Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.923 g; 4.10 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then THF (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (2 ml). The reaction mixture was then heated to 65° C. and stirred for 96 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.00 mmol (50% yield) of diphenylacetylene and 0.54 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:6][C:7]([C:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH:10]=1)=[O:8])[CH3:5].[Cl-].[NH4+]>C1COCC1.C1COCC1.C1(C)C=CC=CC=1.[Cu]I>[CH2:4]([O:6][C:7]([CH:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][CH:10]1[CH3:1])=[O:8])[CH3:5]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)CCN(C(=O)OC(C)(C)C)CC1C
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5.18 g (27.18 mmol) CuI in 85 mL anhydrous THF at −78° C. was added 24 mL (34 mmol) of a 1.4 M solution of methyl magnesium bromide in THF/toluene dropwise under an atmosphere of nitrogen, the reaction was left to warm up to −15° C. and then stirred at this temperature for 45 minutes. It was cooled again at −78° C. and a solution of 3.85 g (13.59 mmol) 5-oxo-2,5,6,7-tetrahydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 30 mL anhydrous THF was added dropwise. The resulting reaction mixture was stirred at −78° C. for 30 minutes and then left to warm up to room temperature over a period of 60 minutes. 100 mL saturated aqueous ammonium chloride was added and the resulting mixture was extracted with EtOAc (3×150 mL), the organic layers were combined, washed with H2O (2×200 mL) and saturated brine (200 mL) and dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 8:2) to give crude material that was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[Cl:23][CH2:16][C:15](=[O:17])[C:9](=[N:8][O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A mixture of ethyl 2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 74.08 g.), sulfuryl chloride (41.70 g.) and acetic acid (75 ml.) was stirred at at 40° to 42° C. for 4 hours. Nitrogen gas was bubbled into the reaction mixture. After adding the mixture into ice water, the mixture was extracted with methylene chloride. The extract was washed with sodium bicarbonate saturated aqueous solution and sodium chloride saturated aqueous solution in turn and dried over magnesium sulfate. After removing the solvent in vacuo, the residue was allowed to stand in a refrigerator overnight. The precipitates were removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with benzene and ethyl acetate. The eluate was concentrated in vacuo to give ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.9 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:8]3[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc12
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.[H-].[Na+].[Cl-].[NH4+]>CS(C)=O>[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0.163 mmol) synthesized in Example (38d) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75 mg, 0.325 mmol) synthesized in Example (60a) were dissolved in dimethyl sulfoxide (5.0 mL), and sodium hydride (60%, 30 mg, 0.75 mmol) was added, and stirring was carried out at 100° C. for 3.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=85%-100%) to afford the desired compound (58 mg, yield 68%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCCC2)c1

Procedure:
Methyl-3-(bromomethyl)benzoate (0.115 g, 0.5 mmol), pyrrolidine (0.036 g, 0.5 mmol) and K2CO3 (0.069 g, 0.5 mmol) were dissolved in DMF (2.5 ml) and stirred at reflux for 18 h. The reaction mixture was the reduced in vacuo and subject to column chromatography eluting with hexane ethyl acetate (1:1) to give the crude 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester, which was added to a solution of LiOH (0.014 g, 0.33 mmol) in 1:1 THF:H2O (1 ml). The reaction mixture was stirred at ambient temperature for 18 h, reduced in vacuo and dried through azeotrope with toluene (×3). The resulting solid was dissolved in water (1 ml), acidified with 2M HCl (1 ml), reduced in vacuo and dried through azeotrope with toluene (×3) to give a clear, pale yellow gel. This was combined with 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (0.050 g, 0.25 mmol), EDC (0.058 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) and the reaction mixture was stirred at ambient temperature in DMSO (0.75 ml) for 64 h. The reaction mixture was purified by preparative LC/MS to give the formate salt of N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-3-pyrrolidin-1-ylmethyl-benzamide (0.018 g, 9% over 3 steps) as a buff coloured solid. (LC/MS: Rt 1.86, [M+H]+ 387.16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:49][CH3:50])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42](OCC)OCC)=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:51][CH3:52])[N:27]=1.Cl.[CH3:54][O:55][NH2:56].Cl.C1(C)C=CC=CC=1>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:49][CH3:50])[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH:42]=[N:56][O:55][CH3:54])=[CH:38][CH:39]=2)[CH:29]=[C:28]([CH2:51][CH3:52])[N:27]=1
Reactant: CCOC(COc1ccc(C(CC)Nc2cc(CC)nc(Cl)n2)cc1)OCC
Reactant: CON
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1cc(NC(CC)c2ccc(OCC=NOC)cc2)nc(Cl)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 1.0 g of dl-5-chloro-6-ethyl-4-[α-ethyl-4-(2,2-diethoxyethoxy)benzyl]aminopyrimidine obtained in Example 19 dissolved in 40 ml of ethanol was added 0.4 g of methoxyamine hydrochloride. Then, after addition of a catalytic amount of a 6N hydrochloric acid, the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and extracted with ethyl acetate. Then, the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=7:1) to give 0.4 g of the desired product as pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]3)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 29.2 %

