Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH2:20][N:15]2[CH2:14][CH2:13][CH:12]([N:4]3[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:2][C:3]3=[O:18])[CH2:17][CH2:16]2)=[O:22])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4NC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
In this example, 4.00 g 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 3.44 g of α-bromo-p-methoxyacetophenone, 4.2 ml of triethylamine and 60 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 4.71 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 3.79 g of the desired product.
Reaction SMILES: C(N(S(F)(F)F)CC)C.[Cl:10][C:11]1[C:12]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26](O)([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=[N:15][C:16]=1[CH2:17][CH3:18].O>ClCCl>[Cl:10][C:11]1[C:12]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH2:21]2)=[N:13][CH:14]=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)O)CC2)c1Cl
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C=C(C)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.8 g (11 mmol) of diethylaminosulfur trifluoride (DAST) were added to 3.0 g (10 mmol) of the alcohol from Example 1 in 50 ml of dichloromethane at -50° C., and the mixture was stirred at room temperature for 1 hour. It was poured into water and the organic phase was washed with aqueous sodium hydrogen carbonate solution, dried and concentrated. The crude product was chromatographed on silica gel with petroleum ether/ethyl acetate 7:3 to give, first of all, 0.8 g (28.6% of theory) of the product indicated above as a colorless oil, and then 1.5 g (50.5% of theory) of the fluorination product described in Example 6, as a colorless oil (see Example 6).
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CN(C=O)C.C1C(=O)N([Br:32])C(=O)C1>O.C(OCC)(=O)C>[Br:32][C:17]1[S:16][C:15]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH2:3]2)=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCC(O)(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCC(O)(c2ncc(Br)s2)CC1
Yield: 79.7 %

Procedure:
To a flask containing the product of Step 1 (925 g, 33 mmol) was added DMF (36 mL) and then n-bromosuccinimide (6.97 g, 32 mmol). The reaction was allowed to stir until complete by LCMS. The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexane-carboxylate (9.24 g, 25.5 mmol, 78% yield). MS ESI: [M+H]+ m/z 364.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1.C([O:20][C:21]([C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)=[O:22])C.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>COCCOC.CCO.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.O.C(O)(=O)C>[CH3:14][C:10]1[N:9]=[C:8]([C:6]2[N:7]=[C:2]([C:27]3[CH:26]=[N:25][CH:24]=[C:23]([CH:28]=3)[C:21]([OH:22])=[O:20])[C:3]3[CH:17]=[CH:16][NH:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cccc(-c2nc(Cl)c3cc[nH]c3n2)n1
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: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2nc(-c3cncc(C(=O)O)c3)c3cc[nH]c3n2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-chloro-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 2) (1 eq, 1.94 mmol, 500 mg) and 3-ethoxycarbonylpyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) (1.5. eq, 2.91 mmol, 820 mg) in DME/EtOH (1:1, 6 ml), aqueous Na2CO3 solution (2 M, 3 eq, 5.80 mmol, 2.9 ml) and Pd(PPh3)4 (0.05 eq, 0.097 mmol, 116 mg) are added. The resulting mixture is heated using microwave radiation at 120° C. for 20 min. The solvents are evaporated and the remaining residue is suspended in MeOH (30 ml). The mixture is cooled to 0° C., then aqueous NaOH solution (1 M, 1.9 eq, 3.60 mmol, 3.6 ml) is added. After stirring for 10 min at this temperature, the mixture is allowed to warm up to r.t. and stirred for another 1 h. After cooling down to 0° C., glacial acetic acid (5 ml) and water (100 ml) are added. The resulting precipitate is filtered and washed with water giving the title compound; [M+H]+=332.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.[C:30]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[C:31]([CH3:33])=[CH2:32]>>[C:36]([O:35][C:30](=[O:34])[CH:31]([CH3:33])[CH2:32][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[NH:19][S:20]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:14]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)OC(C)(C)C

