Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>ClCCl.CCN(CC)CC>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: CCN
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Neat thiophene-2-carbonyl chloride (1.46 g, 10 mmol) is added dropwise to a solution of ethylamine (70% wt/water) in Dichloromethane (8 mL) and Et3N at 0° C. Additional ethylamine (2.5 ml, 70% wt/water) is added to the reaction mixture and the reaction is stirred at 0° C. for 2 hrs and the warmed to room temperature for 2 h. The reaction mixture is transferred to a separatory funnel and the organic layer is washed sequentially with aqueous 1N HCl solution, water and saturated aqueous NaHCO3 solution. The organic phase is collected, dried over Na2SO4, filtered and concentrated to give the title compound (1.4 g, 90%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1.Cl>CN(C)C=O>[CH:50]1([NH:53][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[CH:21]=[C:17]([C:15]([NH:14][CH:3]([C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:11])[F:13])[CH:5]=4)[C:2]([F:30])([F:1])[F:29])=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:27])[CH2:52][CH2:51]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-({2,2,2-trifluoro-1-[3-(trifluormethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylic acid (100 mg, 0.21 mmol) in N,N-dimethylformamide (1 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (100 mg, 0.46 mmol) and cyclopropylamine (36 mg, 0.63 mmol), and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat, sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10%, acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8]Br)(=[O:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[C:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][N:16]=[N+:17]=[N-:18])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccccc1N(C)C(=O)CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1N(C)C(=O)CN=[N+]=[N-]
Yield: 51.6 %

Procedure:
2.05 g (7.59 mmol) of 2′-acetyl-2-bromo-N-methylacetanilide and 2 g (30.77 mmol) of sodium azide were stirred in 20 ml of dimethylformamide at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic phase was washed twice with water, dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol 5:3 for the elution. There was obtained 910 mg of 2′-acetyl-2-azido-N-methylacetanilide as a colorless gum. MS: m/e 233 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H](O)CN1CCN(C)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.79 mmol), and 1-methylpiperazine (0.26 ml, 2.38 mmol) in DMF (10 ml) was stirred at 70° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, dichloromethane/methanol/0.88 ammonia (100/8/1) and evaporated in vacuo to give (2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (344 mg, 91%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCCCCCCCCS.Cl.C[CH:23]1[CH2:29][C:28](C)(C)[CH2:27][C:25](=[O:26])[CH2:24]1>>[CH:29]1[CH:28]=[C:27]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:25]([OH:26])=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: CCCCCCCCCCCCS
Agent: Cl
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
7.5 mol (705 g) phenol and 0.15 mol (30.3 g) dodecylthiol are introduced into a 1-liter round-bottomed flask equipped with a stirrer, dropping funnel, thermometer, reflux condenser and gas inlet pipe and saturated with dry HCl gas at 28° to 30° C. A solution of 1.5 mol (210 g) dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) and 1.5 mol (151 g) phenol is added dropwise to the resulting solution over a period of 3 hours, HCl gas continuing to be passed through the reaction solution. After the addition, HCl gas is introduced for another 5 hours. The mixture is then left to react for 8 hours at room temperature. The excess phenol is then removed by steam distillation. The residue is hot-extracted twice with petroleum ether (60-90) and once with methylene chloride and filtered off. Yield: 370 g, Mp: 205°-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]#[N:28].C(N(CC)CC)C.O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:28][CH2:27][CH2:26][C:25]#[N:24])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: N#CCCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(NCCC#N)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-(6-Chloro-5-nitro-pyrimidin-4-yl)piperazine-1-carboxylic acid t-butyl ester (3.0 g) was dissolved in acetonitrile (30 mL), and then 3-aminopropionitrile (0.71 mL) and triethylamine (1.58 mL) were added to this solution. After stirring the reaction solution at room temperature for 14 hours, water (60 mL) was added. The reaction solution was stirred at room temperature for 30 minutes, and then the precipitate was collected by filtration. The obtained yellow solid was washed with water and hexane to give the title compound (1.97 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Br:26])=[CH:23][CH:22]=1>>[Br-:26].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N+:4]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:23][CH:22]=1
Reactant: CCCCCCCCCCCCn1nc(C)cc1C
Reactant: Clc1ccc(CBr)cc1
Product: CCCCCCCCCCCC[n+]1c(C)cc(C)n1Cc1ccc(Cl)cc1
Product: [Br-]