Procedure:
6-Hydroxy-2H-isoquinolin-1-one (2 g, 12.41 mmol) and potassium carbonate (3.43 g, 2 mol) were mixed with N, N-dimethylformamide (40 ml) at 100° C. A solution of (R)-3- methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester (5.2 g, 1.5 mol) in dimethylformamide (50 ml) was added dropwise over 15 minutes. The mixture was stirred at 100° C. for 3.5 hours and allowed to cool. The crude material was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with sodium hydroxide (2M) then brine and dried over magnesium sulphate. The residue was purified by flash chromatography on silica (eluent: 0-100% Heptane/Ethyl acetate followed by 5% 2M ammonia in methanol/ethyl acetate) to give (S)-3-(Oxo-1,2-dihydroisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.25g, 29%), El-MS: m/z=345.3 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C1O[C:11]2([C:20]3[C:14]4[C:15](=[CH:21][N:22]([S:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)(=[O:26])=[O:25])[CH2:23][C:13]=4[CH2:12]2)[CH:16]=[CH:17][O:18][CH:19]=3)[O:10]C1>O>[C:27]1([S:24]([N:22]2[CH2:23][C:13]3[CH2:12][C:11](=[O:10])[C:20]4=[CH:19][O:18][CH:17]=[CH:16][C:15]([C:14]=34)=[CH:21]2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(c1ccccc1)N1C=C2C=COC=C3C2=C(C1)CC31OCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2=C3C(=CN(S(=O)(=O)c4ccccc4)C2)C=COC=C13
Temperature: 80 °C
Yield: 78 %

