Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C(=CC=CC=1)C(O)=O)C.[NH2:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[NH:13][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:20]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCOC(=O)Cl
Agent: CCNc1ccccc1C(=O)O
Product: CCOC(=O)Nc1ccccc1C(=O)OCC
Yield: 95.5 %

Procedure:
A mixture of ethyl 2-aminobenzoate (ethyl anthranilate) (50.0 g, 0.30 mole) and ethyl chloroformate (32.8 g, 0.30 mole) in 400 mL of xylenes was heated at reflux for 8 hours. The xylene was removed and the residue was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide, dried (Na2SO4), filtered, and the chloroform removed to give an oil which crystallized. The solid was triturated with isopropyl ether and placed in the freezer. Two crops of white solid were obtained and dried in vacuo overnight at room temperature. This provided 67.95 g (97.6% yield) of white crystalline solid, mp 41°-42° C.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH2:18])[N:16]=[C:11]2[CH:10]=[CH:9]1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28](O)=[O:29].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH:18][C:28]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]3[CH3:21])=[O:29])[N:16]=[C:11]2[CH:10]=[CH:9]1
Reactant: CC1CCCCC1C(=O)O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NN)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCC1C(=O)NNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
A flask containing a mixture of [5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazine hydrochloride (336 mg, 1.06 mmol) and (+/−)-2-methyl-1-cyclohexane-carboxylic acid (0.18 mL, 1.22 mmol) in dry dichloromethane (11 mL) was cooled to 0° C. (ice bath) under nitrogen atmosphere. To this cooled mixture was added triethylamine (0.31 mL, 2.1 mmol) and EDCI (278 mg, 1.45 mmol). After 30 minutes the cooling bath was removed and the material was stirred for 3 hours. An aqueous solution of 5% sodium bicarbonate (40 mL) and methylene chloride (30 mL) were added and the mixture was shaken in a reparatory funnel. The organic phase was collected and washed with brine (40 mL). The aqueous phases were back extracted with methylene chloride (2×30 mL). The organic phases were combined, dried (MgSO4), filtered and stripped. The crude remainder was purified by preparative TLC, using 45% ethyl acetate in hexanes to elute. The product band was collected, affording 152 mg of (+/−)-2-methyl-cyclohexanecarboxylic acid-N′-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazide as a golden brown oil, which solidified on standing. MS (M+H)+=404.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@@H:5]([NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.CN(C)C=O.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]([C:6]1[S:7][C:8]([Br:36])=[CH:9][CH:10]=1)[NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-thiophen-2-yl-propionic acid methyl ester (0.420 g, 0.000971 mol;) was dissolved in N,N-Dimethylformamide (20 mL, 0.2 mol;) and N-Bromosuccinimide (0.19 g, 0.0011 mol;) was added. The reaction was allowed to stir o/n and LC-MS showed formation of product at 1.87 510.95. The reaction was diluted with methylene chloride and washed 1× with saturated bicarbonate, 1× with 5% citric acid, and 1× with brine. The organic layer was then dried with magnesium sulfate and concentrated to give the crude material. The crude was dissolved in methylene chloride and purified by combiflash 0-100% hexanes/ethyl acetate to give the pure product. ES (+) MS m/e=510.95
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.Cl.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:30]=1)[CH2:28][NH2:29].C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH2:28][NH:29][C:18](=[O:19])[CH2:17][N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:30]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NCc1cc(Br)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.144 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 93A, 36.0 mg (0.150 mmol) of 5-bromo-2-fluorobenzylamine hydrochloride, 22.1 mg (0.163 mmol) of HOBt and 17.6 mg (0.136 mmol) of N,N-diisopropyl-ethylamine are placed in 1.5 ml of dimethylformamide and treated with 33.9 mg (0.177 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then diluted with 15 ml of water and extracted with ethyl acetate. After evaporation of the organic phase, the crude product is purified by preparative HPLC [Method 13]. 21 mg (32% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[CH3:30][OH:31]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:30][O:31][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (1.10 g) was dissolved in methylene chloride (12 ml) and to this solution was added methanol (3 ml). And to the solution was added silver fluoroborate (0.45 g) under stirring under cooling at -10° C. and the mixture was stirred for 2 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate aqueous solution and then with water, dried over magnesium sulfate and thereafter concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of about 20 ml and the first and second fractions were collected. After distilling off the solvent, the residue was dried to give oily 2,2,2-trichloroethyl 2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li]CCCC.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].[Br:23]N1C(=O)CCC1=O>C1COCC1.CCCCCC.N1C=CC=CC=1>[Si:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([Br:23])=[CH:2]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2ccccc21
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a cold (-78°) solution of indole (4.0 g, 34 mmol) in THF (120 mL) was added nBuLi (2.5M/Hexanes) over 5 minutes. The solution was warmed to -10° (ice/salt bath) for 15 minutes, re-cooled to -78° and TBDMS-Cl (5.8 g, 38 mmol) was added in THF (30 mL). The solution was held at 0° for 3 hours, cooled to -78° and N-Bromosuccinimide (6.0 g, 34 mmol) was added in one portion. The solution was stirred coldfor 2 hours and then was allowed to warm to ambient temperature at which time hexane/pyridine (100 mL) was added to the solution and the resulting suspension was filtered over Celite. The organics were evaporated and the residue quickly purified by flash chromatography (hexanes/methylene chloride 2:1) giving 8.5 g of the desired compound as a slightly purple solid.