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and t-butyl methacrylate analogous to Example 133 with the modification that the TMS-ethyl group is removed after the Heck reaction.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[C@H:10]([CH2:11][C:12]([O:14]C)=[O:13])[CH2:9][C:8]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][C:7]=2[CH2:6][N:5]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.O>[O:3]=[C:4]1[C@H:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][C:8]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][C:7]=2[CH2:6][N:5]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H]1Cc2ccc(OCCCNc3ccccn3)cc2CN(CCc2ccccc2)C1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
1.0 N LiOH (0.3 mL, 0.3 mmole) was added to a solution of methyl (S)-3-oxo-8-[3-(pyridin-2-ylamino)-1-propyloxy]-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (133 mg, 0.27 mmole) in THF (1.5 mL) and H2O (1.2 mL) at 0° C. The mixture was allowed to warm to RT over 18 hr. The mixture was washed with Et2O (2×5 mL) then a mild vacuum was applied to remove residual organic solvents. The aqueous layer was passed through a 0.45 μm Acrodisk filter, then was carefully acidified to pH 6 using 10% HCl in H2O at 0° C. The precipitate was collected, washed with H2O, and dried under vacuum at 50° C. to give the title compound as a white solid (62 mg, 48%): MS (ES) m/e 474 (M+H)+. Anal. Calcd for C28H31N3O4.0.75 H2O: C, 69.05; H, 6.75; N, 8.63. Found: C, 69.05; H, 6.66; N, 8.55.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7][CH:6]=1)#[N:4].CN(C)C=O.Br[CH2:27][CH2:28][CH2:29][Cl:30]>O1CCCC1>[Cl:30][CH2:29][CH2:28][CH2:27][N:13]([CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=1)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCl)CCc1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
At room temperature, 0.23 g (9.03 mmol) of sodium hydride (95%) was added to a solution of 1.482 g (6.02 mmol) of tert.-butyl [2-(4-cyanophenyl)ethyl]carbamate in 25 ml of tetrahydrofuran/25 ml of dimethylformamide. The mixture was stirred for a further 15 minutes. 1.49 ml (15.04 mmol) of 1-bromo-3-chloropropane were then added, and the reaction mixture was stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][NH:28][C:29](=[O:33])[O:30][CH2:31]Cl)=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][NH:28][C:29]([O:30][CH2:31][P:36](=[O:41])([O:39][CH3:40])[O:37][CH3:38])=[O:33])=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCCl)cc1
Reactant: COP(OC)OC
Solvent: ClCCl
Product: COP(=O)(COC(=O)NCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OC
Temperature: 100 °C

Procedure:
Chloromethyl [4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]carbamate (0.96 g, 1.860 mmol) and trimethyl phosphite (1 ml, 8.48 mmol) were combined in a microwave vial. The vial was capped and the reaction was allowed to heat for 3.5 hours at 100° C. The reaction was cooled and diluted with dichloromethane. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane. MS: calc'd 490 (MH+-Boc), exp 490 (MH+-Boc).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:16].C(OC(=O)C)(=[O:19])C>>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:19])[C:5]=2[N:4]=[C:3]1[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1C
Product: Cc1nc2c(O)nc3ccccc3c2n1C

Procedure:
Using the method of Example 133, 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 91) was reacted with acetic anhydride to provide 1,2-dimethyl-4-hydroxy-1H-imidazo[4,5-c]quinoline, m.p. >300° C. Analysis: Calculated for C12H11N3O: %C, 67.7; H, 5.2; %N, 19.7; Found: %C, 67.1; %H, 5.1; %N, 19.5.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])[CH2:8]2)=[CH:13][CH:14]=1)=[O:23]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: Cc1ccccc1C(=O)Nc1ccc([C@H]2CCC(N3CCC[C@@H]3C)C2)cc1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 2-methylbenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])[C:4](=[O:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC.[Cl-].[Na+].O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:14])([CH3:15])[CH:9]=[O:10])[C:4](=[O:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Temperature: -40 °C
Yield: 61.2 %

Procedure:
A solution of ethyl 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (43 g) in tetrahydrofuran was added to lithium aluminium hydride (220 ml of a 1M solution in ether) with stirring at -40° C. After 1 hour the solution was cooled to -70° C., diluted with ether, and treated with brine via dropwise addition, initially at -70° C. and then at -30° C. After warning to room temperature the organic layer was dried (magnesium sulphate), evaporated and the residue purified by dry column chromatography on silica gel eluting with dichloromethane to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde as a cream solid (22.5 g), NMR 1.35(s,6H), 1.95(s,3H), 5.25(s,2H), 7.22-7.38(m,5H), 9.42(s,1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:26][C@H:27]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[O:33][C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:26][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: CCCCC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H](COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)OC1CCCCO1
Temperature: 80 °C
Reaction time: 5 h
Yield: 121.5 %

Procedure:
In a 500 ml four-necked flask were charged 12.2 g (43.7 mmol) of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine, 24 g (65.5 mmol) of (R)-2-tetrahydropyranyloxyheptyl tosylate, 12 g of potassium carbonate, and 183 ml of DMF, and the mixture was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into 500 ml of ice-water and extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by distillation under reduced pressure to obtain 28.6 g of a crude product, which was purified by silica gel column chromatography to obtain 25.3 g of the titled compound.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[C:8]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([O:21]CC)=O>>[NH2:2][C:3]1[C:8]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][C:19]([NH2:1])=[O:21]
Reactant: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Reactant: N
Product: NC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N

