Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[N:15]1([CH2:21][CH2:22][C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[CH:25][N:24]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:25]1[N:24]=[C:23]([CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=12)=[O:6]
Reactant: c1ccn2c(CCN3CCOCC3)ncc2c1
Reactant: O=C(O)c1ccccc1I
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1I)c1nc(CCN2CCOCC2)n2ccccc12
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (201 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (63 mg, 16%). %). 1H NMR (DMSO-d6) 8.54 (1H), 8.10 (1H), 7.92 (1H), 7.50 (1H), 7.41 (2H), 7.22 (1H), 7.10 (1H), 3.52 (4H), 3.18 (2H), 2.67 (2H), 2.40 (4H); m/z (M+H)=462.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[O:17][N:16]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc(I)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 2 ml DMF 1.1 g caesium carbonate and 547 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 630 mg.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](Cl)=[O:8].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:25])=[C:17]([CH:24]=1)[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:25][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:7]([C:6]2[C:5]([CH3:10])=[C:4]([CH3:11])[O:3][C:2]=2[CH3:1])=[O:8])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1oc(C)c(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)c1C
Temperature: 60 °C
Yield: 42.6 %

Procedure:
A solution of 2,4,5-trimethyl-3-furancarbonyl chloride (7.8 g, 0.045 mole) in toluene (25 ml) was added to 1-methylethyl 5-amino-2-chlorobenzoate (10.6 g, 0.050 mole) and triethylamine (6 g) in toluene (25 ml). The mixture was warmed to 60° C. for about 1 hour,then washed in sequence with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. The solution was dried with magnesium sulfate, filtered and evaporated. The residue was crystallized from toluene/petroleum ether to give 6.7 g of a pale yellow solid, m.p. 83°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added drop wise. The mixture was stirred an additional 0.5 h at −20° C. HPLC indicated the reaction was ˜30% complete. The addition of NaH and bromoacetonitrile was repeated two more times. HPLC indicated the reaction was ˜60% completed. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated to give the crude product as brown oil (36.8 g), which was used for the next step without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:26]([C:32](OCC)=[O:33])[C:27](OCC)=[O:28])#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:7]([CH:26]([CH2:27][OH:28])[CH2:32][OH:33])[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC#CC(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCC#CCC(CO)CO
Reaction time: 48 h
Yield: 56.5 %

Procedure:
A mixture of 1.8 g of lithium aluminum hydride in 150 ml of ether is prepared at 0° C. To this is added a solution of 11.7 g of 2-nonadecynylpropanedioic acid, diethyl ester in ether. This mixture is refluxed for 4 hours then the reaction is quenched with aqueous sodium sulfate. After stirring for 2 days, the reaction is diluted with ethyl acetate and filtered. The residue is treated with methanol, IN sodium hydroxide and tetrahydrofuran and then evaporated. The residue is dissolved in ether and washed with brine and purified by flash chromatography, (4:6 ethyl acetate:petroleum ether), to give 5.3 g of the desired product as white plates, mp. 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].CN(C)[CH:40]=[O:41]>>[CH2:19]([O:20][C:40](=[O:41])[C:2]([O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[C:9]([CH3:33])([CH3:34])[CH2:10]3)[C:18]=2[CH:31]=1)([CH3:7])[CH3:3])[CH3:18]
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a cooled (0° C.) solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (250 mg, 0.51 mmol) in dimethylformamide (7 mL) was added sodium hydride (60% dispersion in oil, 31 mg, 0.76 mmol). The resulting mixture was stirred at 0° C. for 10 min. Ethyl 2-bromo-2-methyl propionate (149 mg, 0.76 mmol) was added. Stirring at 0° C. was continued 10 min before the mixture was warmed to rt and stirred 4h. The reaction was then partitioned between ethyl acetate and water; the aqueous phase was back-extracted with additional ethyl acetate. The combined organic phases were washed thrice with water, brine and dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride-95:5 methylene chloride:methanol gradient) to afford the titled compound (233 mg, 76%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.ClC1C=CC(S[CH2:14][N:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]2=[O:22])=CC=1.C1CCCCC=1>ClCCl>[Cl:4][CH2:14][N:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]1=[O:22]
Reactant: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1CCl
Reaction time: 0.25 h