Reaction SMILES: [C:1]([O:9]C(C)(C)C)(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH:6]=[CH2:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC=CC(=O)O
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of oxalyl chloride (3.36 mL, 39.2 mmol) in CH2Cl2 (100 mL) at −78° C. was added DMSO (5.56 mL, 78.3 mmol). After stirring for 5 min, 4-penten-1-ol (2.00 mL, 19.6 mmol) was added, and after another 15 min Et3N (13.6 mL, 97.9 mmol) was added. The reaction mixture was warmed to rt and then treated with 0.1M HCl. The organic layer was separated, washed with saturated aqueous NaCl solution, dried (MgSO4), and treated with Ph3PCHCO2t-Bu (7.38 g, 19.6 mmol) at rt. The reaction mixture was stirred for 5 h and then treated with saturated aqueous NH4Cl solution and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was filtered through a silica plug (CH2Cl2/pentane 1:1) to give t-butyl (E)-2,6-heptadienoate. To a solution of this ester in CH2Cl2 (40 mL) was added TFA (5 mL) at rt. After stirring for 12 h, the reaction mixture was concentrated under reduced pressure. Purification of the crude product by FC (hexane/EtOAc 15:1→5:1) afforded 2,6-heptadienoic acid 6 (1.67 g, 68%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ7.12-7.05 (m, 1H), 5.88-5.76 (m, 2H), 5.08-5.02 (m, 2H), 2.37-2.32 (m, 2H), 2.26-2.21 (m, 2H).
Reaction SMILES: CC1C=CN=CC=1.N1C=CC([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=CC=1>>[O:16]1[CH:17]=[CH:18][CH:14]=[C:15]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1occc1-c1ccncc1
Solvent: Cc1ccncc1
Product: CCOC(=O)c1ccco1

Procedure:
In a manner similar to that in Reference Example 13, by using 4-methylpyridine in place of 3,4-dimethylpyridine and using ethyl 3-(4-pyridyl)furan-2-carboxylate (133 mg, 0.612 mmol) obtained in Step 1, in place of ethyl furan-2-carboxylate, the entitled Compound ad (35.3 mg, 18%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:11][C:10]1([C:20](=[O:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[K+]>CO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:11][C:10]1([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH:20]([OH:22])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(±)-[2-Acetyl-2-(3,4-dichlorophenyl)-cyclopropylmethyl]-carbamic acid tert-butyl ester was added to methanol and stirred at ambient temperature under Ar (g) in a 50 mL round-bottomed flask. Potassium borohydride was added portion wise and the suspension stirred overnight. The resulting suspension partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL), and the combined layers washed with brine (10 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 0.523 g of a white sticky solid. The solid was purified on a filter pad of silica eluting with 4/1 hexanes/EtOAc (v/v), switching to 6/4 hexanes/EtOAc (v/v) upon collection of the major spot. The second (other) diastereomer was collected. The desired compound is pale oil; Yield: 0.328 g 49%; The undesired diastereomer is a white solid; Yield: 0.120 g 18%; 1H NMR: Desired diastereomer: (300 MHz, DMSO-d6) 7.50-53 (m, 2H, J=2.1 Hz, ArH), 7.22-25 (dd, 1H, J=9.0 Hz, J=1.8 Hz, ArH), 6.91 (bs, 1H, OH), 4.26 (m, 1H, NH), 3.50 (m, 1H, CH2N), 3.32 (m, 1H, CH2N), 3.26 (m, 3H, CH3), 1.40 (s, 9H, tert-Bu), 1.02 (m, 2H, ArCCH2), 0.55 (m, 1H, CHCH2N); Undesired diastereomer (not shown): (300 MHz, CDCl3) 7.57 (m, 1H, ArH), 7.50 (d, 1H, J=8.1 Hz, ArH), 7.31 (dd, 1H, J=8.4 Hz, J=1.8 Hz, ArH), 7.11 (bs, 1H, OH), 4.63 (d, 1H, J=3.3 Hz, NH), 3.46 (m, 1H), 3.33 (s, 3H), 3.12 (m, 2H), 1.38 (s, 9H, tert-Bu), 1.30 (m, 1H), 0.85 (d, 2H, J=6.0 Hz, ArCCH2), 0.78 (m, 1H, CHCH2N)
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:62]=[C:63]([F:66])[C:64]=1[F:65])[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:27]=[C:25]([N:59]1[CH2:60][CH2:61][CH:56]([O:55][C:54]2[CH:53]=[C:52]([F:51])[C:64]([F:65])=[C:63]([F:66])[CH:62]=2)[CH2:57][CH2:58]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Fc1cc(OC2CCNCC2)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)c(F)c(F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 18.9 %

Procedure:
DIPEA (135 mg, 1.0 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (69 mg, 0.3 mmol) in DMF (2.0 mL) followed by HOBt (61 mg, 0.45 mmol) and EDCI.HCl (85 mg, 0.45 mmol). After 2 minutes of stirring, 4-(3,4,5-trifluoro-phenoxy)-piperidine hydrochloride (75 mg, 0.3 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 26 mg (19% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3,4,5-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 459.16, 97.98%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 4.7 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 2.0 (m, 3H), 1.7 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:5](=[N:6][OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1>CN(C=O)C.CCOC(C)=O.O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:7][N:6]=[C:5]2[C:2]([CH3:24])([CH3:1])[C:3]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[C:4]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:27]=1