Procedure:
Ammonia is condensed in a tube containing 2-amino-3-(4-bromobenzoyl)benzeneacetic acid, ethyl ester. The tube is sealed and the reaction mixture is warmed. The sealed tube was cooled and opened. Solvent was evaporated and the residue was purified by standard methods to give Compound 15.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][Si:10]([CH3:48])([CH3:47])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:17]=1>CC#N>[CH3:46][Si:43]([CH3:44])([CH3:45])[CH2:42][CH2:41][O:40][CH2:39][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:47])[CH3:48])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([I:8])=[C:20]2[N:19]=[C:18]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NIS (288 mg, 1.28 mmoL) as added to a solution of tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (741.6 mg, 1.25 mmoL) in CH3CN (10 mL). The mixture was stirred at room temperature for 1 h. Purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate: LCMS tR=3.02 Min (5 min run, UV254nm). Mass calculated for, M+ 717.2, observed LC/MS m/z 718.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]([CH3:15])=[C:13]=[S:14].CCN(CC)CC>CCO>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:13](=[S:14])[N:12]([CH3:15])[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CN=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=S)[nH]c2c(Br)cccc2c1=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A solution of 2-amino-3-bromobenzoic acid (Maybridge, Trevillett, UK; 3.03 g, 14.02 mmol) and isothiocyanatomethane (Aldrich; 1.151 mL, 16.82 mmol) in EtOH (28 mL) was stirred at 75° C. for 3.5 d. Additional isothiocyanatomethane (2.302 mL, 33.64 mmol) and Et3N (2.74 mL, 19.63 mmol) were added, and the resulting mixture was stirred at 75° C. for 1 d. The mixture was concentrated in vacuo and the residue was triturated with Et2O (40 mL) to provide 8-bromo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2.90 g, 10.70 mmol, 76% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (1H, br. s.), 8.11 (1H, d, J=8.0 Hz), 7.85 (1H, dd, J=7.9, 1.3 Hz), 7.20 (1H, t, J=7.9 Hz), 3.83 (3H, s). m/z (ESI, +ve) 271.0 (M+H)+.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2=[O:27]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2([OH:27])[C:8]1[C:7]([OH:10])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2c(Br)cccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of sesamol (7.32 g, 53.1 mmol) in anhydrous tetrahydrofuran (150 mL) were added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 30.1 mL, 60.2 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min, followed by the addition of 7-bromo isatin (8.0 g, 35.4 mmol). The suspended mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (300 mL) and ethyl acetate (250 mL), and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL), and the combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was triturated with diethyl ether, filtered and dried under the reduced pressure to afford 7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (9.8 g, 77%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ10.64 (s, 1H), 9.18 (s, 1H), 7.33 (dd, J=7.8, 1.4 Hz, 1H), 7.21 (s, 1H), 6.84-6.75 (m, 2H), 6.54 (s, 1H), 6.21 (s, 1H), 5.92 (dd, J=6.1, 0.8 Hz, 2H); MS (ES+) m/z 363.8 (M+1), 365.8 (M+1).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:37]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[C:38]1([C:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=C(c1ccccc1)c1ccccc1
Yield: 55.5 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g), dimethylsulfoxide (100 mL), (7-carboxyheptyl)triphenylphosphonium bromide (39.95 g), benzophenone (18.2 g), and tetrahydrofuran (100 mL). The crude acid, isolated in the usual manner, required further purification by HPLC (hexane-ether; 3:2). The appropriate fractions were combined and evaporated and the residue was crystallized from hexane to provide 14.1 g of 9,9-diphenyl-8-nonenoic acid, mp 77.5°-78.5° C. Anal. Calculated for C21H24O2 : C, 81.78; H, 7.84. Found: C, 81.71; H, 7.70.
Reaction SMILES: COC1N=CC(N2CCC(N3CC[C@@H](NC(=O)C[NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27](C(F)(F)F)[CH:26]=4)C3)CC2)=CC=1.CC1C(N)=C(C)ON=1.COC1N=CC(N)=CC=1>>[C:24]([NH2:23])(=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N)cn1
Agent: Cc1noc(C)c1N
Product: NC(=O)c1ccccc1

Procedure:
N-[2-({(3R)-1-[1-(3,5-dimethylisoxazol-4-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, 3,5-dimethylisoxazol-4-amine was substituted for 6-methoxypyridin-3-amine. The crude product was purified by preparative HPLC. MS m/z: 494 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1

Procedure:
Similar procedure as described in example 10c was used, starting with (1R,2S)-2-phenyl-cyclopropylamine, rhodanine, mercuric chloride and DIEA to give 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one. LC-MS m/e 232 (MH+).