Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[CH:11][CH:10]=1)=[O:4]>[Pd].C(OCC)(=O)C>[CH3:32][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[O:30][CH3:31])=[CH:11][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C=CCCC(=O)N(C)C)cc23)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(CCCCC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 4 h
Yield: 104.1 %

Procedure:
A mixture of methyl 4-[7-[4-(dimethylcarbamoyl)but-1-enyl]naphth-1-ylmethyl]-3-methoxybenzoate (1.1 g), 10% w/w palladium-on-carbon/50% water (110 mg) and ethyl acetate (10 ml) was hydrogenated under atmospheric pressure for 4 hours. Filtration through diatomaceous earth with ethyl acetate wash and evaporation afforded methyl 4-[7-(4-dimethylcarbamoylbutyl)naphth-1-ylmethyl]-3-methoxybenzoate (1.15 g, quantitative) as a light yellow syrup; MS(CI), m/e=434(M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C)[CH:9]=2)[C:4](SC(C)(C)C)=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21].C(S)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2ccc(OC)cc2n1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)C(C)(C)Cc1cc2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 940 mg of the indole ester from Step B and 1.6 mL of ethanethiol in CH2Cl2 (50 mL) was added portion-wise 4.3 g of AlCl3. After complete addition, the mixture was stirred at R.T. for 2 h. The mixture was then cooled to 0 ° C. and carefully quenched with a solution of 0.5M Na,K tartrate (200 mL) and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated to dryness to give a solid which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to afford the title compound; m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Yield: 78.9 %

Procedure:
A solution of tert-butyl (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (109 mg, 0.202 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 70 mg (79%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43-1.82 (m, 4 H) 1.91-2.03 (m, 1 H) 2.67 (dt, J=11.68, 7.16 Hz, 2 H) 2.76-2.94 (m, 1 H) 3.21 (dd, J=11.82, 2.87 Hz, 1 H) 4.28 (br. s., 1 H) 6.11 (d, J=6.12 Hz, 1 H) 6.98-7.57 (m, 8 H) 8.36 (s, 1 H), [M+H]+ 439.6.
Reaction SMILES: C=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C=O.[O:15]=[O+][O-]>CO.[Pd]>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:15]
Reactant: O=[O+][O-]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Agent: [Pd]
Agent: C=O
Solvent: CO
Product: CCOC(=O)C(=O)C(=O)OCC
Yield: 82 %

Procedure:
258 g of diethyl methylenemalonate, prepared by a Knoevenagel condensation of malonic ester and formaldehyde, are dissolved in 1 liter of methanol and reacted with ozone, and subsequently hydrogenated, analogously to the procedure indicated in Example 5. 5 g of 10% Pd-on-C in 200 ml of methanol are initially taken as the hydrogenation catalyst. The consumption of hydrogen is 28.9 standard liters (86% of theory). Working up as in Example 5 and rectification in vacuo gives 214 g of diethyl mesoxalate boiling at 110°-112° C./20, corresponding to a yield of 82% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH3:12]>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH2:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: N
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2[nH]ccc12
Temperature: 100 °C

Procedure:
A mixture of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.53 mmol) in Ammonia (7 N in MeOH, 1 mL) was heated at 100° C. for 24 h, then it was diluted with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOCc1c(OC)cccc1C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCOCc1c(OC)cccc1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 110 %

Procedure:
Into a 200 mL round bottom flask was added 6.6 g (0.0297 mol) of 2-allyloxymethyl-3-methoxy benzoic acid and 40 mL of ethyl acetate. 24.05 g of a 25% pentafluorophenol (6.01 g, 0.0327 mol) solution in ethyl acetate was added while stirring. The reaction flask was placed into a water bath and while stirring small portions of DCC (6.2 g, 0.030 mol) were added. The stirring continued overnight at room temperature. The reaction was filtered through two Whatman #541 filters to remove the DCU precipitate. The ethyl acetate solution was concentrated to yield 12.8 g (110% yield), indicating presence of DCC and DCU. This was confirmed by TLC (1:1 ethyl acetate:hexane), which indicated a Rf of 0.72 plus other less polar compounds (12 stain indicates about 85% purity). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.7 (d, 1H), 7.45 (t, 1H), 7.15 (d, 1H), 6.0-5.9 (m, 1H), 5.3-5.1 (2d, 2H), 4.88-4.83 (d, 2H), 4.06 (d, 2H), 3.90 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([OH:29])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.Cl[CH2:31][C:32]1[N:33]=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:35][CH:36]=1.O>CN(C)C=O>[C:37]1([C:34]2[S:35][CH:36]=[C:32]([CH2:31][O:3][C:4]3[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:31][C:32]4[N:33]=[C:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[S:35][CH:36]=4)[CH:28]=3)[CH2:7][N:8]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]3)[N:33]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(O)c2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
Sodium hydride (601, oily, 0.30 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.83 g) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (1.05 g) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (513 mg, yield: 14%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 93.6 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4,4'-dichlorobenzhydrol (14.7 g, 58.1 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) to give 21.0 g (yield: 94%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: FC(F)(F)c1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3C(F)(F)F)cc2)c1C
Yield: 13.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.25 g, 0.67 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.038 g, 0.033 mmol), crude 1-bromo-4-(2-(trifluoromethyl)phenylsulfanyl)-benzene (0.27 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-phenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.045 g, 16%) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[CH:3]=[N:2]1.[CH2:9]([NH2:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([NH:11][C:6]([C:4]1[CH:3]=[N:2][NH:1][CH:5]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1cn[nH]c1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cn[nH]c1
Yield: 97 %

