Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)=[CH:11]2)([O-:5])=[O:4].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O.O1CCCC1>[CH3:20][O:21][CH2:22][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N+:3]([O-:5])=[O:4])[CH:11]=[C:12]1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1
Reactant: O=[N+]([O-])c1cccc2cc(-c3nccs3)[nH]c12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(-c2nccs2)cc2cccc([N+](=O)[O-])c21
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.47 g) in N,N-dimethylformamide (15 mL) was slowly added 7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (2.21 g) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of chloromethyl methyl ether (0.81 mL) in tetrahydrofuran (2 mL) at 0° C. over 20 min, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.14 g, yield 82%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13]O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N-:15]=[N+:16]=[N-:17].[Na+].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C>[N:15]([CH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][F:1])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(CO)cc(CF)c1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CF)cc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 93 h
Yield: 52.9 %

Procedure:
Methyl 3-fluoromethyl-5-hydroxymethylbenzoate (34) (2.30 g, 11.6 mmol) was dried for 24 hours. Sodium azide (3.77 g, 58.1 mmol), carbon tetrabromide (4.24 g, 12.1 mmol), and triphenylphosphine (3.66 g, 13.9 mmol) were dried for 48 hours. Under Ar atmosphere, these were mixed with triethylamine (3.6 mL), dissolved in DMF (88 mL), and stirred for 93 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=10:1) to isolate methyl 3-azidomethyl-5-fluoromethylbenzoate (35) (1.37 g, 53%) as a pale yellow oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>O>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CCc1cc(NC(=O)C(CSC(C)=O)Cc2ccccc2)cc(C(=O)O)c1
Agent: Cl
Solvent: C1CCNC1
Solvent: O
Product: CCc1cc(NC(=O)C(CS)Cc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-5-ethylbenzoic acid (compound of Example 64) (1.0 g) is suspended in water (10 ml), and thereto is added pyrrolidine (0.6 g) under nitrogen, and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is adjusted to pH 1 with conc. hydrochloric acid and is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure. The residue is dissolved in methanol and purified by a medium pressure column chromatography with CHP-20P (eluant, water-methanol). The fractions containing the desired compound are collected and concentrated into dryness to give the title compound (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:16][NH2:17])=[O:12])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)CNc1ccc(Cl)cc1
Yield: 58.4 %

Procedure:
Ethyl 2-(4-chlorophenylamino)acetate (A) (25.6 g, 120 mmol) and hydrazine monohydrate (7.0 mL, 144 mmol) were heated to reflux in ethanol (120 mL) for 22 hours. After concentration in vacuo, the solid obtained was recrystallised from ethanol to yield the title compound (14.0 g, 59%) as a pale brown powder. 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, d), 4.18 (2H, br), 6.53 (2H, d), 7.16 (2H, d), 7.60 (1H, br).
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:32][CH:33]([CH3:35])[CH3:34]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC1C(=O)N(NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 3-E) in DMF was treated with Cs2CO3 (0.22 g, 0.678 mmol) and warmed to 60° C. To the reaction mixture was added 1-iodo-2-methylpropane (0.078 mL, 0.678 mmol) and stirring continued for 17 hours. After cooling to 23° C. the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3/MeOH 9:1).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[O:30][CH3:31]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([O:30][CH3:31])[CH:25]=3)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: COc1cc(N)ccc1Cl
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc(C(=O)NCC3CCCCC3)c(C(F)(F)F)n2)ccc1Cl
Yield: 47.9 %

Procedure:
In a manner similar to Example 243, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) and 4-chloro-3-methoxy-phenylamine (Wychem) (122 mg) were reacted to give the title compound (33 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)c1

Procedure:
The title compound was prepared from 3-methoxybenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 60-168° C.; LC-MS: 373 (MH+); HPLC RT: 4.75 minutes.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:13]=[CH:12]2)C(=O)C2=CC=CC=C12.Cl>CO>[NH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[CH:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cnc(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NCCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 88.1 %