Reactant: CC1(C)C(=NO)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=NOCc2cccnc2)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C

Procedure:
To a solution of Example 45 (102 mg) in DMF (3 mL) was added Cs2 CO3 (390 mg) and a solution of 3-picolylchloride hydrochloride (154 mg) in DMF (3 mL). The mixture was heated at 80° C. for 18 hr, diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc, the combined organic phase was washed with brine, dried (MgSO4) and the solvent evaporated. The resulting residue was purified by flash chromatography (silica gel; hexane/EtOAc (40:60)) to give the title compound as white foam; 1H NMR (300 MHz, Ace-d6): δ 1.61 (s,6H), 3.17 (s, 3H), 5.22 (s, 2H), 7.36-7.41 (m, 4H), 7.69 (m, 2H), 7.85 (m, 3H), 7.98 (d, 2H), 8.52 (dd, 1H), 8.68 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH:13]([O-])=[O:14].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH:13]=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C[O-]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A slow stream of CO was passed into a suspension of methyl 4-bromo-2-chlorobenzoate (1.50 g, 0.00601 mol), bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.0001 mol), sodium formate (613 mg, 0.00902 mol), and dry DMF (10 mL). The mixture was vigorously stirred at 110° C. for 2 h. After cooling, the mixture was treated with aqueous Na2CO3 solution and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt-hexane to give the product as a colorless oil (becomes a white solid when stored in a refrigerator).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16]#[N:17].[SH2:21]>N1C=CC=CC=1>[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16](=[S:21])[NH2:17]
Reactant: Cn1c(Br)c(Br)c(C#N)c1Br
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Br)c(Br)c(C(N)=S)c1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Diisopropylethylamine (1.1 mL, 6 mmol), 2,4,5-Tribromo-1-methylpyrrole-3-carbonitrile (2.16 g, 6 mmol) and pyridine (10 mL) are added to condensed hydrogen sulfide in a pressure tube at -78° C. The tube is sealed and the reaction mixture is stirred for 5 days at room temperature. The reaction mixture is then concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.47 g, mp 100.5°-102° C. dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C@@H:21]([CH:23]=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CCOCC>[C:13]([NH:20][CH:21]([CH:23]=[CH:9][CH:3]1[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]1([CH3:8])[CH3:7])[CH3:22])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: CC1(C)CCC(C)(C)C1CBr
Agent: [Mg]
Solvent: CCOCC
Product: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium has dissolved. At 0° C. a solution of N-Boc-D-alaninal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated, as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C1(C)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=C(O)c1ccccc1
Agent: [H+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 91 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 8 mg of benzoic acid added. Then, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39%) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 97.5% and n-octyltriethoxysilane was produced at a yield of 91%.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.[Cu]>[F:8][C:7]1[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Sc1ccccc1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: [Cu]
Solvent: ClCCl
Product: Fc1cc(C(F)(F)F)cnc1Sc1ccccc1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
At 148-156° C., 59.6 g (0.326 mol) of 2,3-difluoro-5-trifluoromethylpyridine were added over a period of 2.5 h to 37.7 g (0.338 mol) of 98.7% pure thiophenol and 2.1 mg (0.01 mol %) of copper powder, and the mixture was stirred at 156-164° C. for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5 N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure. 88.9 g (100% of theory) of the title compound of 24 n D
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[I-].[Na+].C(#N)C>CN1C(=O)CCC1>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][C@H:39]([CH2:47][OH:48])[CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@H](CO)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (46.8 mg, 90 μmol) of Example 4, L-phenylalaninol (271 mg, 1.80 mmol) and sodium iodide (6.75 mg, 45 μmol) are placed in a 0.5-2.5 ml microwave vial. Acetonitrile (0.25 ml) and NMP (0.25 ml) are added and the reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 200° C. The reaction is shown to be complete by LCMS after 1 hour. The title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 636 (MH+).