Procedure:
Sulphuryl chloride (3.0 mmol) in dry dichloromethane (10.0 ml) was added to 1-(4-chlorophenylsulphenyl) methyl-5-chloropyrimidin-2-one (see Example 2) (3.0 mmol) in dry dichlormethane 30.0 ml) at -30° C. for 3 mins. The mixture was stirred at -25° C. for 50 mins before cyclohexene (3.5 mmol) in dry dichloromethane (10 ml) was added. After stirring for 15 mins the mixture was filtered, evaporated and the residue washed three times with Pet. ether. Insoluble 1-chloromethyl-5-chloropyrimidin-2-one (0.45 g), 84% was used in Example 31 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(COc2cccc(Br)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3cccc(Br)c3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 4-((3-bromophenoxy)methyl)benzoic acid (0.1 g, 0.32 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (147 mg, 0.76 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (104 mg, 0.77 mmol) and triethylamine (77 mg, 0.7 mmol). The mixture was stirred for 0.5 hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.4 mmol) was added and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 4-((3-bromophenoxy)methyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (80 mg, 57%). LRMS (M+H+) m/z: calcd 440.07. found 440.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].C(N(CC)CC)C.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:32][C@@H:33]1[O:35][CH2:34]1)(=O)=O>CN(C=O)C>[CH2:19]([N:10]1[C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][CH2:32][C@H:33]3[CH2:34][O:35]3)=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:20]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CN)ccc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CNC[C@H]3CO3)ccc21

Procedure:
To a solution of 2-amino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide (6.1 g, 23 mmol) and triethylamine (6.3 mL, 45 mmol) in DMF (50 mL) was added a solution of (R)-(−)-glycidyl nosylate (5.9 g, 23 mmol) in DMF (20 mL). The resultant solution was stirred two days under nitrogen to form (S)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(oxiranylmethyl-amino)-acetamide, which was then directly treated with diethyl amine (23 mL, 227 mmol) and methanol (100 mL). The mixture was stirred an additional two days, and then concentrated under reduced pressure to remove the methanol. The concentrated reaction was diluted with ethyl acetate (1 L) and washed with saturated aqueous Na2CO3 (1 L), water (2×500 mL), and then brine (250 mL). The organic solution was then dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (10:3:1 to 7:3:1 hexanes/diethylamine/acetonitrile) to give the title compound (4.4 g, 49%) as a brown oil which was converted to the dihydrochloride salt (methanol, ethereal HCl). The salt was then re-pulped from refluxing 2:1 ether/methanol to afford the dihydrochloride salt of the title compound as a colorless solid (3.5 g, 33%). MS m/z @ 397 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([C:7]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Product: O=C(Cl)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid chlorides used in the synthesis of the parent amides were all synthesized as described below. In a 1-liter 3-neck flask, 200 gm (1.05 mole) of 1-phenylcyclopentanecarboxylic acid (ACROS ORGANICS) was added drop-wise to stirring excess of thionyl chloride (Aldrich) under nitrogen. The resulting mixture was heated at reflux for two hrs. The reaction was further stirred at room temperature overnight. The resulting brown-red solution was concentrated at reduced pressure and heat on a rotary evaporator to remove excess thionyl chloride. The reaction yielded 216 gm of a lachrymator substance whose 1H-NMR and 13C-NMR spectra were ideal for the desired acid chloride.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[CH3:15])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:18][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH3:14])[S:11][C:10]=1[CH3:15]
Reactant: Cc1cc(C(O)C2CCCCC2)c(C)s1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(Cl)C2CCCCC2)c(C)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of cyclohexyl(2,5-dimethylthiophen-3-yl)methanol (643 mg) synthesized above in toluene (10 mL) was added thionyl chloride (314 μL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (653 mg, 94%) as a brown oil.
Reaction SMILES: Cl.CO.[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C:17]4[CH2:18][CH:19]=[C:20]([O:25]C)[CH2:21][C:22]=4[CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])[CH:5]([CH3:7])[CH3:6]>O>[CH2:4]([C@:8]12[CH2:16][CH2:15][C@@H:14]3[C@@H:17]4[C:22]([CH2:23][CH2:24][C@H:13]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[OH:27])=[CH:21][C:20](=[O:25])[CH2:19][CH2:18]4)[CH:5]([CH3:7])[CH3:6]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
Add to a mixture of concentrated hydrochloric acid (4.8 cc.), water (3.2 cc.) and methanol (.72 cc.) 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17β-ol (2.0 g.). Heat the resulting solution on a steam bath for 30 minutes with stirring. Cool to room temperature, dilute the solution with water (160 cc.) and extract with ether. Wash the ethereal solution with water, sodium bicarbonate, and water, dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure to give a gum. Recrystallize from ethyl acetate to obtain the title compound (0.8 g., 43%, m.p. 124.0°-125.5°; ultraviolet absorption peak at 240 mμ (ε18,200).
Reaction SMILES: [C:1]([NH:8][C:9]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:10]S(C(F)(F)F)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[CH2:29]([N:32]1[CH2:37][CH2:36]N[CH2:34][CH2:33]1)[C:30]#[CH:31]>>[C:22]([O:21][C:19](=[O:20])[NH:18][C:9](=[N:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:10]1[CH2:36][CH2:37][N:32]([CH2:29][C:30]#[CH:31])[CH2:33][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: C#CCN1CCNCC1
Solvent: ClCCl
Product: C#CCN1CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of N,N′-di-Boc-N″-trifluoromethanesulfonylguanidine (1.72 g, 4.40 mmol) in anhydrous CH2Cl2 (20 mL) Et3N (674 μL, 4.84 mmol) and N-propargyl piperazine (600 mg, 4.84 mmol) are added. The mixture is left reacting at room temperature for 16 h, then the solvent is evaporated. The residue is taken up in EtOAc, and treated with a saturated aqueous NaHCO3 solution and brine. Crude compound is purified by flash chromatography (2:1 EtOAc-petr. et., Rf=0.37) giving compound 4 as a yellow oil (1.01 g, 2.77 mmol) in 63% yield. 1H NMR (CDCl3, 200 MHz) δ 9.61 (br, 1H), 3.44 (m, 4H), 3.16 (d, J=2.6 Hz, 2H), 2.41 (m, 4H), 2.18 (m, 1H), 1.27 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28](I)[CH:27]=1>CO.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>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:31]=1
Reactant: OB(O)c1c(O)cccc1F
Reactant: Fc1ccc(Br)cc1I
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: Cc1ccccc1
Solvent: CO
Product: Oc1cccc(F)c1-c1cc(Br)ccc1F
Temperature: 105 °C
Yield: 88.5 %