Procedure:
Step 3): 80% Hydrazine monohydrate (0.062 ml, 1.3 mmol) was added to a solution of 1-(2-phthalimidoethyl)-4,5-diphenylimidazole (0.32 g, 0.8 mmol) in methanol (20 ml) under refluxing. The reaction mixture was refluxed for 1 hour, then cooled. The mixture was made acidic slightly with 6N HCl and then filtered to remove phthalhydrazide. The filtrate was concentrated and then the residue was suspended in 2N NaOH. The suspended mixture was extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated. The precipitates were recrystallized (ethyl acetate/hexane) to give 1-(2-aminoethyl)-4,5-diphenylimidazole (88.1%): mp 96°-98° C.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:22])[F:23])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 80 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (80 mg, 0.19 mmol) was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (75 mg, 80%) which was obtained as a white foam. MS: m/e=483.2 [M+H]+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[C:20]1=[O:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:31])=[O:32])[C:20]1=[O:39]
Reactant: CC(C)(C)[Si](OC1CCN(c2ccccc2S(=O)(=O)Nc2nccs2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(O)CCN1c1ccccc1S(=O)(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Synthesized according to General procedure 8. To a solution of (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (5.5 g, 9.53 mmol) in THF (40 mL) under N2, was added a solution of tetrabutylammonium fluoride in THF (1M, 40 mL, 38.1 mmol). Upon completion of addition, the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with CH2Cl2 (2×50 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (2.6 g, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.0; tR=0.54 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[N:24][C:23]1=[O:34].C(N(CC)CC)C>CN(C)C=O>[C:28]1([C:26]2[CH:25]=[N:24][C:23](=[O:34])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:27]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=c1ncc(-c2ccccc2)cn1CCCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1ncc(-c2ccccc2)cn1CCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (52 mg, 0.23 mmol, prepared with a similar procedure to that reported in WO 2005080382) in N,N-dimethylformamide (DMF) (3 ml) were added at room temperature 1-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinone (Prep51, 60.1 mg, 0.23 mmol, D1) and triethylamine (0.064 ml, 0.46 mmol). The reaction mixture was heated at 100° C. for 24 hours, then passed through a SCX cartridge (10 g) (eluting with methanol followed by 2N ammonia solution in methanol). The crude obtained was then purified by column chromatography on silica gel eluting with DCM/methanol 96/4. After evaporation of the solvent the compound recovered (20 mg, 0.044 mmol) was dissolved in DCM (1 ml) and treated with HCl (1.1 eq of a 1.25 M solution in methanol, 0.048 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. Evaporation of the solvent and trituration with diethyl ether (2×3 ml) gave the hydrochloride salt of the title compound. The recovered material was passed through SCX (2 g) cartridge (eluting with methanol followed by 2N ammonia solution in methanol) to recover (6 mg, 0.013 mmol) of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][CH2:23][C:20]2[S:19][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:22][CH:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Reactant: CC(C)(C)c1ccc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(SCc2ccc(C(C)(C)C)s2)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone and 1.9 g of 2-t-butyl-5-chloromethylthiophene, and thereto was added under stirring 1.5 g of potassium carbonate at room temperature. After additional stirring for 8 hours at room temperature, the mixture was poured into 50 ml of water and then extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 3.5 g of a crude product. The crude product was separated and purified through thin layer chromatography (on silica gel; benzene) to give 2.2 g of 2-t-butyl-5-{(5-t-butyl-2-thienyl)-methylthio}-4-methyl-3(2H)-pyridazinone as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:28][CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([N:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:31][C:30]4=[O:43])=[CH:22][CH:23]=3)[N:18]([CH3:44])[C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][N:29]([C:21]2[CH:20]=[C:19]3[C:24]([C:25]4[CH2:26][CH2:27][CH2:28][NH:15][CH2:16][C:17]=4[N:18]3[CH3:44])=[CH:23][CH:22]=2)[C:30](=[O:43])[CH:31]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (54 mg, 0.11 mmol) in CH2Cl2 (2.0 mL), and the resulting solution was stirred at ambient temperature for 30 min. The mixture was carefully quenched with saturated NaHCO3 solution until the solution was basic. The mixture was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 0:100 over 20 column volumes and held for 15 column volumes) provided the title compound (31 mg, 73%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.5 Hz, 1H), 7.43-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 6.03 (dd, J=7.5, 3.0 Hz, 1H), 5.05 (s, 2H), 4.10 (s, 2H), 3.64 (s, 3H), 3.23 (t, J=5.5 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 1.90-1.86 (s, 2H); ESI MS m/z 400 [M+H]+.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][C:9]1[S:33][C:12]2[N:13]([C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=3)=[O:20])[CH2:14][CH2:15][CH2:16][CH:17](O)[C:11]=2[C:10]=1[CH3:34]>CCCCCC.C(#N)C.C(OCC)(=O)C>[CH3:8][C:9]1[S:33][C:12]2[N:13]([C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=3)=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[C:10]=1[CH3:34]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC(O)c3c2sc(C)c3C)cc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: COC(=O)c1ccc(C(=O)N2CCCCc3c2sc(C)c3C)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
A solution of sodium iodide (462 mg), chlorotrimethylsilane (335 mg) and acetonitrile (0.2 ml) in hexane (0.5 ml) was cooled to 0° C. To the solution was added methyl 4-(2,3-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl)carbonyl-2-methoxybenzoate (200 mg) in acetonitrile (1.0 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (SiO2; 30 g, CHCl3) to give methyl 4-(2,3-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl)carbonyl-2-methoxybenzoate (150 mg).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:46][C:47]1[C:51]([CH3:52])=[N:50][O:49][N:48]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:46][C:47]3[C:51]([CH3:52])=[N:50][O:49][N:48]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC(F)(F)C(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and p-tolyl boronic acid (86 mg, 0.63 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (150 mg, 73%). LCMS: 488.20 (M+1)+; HPLC: 99.33% (@ 254 nm) (Rt; 5.393; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.51 (d, 2H, J=8 Hz), 7.37 (s, 1H), 7.25 (d, 2H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.81-3.83 (m, 2H), 3.22-3.27 (m, 2H), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.55 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C(N(CC)CC)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]1([NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (32.2 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (62 μL), aniline (25 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62.7 mg) and 4-dimethylaminopyridine (˜1 mg) were added in that order. Mixture stirred 16 h at room temperature then 2 mL more CH2Cl2 added (reaction had gone dry overnight) and thin layer chromatography showed complete conversion of starting material. Concentrated under reduced pressure then purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 16.9 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.48 (br s, 1H); 8.48 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.00 (s, 1H); 7.75-7.84 (m, 3H); 7.61-7.66 (m, 3H); 7.51 (t, J=7.8 Hz, 1H); 7.33-7.41 (m, 4H); 7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=5.5 Hz, 1H); 5.73 (br s, 1H); 5.28 (br s, 1H); 1.68 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 435.1 (M+1).