Procedure:
Following the same procedure in Example 28 (Step C of Method B), using 1H-pyrazole-4-carbonyl chloride (0.47 g, 3.6 mmol), ethylamine (3.0 mL, 2.0 M in THF, 6.0 mmol) and triethylamine (1.01 g, 1.39 mL, 10 mmol) in CH2Cl2 (15 mL), provided the title compound as a white solid. Yield: 0.49 g (97% yield). 1H NMR (400 MHz, METHANOL-D4) δ 1.18 (t, J=7.23 Hz, 3 H) 3.34 (q, J=7.23 Hz, 2 H) 7.92 (s, 1 H) 8.09 (s, 1 H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ccc(Br)cc1C
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: COc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-methoxy-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 311.3 [M+H]+) was prepared from 4-bromo-2-methyl-anisole instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=4[C:16]=3[CH2:17][CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=4[C:16]=3[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)COc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Yield: 47.4 %

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-({1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthyl}oxy)acetate (0.180 g, 0.345 mmol) was hydrolyzed with potassium hydroxide (0.077 g, 1.4 mmol) in THF (5 mL) and water (5 mL). Crystallization from acetonitrile and drying for 12 hours at 80° C. yielded 2-({1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthyl}oxy)acetic acid as a cream-colored solid (0.0807 g), mp 155-156° C. Mass spectrum (−ESI, [M−H]−) m/z 491; 1HNMR (500 MHz, DMSO-d6): δ13.0-13.5 (br s, 1H), 8.35 (d, 1H, J=1.2 Hz), 8.25 (d, 1H, J=8.9 Hz), 8.10 (d, 1H, J=9.0 Hz), 8.05 (dd, 1H, J=9.0 Hz and 1.7 Hz), 7.7 (d, 1H, J=7.8 Hz), 7.6 (d, 1H, J=7.9 Hz), 7.45 (d, 1H, J=9.2 Hz), 7.35-7.4 (m, 1H), 7.30-7.35 (m, 1H), 5.0 (s, 2H), 3.0 (t, 2H, J=7.9 Hz), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 4H), 1.5-1.6 (m, 2H), 1.4-1.5 (m, 2H), and 1.15-1.25 ppm (m, 2H). Elemental Analysis for C27H25BrO4: Calculated: C, 65.13; H, 5.16; N, 0.00. Found: C, 64.83; H, 4.94; N, 0.06.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].C([Sn](CCCC)(CCCC)[C:46]1[N:47]=[CH:48][S:49][CH:50]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[N:47]=[CH:48][S:49][CH:50]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cscn3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 90 °C
Yield: 99.4 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (300 mg, 0.436 mmol) in toluene (20 mL), 4-(tributylstannyl)thiazole (243 mg, 0.25 mL, 0.653 mmol) was added, followed by Pd(PPh3)4 (25 mg, 0.0217 mmol). The reaction mixture was heated at 90° C. overnight. The reaction was diluted with EtOAc (250 mL), washed with water (100 mL). The organic layer was washed with brine, dried over Na2SO4, concentration under reduced pressure gave an oil which was purified by column chromatography. The title compound was eluted with 50% EtOAc/Hexanes to provide title compound (280 mg, 99%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].Cl[C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]>>[CH:29]1[C:30]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[S:9]([OH:12])(=[O:11])=[O:10])=[O:15])[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(F)cc1S(=O)(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: O=C(Nc1ccc(F)cc1S(=O)(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-5-fluoro-benzenesulfonic acid was prepared from 2-Amino-5-fluoro-benzenesulfonic acid (5.0 g, 0.026 mol) (Suter, C. M.; Weston, A. W., J. Amer. Chem. Soc., 1940, 62, 604-606) and 9-Fluorenylmethyl chloroformate (7.4 g, 0.029 mol) in an analogous manner to Example 820a. Product isolated as a white solid (8.08 g, 74%). 1H NMR (400 MHz, DMF-d7, δ, ppm): 10.25 (br s, 1H), 8.20-8.00 (m, 1H), 7.95 (d, 2H, J=7.3 Hz), 7.77 (d, 2H, J=7.3 Hz), 7.54 (dd, 1H, J=8.8 and 3.0 Hz), 7.45 (t, 2H, J=7.3 Hz), 7.38 (t, 2H, J=7.3 Hz), 7.21-7.12 (m, 1H), 4.70-4.10 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(Br)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromobenzaldehyde. Mass spectrum (ES) MH+=349.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>>[CH3:1][NH:2][C:3]1[C:12]([C:13]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([C:17]([F:16])([F:26])[F:27])[CH:19]=2)=[O:15])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CNc1nc2ncccc2cc1C(=O)O
Product: CNc1nc2ncccc2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 69 %

Procedure:
2-(Methylamino)-1,8-naphthyridine-3-carboxylic acid was coupled to 3-(trifluoromethyl)benzylamine using the general amide coupling procedure. The crude product was purified by flash chromatography, CH2Cl2/MeOH 95:5, yielding 62.4 mg (69%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([NH:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:7][CH:8]=1)[CH3:15])=[O:20])[CH3:17]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CCN(CC)C(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and N,N-diethylcarbamoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[F:21][C:19]([F:20])([F:22])[C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: FC(F)(F)c1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 3.59 mmol 4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml dioxane was added dropwise 53.8 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as an off-white crystalline solid (yield 99%). MS (m/e): 238.1 (M+H+, 100%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 170, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.93 (s, 1H), 7.80-7.74 (m, 2H), 7.44-7.38 (m, 2H), 7.03-6.85 (m, 6H), 6.74-6.62 (m, 2H), 5.31 (d, 1H), 5.20 (d, 1H), 4.76 (d, 1H), 3.79-3.73 (m, 1H), 3.34 (t, 1H), 2.98-2.76 (m, 3H), 2.55 (dd, 1H), 1.83-1.74 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).