Procedure:
(2-Fluoro-6-hydroxyphenyl)boronic acid (50 mg, 0.321 mmol, 1.0 equiv), Pd(PPh3)4 (37.1 mg, 0.032 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 401 μl, 0.802 mmol, 2.5 equiv) were mixed with toluene (2 mL) in a sealed microwave tube. 4-Bromo-1-fluoro-2-iodobenzene (96 mg, 0.321 mmol, 1.0 equiv) in MeOH (1.00 mL) was added to the above mixture. The resulted mixture was heated at 105° C. overnight. TLC showed the starting material disappeared and a new spot was produced. The reaction was allowed to cool to ambient temperature and then loaded on 12 g ISCO column and purified by 30% EtOAc/hexane to afford 5′-bromo-2′,6-difluoro-[1,1′-biphenyl]-2-ol (81 mg, 89%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (dd, J=6.3, 2.5 Hz, 1H), 7.48 (ddd, J=8.7, 4.5, 2.6 Hz, 1H), 7.21 (td, J=8.2, 6.7 Hz, 1H), 7.07 (t, J=8.9 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.71 (t, J=8.8 Hz, 1H). LCMS (M+1)=286.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[CH2:11](O)[CH3:12].C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH2:11]([O:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:12]
Reactant: O=C(O)c1cnccc1Cl
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnccc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A suspension of 4-chloro-pyridine-3-carboxylic acid (5.0 g, 31.7 mmol) in thionyl chloride (100 ml) is heated at 80° C. for 1.5 h. The reaction mixture is cooled to RT and excess thionyl chloride is distilled off. The crude product is azeotropped with toluene (3×30 ml) to afford a solid, which is added in portions to a mixture of ethanol (40 ml) and diisopropylethylamine (25 ml) at 0° C. The resulting reaction mixture is stirred at RT for 4 h. After completion of the reaction, the mixture is evaporated to dryness; the residue is diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated to get 4-chloro-pyridine-3-carboxylic acid ethyl ester (4.50 g, 24.3 mmol, 77%), which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([O:28]C)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>[OH-].[Li+].CO>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OC)c4c3OCC4)nc2N1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Yield: 97.7 %

Procedure:
Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate 1p (5 g, 11 mmol) was dissolved in 180 mL mixture solution of 1 mol/L lithium hydroxide solution and methanol (V/V=1:1). The resulting mixture was heated to reflux for 3 hours with stirring. The reaction solution was added with 50 mL of water, concentrated under reduced pressure and extracted with ethyl acetate (50 mL×3). 1 M hydrochloric acid was added dropwise to adjust the aqueous phase pH to 2 resulting in the formation of precipitate. The precipitate was filtered, and dried to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (4.70 g, yield: 97.0%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:32][NH2:33].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[CH2:32][NH:33][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (20.0 g), 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (17.2 g) and 1-hydroxybenzotriazole (8.07 g) in N,N-dimethylformamide (200 ml) was added dropwise 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10.9 ml) at 0° C. The mixture was stirred at 4° C. for 15 hours, then poured into ice water (500 ml), and extracted with ethyl acetate (500 ml×2). The combined organic layer was successively washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (from 1:1 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (30.5 g) as a colorless oil.