Procedure:
Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound (34) 48.4 mg. The mixture was heated at 80° C. for 15 min and concentrated under reduced pressure. Ice-water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:2) to give the titled compound (35) as a colorless oil, 33.2 mg. Yield 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:17][OH:18])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
Dissolve 1-(4-chlorobenzyl)-4-piperidone (0.0456 mmol), hydroxylamine hydrochloride (0.0456 mmol) and sodium acetate (0.0456 mmol) in aqueous ethanol (450 mL). Stir approximately 30 minutes to 2 hours while warming. Add methylene chloride (450 mL), separate the organic phase, and extract the aqueous phase with methylene chloride (100 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[O:10][N:9]=2)[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]([C@@H:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[CH3:31])C(=O)OC(C)(C)C)[CH:17]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:16]1.[ClH:48].O1CCOCC1>>[ClH:48].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[O:10][N:9]=2)[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C@@H:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH:17]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:16]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(-c3noc(=O)[nH]3)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2c(F)cc(-c3noc(=O)[nH]3)cc2F)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 183 mg of tert-butyl ({1-[2,6-difluoro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-3-phenylpiperidin-4-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate was added 1.5 mL of a 4 M hydrogen chloride/1,4-dioxane solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol), followed by addition of 0.5 mL of a 4 M hydrogen chloride/1,4-dioxane solution, and further concentration under reduced pressure. To the obtained residue were added ethanol and ethyl acetate, followed by heating under reflux, and then being left to be cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure, and isopropanol and ethyl acetate were added thereto, followed by heating under reflux, and then being left to be cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to obtain 57 mg of 3-{3,5-difluoro-4-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]phenyl}-1,2,4-oxadiazol-5(4H)-one hydrochloride as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH:26]CC2C=CC(OC)=CC=2OC)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C:7]1[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:16]2[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3cccc(-c4cc5c([nH]4)CCNC5=O)c3nc2NC(C)(C)C)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1N
Temperature: 40 °C
Yield: 22.5 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-((2,4-dimethoxybenzyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (304d) (40 mg, 0.08 mmol) and TFA (1.0 mL, 12.98 mmol) in DCM (1.0 mL) was stirred at 25° C. for 1 h. The reaction mixture was subsequently heated at 40° C. for 1 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and saturated aq. NaHCO3 (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-amino-3-(tert-butylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.4 mg, 0.018 mmol, 23% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (1H, br. s.), 7.53 (1H, dd, J=7.0, 1.8 Hz), 7.19-7.22 (1H, m), 7.14-7.19 (1H, m), 6.92 (1H, br. s.), 6.90 (1H, d, J=2.0 Hz), 6.86 (2H, s), 6.33 (1H, s), 3.43 (2H, td, J=6.9, 2.2 Hz), 2.86 (2H, t, J=6.7 Hz), 1.56 (9H, s). m/z (ESI, +ve) 351.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[OH:56]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+]>CC(O)(C)C.CC(O)=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([OH:56])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To the solution of aldehyde 101 (830 mg, 1.17 mmol) in t-BuOH (34 mL) was added 2-methyl-2-butene (5.9 mL, 55.2 mmol), KH2PO4 (1.1 g, 8.3 mmol) and NaClO2 (960 mg, 10.6 mmol in H2O (20 mL)). The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was acidified with AcOH and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the desired acid 104 (815 mg, 96%) as a solid. The obtained acid was used without further purification. MH+722.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.O>[Si:14]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccnc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of (2-chloropyridin-4-yl)methanol (0.307 g, 2.14 mmol) in 20 mL of DMF at 0° C. under an atmosphere of nitrogen was added tert-butyldimethylchlorosilane (0.355 g, 2.35 mol) and imidazole (0.160 g, 2.35 mmol). After 1 h, the mixture was diluted with water, washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to silica gel chromatography eluting with 0-15% EtOAc in hexanes to provide 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloropyridine that gave a mass ion (ES+) of 258.1 for [M+H]+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:30][CH2:31][CH2:32][CH2:33][N:34]=2)=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.CO>O1CCOCC1.[Pd]>[NH2:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:34][CH2:33][CH2:32][CH2:31][N:30]=2)=[CH:23][CH:24]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)C(=O)O
Reaction time: 2 h

Procedure:
100 mg (0.2 mmol) of (2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetra-hydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid (Example 3e) were dissolved in 15 ml of dioxane, treated with 0.012 ml of glacial acetic acid and hydrogenated at RT and 1 bar H2 over Pd/C (5%). After 2 h, 15 ml of methanol were added and the mixture was hydrogenated at RT and 1 bar H2 for a further 5 h. It was filtered and the solvent was evaporated in vacuo. Yield: 67.4 mg (93%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7](C)([C:13](OCC)=O)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.C>O.C(O)C.[OH-].[Na+]>[CH3:13][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][CH:19]=1)[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 205 °C
Yield: 88 %

Procedure:
A solution of sodium hydroxide (34.0 g) in water (155 ml) was added to a solution of diethyl 2-(4-bromobenzyl)-2-methylmalonate (29.2 g) in ethanol (165 ml), and then heated under reflux for 9 hours. The reaction mixture was cooled, the solvent was evaporated and the residue taken up in water (150 ml). Sodium hydroxide pellets were added (25.4 g) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled and acidified to pH<1 with concentrated hydrochloric acid, which caused precipitation of a solid. The reaction mixture was extracted with diethyl ether (3×150 ml), the combined organic layers were dried (MgSO4) and then the solvent was evaporated to give a white solid. This solid was heated at 205° C. for 20 minutes, cooled to ambient temperature, dissolved in 1.0M sodium hydroxide solution (150 ml), treated with activated charcoal and then filtered through diatomaceous earth. The resulting clear solution was re-acidified and then extracted with diethyl ether (3×150 ml). The combined organic layers were dried (MgSO4) and evaporated to give a yellow oil which crystallised on standing to give 2-methyl-3-(4-bromophenyl)propanoic acid as a white solid (18.2 g), m.p. 69°-70° C.; mass spectrum (+ve CI): 243 (M+H)+.