described in Reference Preparation example 89) 14.8 g and toluene 100 ml was added N-methyl hydrazine 29 g, and the resulting mixture was stirred for twelve hours. The toluene was distilled off. At room temperature, to the reaction mixture was added water 100 ml and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was stirred for three hours. The precipitates were filtered and were washed with water 400 ml and ethyl acetate 500 ml, and then were dried under reduced pressure to give 5-hydroxy-3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 9.3 g.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[N:29]([CH2:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:28](=[O:37])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:38]4[CH2:44][CH2:43][CH2:42][N:41]([CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[CH:26]=3)[N:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[N:29]([CH2:30][C:31]([NH:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:28](=[O:37])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:38]4[CH2:44][CH2:43][CH2:42][N+:41]([O-:6])([CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[CH:26]=3)[N:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(N3CCCN(C(C)C)CC3)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(N3CCC[N+]([O-])(C(C)C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
3-Chloroperoxybenzoic acid (19 mg, 0.078 mmol) was added to a stirred solution of 2-[2-(3-chloro-4-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6k) (40 mg, 0.078 mmol) in DCM (5 mL). The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous sodium bicarbonate solution (10 mL). The organic phase was dried (Na2SO4), concentrated under reduced pressure and purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (4:1, v/v) as eluent to afford 4-(2-(3-chloro-4-fluorophenyl)-3-(2-(isopropylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-1-isopropyl-1,4-diazepane 1-oxide (EXAMPLE 12a) (25 mg, 0.047 mmol, 61%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CC(=O)Nc1ccccc1
Product: Cc1cccc2nc(C)n(-c3ccccc3)c12

Procedure:
Method A applied to 2-chloro-3-nitrotoluene (68 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a pale yellow solid. mp 107-109° C. 1H NMR (DMSO) δ 1.83 (s, 3H), 2.34 (s, 3H), 7.02 (d, J=7.8Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 7.55-7.63 (m, 5H); 13C NMR δ 13.3, 17.1, 114.8, 121.7, 123.0, 125.5, 128.6, 129.4, 129.9, 136.0, 144.5, 151.2, 157.2. HRMS (FAB): cal. for C15H15N2 [M+H+]: 223.1235; found: 223.1231.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](O)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)CC.O.[CH3:31][CH2:32][CH2:33][CH2:34]CC>>[C:1]1([NH:7][C:8]2([C:22](=[O:23])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Solvent: CCOCC
Solvent: O
Product: CCCCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (-5° C) suspension of 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid in 525 parts of dry 1,1'-oxybisethane, are added dropwise 228.5 parts of 1-lithiumbutane solution 20% in hexane at 0° C. Upon completion, stirring is continued for 3 hours at 0° C. The reaction mixture is decomposed by addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 2.5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oil residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleum-ether, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-pentanone; mp. 71.3° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([C:20]([F:21])([F:22])[F:23])[CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (35.3 mL of a 0.31M stock solution, 10.9 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.16 g, 5.52 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The organics were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.28 g, 84.3%) as a white solid: mp 66-68° C.; El-HRMS m/e calcd for C15H16F4O2(MM 305.1165, found 305.1174.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:37][C:32]1[CH:31]=[C:30]([CH2:29][C@H:16]([NH:15][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:14])[CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: N[C@@H](Cc1ccc(Cl)c(Cl)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2ccc(Cl)c(Cl)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.26 g, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting 3,4-dichloro-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (2.03 g, 6.07 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (376 mg, 0.80 mmol) in chloroform (4 mL). DIEA (0.55 mL, 3.15 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 30%): LC-MS (ES) m/z=539 (M+H)+
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:23]=[C:24]=[S:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:10][C:9]=2[S:19]([OH:22])(=[O:21])=[O:20])([OH:4])(=[O:3])=[O:2].[Na:26].C[N:28](C)CC=C>O>[S:1]([C:5]1[CH:6]=[C:7]([NH:23][C:24]([NH2:28])=[S:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:10][C:9]=2[S:19]([OH:22])(=[O:21])=[O:20])([OH:4])(=[O:3])=[O:2].[Na:26]
Reactant: O=S(=O)(O)c1cc(N=C=S)c2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reactant: C=CCN(C)C
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12

Procedure:
Solid sodium 3,6,8-trisulfonaphthylisothiocyanate (250 mg; 0.5 mmol) was added to a solution of PAMAM 4.0 (51 mg; 0.01 mmol) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 1 ml) in water (2 ml) and the mixture heated under nitrogen at 53° for two hours and then cooled. The mixture was concentrated under reduced pressure to give an orange solid. The residual solid was dissolved in water (2 ml) and passed through a short column of Amberlite IR-120(Na). The filtrate was then concentrated and the residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined and freeze dried to give the sodium 3,6,8-trisulfonaphthylthiourea terminated PAMAM 4.0 dendrimer as an off-white solid (102 mg). 1H nmr (D2O): δ2.65; 3.02; 3.30; 3.66; 8.05; 8.42; 8.59; 8.67. 13C nmr (D2O): δ33.2; 38.7; 43.2; 43.7; 47.8; 54.0; 54.3; 56.7; 131.0; 131.3; 131.9; 135.9; 138.0; 139.6; 143.8; 144.1; 145.6; 176.2; 176.5; 186.0.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[C:26]([CH:28]=[C:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27].N12CCCN=C1CCCCC2>>[C:26]([CH2:28][C:29]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)C1CC(=CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.01 g, 0.00637 mol) in acetonitrile (4.0E1 mL, 0.77 mol) was added methyl 3-(cyanomethylene)cyclobutanecarboxylate (1.93 g, 0.0127 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.953 mL, 0.00637 mol). The resulting mixture was stirred at 50° C. overnight. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired Micheal addition product as a mixture of cis- and trans-isomers (2.12 g, 71.3%). LCMS calculated for C23H31N6O3Si(M+H)+: 467.2; Found: 467.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:26]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:12])[CH:10]=[CH:9][CH:8]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Reaction time: 24 h
Yield: 44.4 %

Procedure:
A mixture of 46.5 g of 3-hydroxybenzeneacetic acid methyl ester, 77.6 g n-tetradecyl bromide and 42.54 g of potassium carbonate in 500 ml of acetone is refluxed for 24 hours. Another 15.5 g of potassium carbonate is added and reflux continued for another 24 hours. An additional 15.5 g of potassium carbonate is added and reflux continued for another 24 hours. The mixture is filtered and the filtrate evaporated to a residue which is poured into water and extracted with ether. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 45 g of the desired product as a white solid, m.p. 31°-33° C.