Procedure:
Reaction of 3,5-dimethyl-1-dodecyl-pyrazole with p-chlorobenzyl bromide yields 2-(p-chlorobenzyl)-3,5-dimethyl-1-dodecyl-pyrazolium bromide; m.p. 166.5°-167.5° C.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>ClCCl>[CH3:3][N:4]([CH2:1][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: CNC
Reactant: C=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: CN(C)Cn1ccc2ccccc21
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
Formaldehyde (37% in water, 0.19 mL, 2.6 mmol) was added to cooled (ice/water bath) aqueous dimethylamine (40% in water, 0.32 mL, 2.6 mmol). The mixture was stirred for 10 min and then indole 31 (0.3 g, 2.6 mmol) was added. The suspension was stirred for 1 h in an ice/water bath and then 24 h at RT. Indole was not completely dissolved. Dichloromethane (10 mL) was added and the organic layer was separated. The solvent was evaporated and the residue was chromatographed on a Chromatotron with dichloromethane/hexanes, 5:2 mixture as eluent to remove non-polar impurities. This was followed by elution with dichloromethane/EtOAc, 5:1 to 1:1. Appropriate fractions were collected to give indole Mannich base 32 as an oil (0.25 g, 57%) which was pure by TLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.Cl>C(Cl)Cl>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:8]([C:7]1[C:2]([Cl:1])=[C:3]([CH3:11])[CH:4]=[CH:5][CH:6]=1)=[O:9]
Reactant: Cc1cccc(C(=O)Cl)c1Cl
Reactant: c1ccsc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cccs2)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred and cooled mixture of 28.4 parts of 2-chloro-m-toluoyl chloride, 12.6 parts of thiophene and 80 parts of methylene chloride is added dropwise a mixture of 39 parts of stannic chloride in 40 parts of methylene chloride at 10° C. Upon completion, stirring is continued first for 2 hours a 20° C and further for 3 hours at reflux. The reaction mixture is poured onto a mixture of ice-water and concentrated hydrochloric acid solution. The methylene chloride solution is separated, washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding 2-chloro-m-tolyl 2-thienyl ketone; bp. 197° -199° C at 12 mm. pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:47].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:47])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(Cc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-{4-[3-(tosyloxy)propyl]benzyl}-L-glutamate (see Example 10) (100 mg, 0.15 mmol) was dissolved in 1 ml acetonitrile, and tetra-n-butylammonium tetra-(tert-butyl alcohol)-coordinated fluoride (Angew. Chem. 2008, 120, 8532-8534) (169 mg, 0.30 mmol) were added. The mixture was stirred at 70° C. for 2 h. Another 169 mg of the fluoride source was added and the reaction stirred for further 1.5 h at 70° C. After cooling to room temperature, the mixture was poured into water (10 ml) and extracted with tert-butyl methyl ether (3×10 ml). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a reversed phase (RP-18) column with an acetonitrile/water gradient. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccc(F)cc2)CC1
Reaction time: 16 h

Procedure:
0.856 g (0.00846 mol) of 4-hydroxypiperidine was dissolved in 40 ml of dimethylformamide and cooled to 0°. 2.0 g (0.0106 mol) of 4-fluorobenzyl bromide and 3.3 ml (0.0233 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (17:3) as the eluent. An analytically pure sample was obtained after a second chromatography on silica gel with dichloromethane/methanol (17:3) as the eluent. The remainder was used directly in the next step. 0.176 g (8%) of 1-(4-fluoro-benzyl-piperidin-4-ol was obtained as a yellow oil. MS: me/e=210 (C12H17FNO+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][S:2]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][O:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCOC1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Methanesulfonyl chloride (18 mmol, 1.39 mL) was added to a flask containing (±)-tetrahydro-3-furanmethanol (1.53 g, 15.0 mmol) in tetrahydrofuran (25 mL) and triethylamine (3.13 mL, 22.5 mmol) at 0° C. under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was stirred overnight. A saturated solution of NaHCO3 (15 mL) was added to the reaction mixture followed by extraction with diethyl ether (3×15 mL). The combined organic extracts were dried over anhydrous magnesium sulfate. Filtration followed by concentration on a rotary evaporator yielded the product as a pale yellow solid (2.13 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C1N2CCN(CC2)C1.C(Cl)([Cl:20])=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:7]([Cl:20])=[O:9])=[CH:5][N:6]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ncc(C(=O)O)s1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Product: Cc1ncc(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.0 g (0.07 mole) of 2-methylthiazole-5-carboxylic acid were suspended in 100 ml of xylene, followed by the addition of 0.03 g of triethylenediamine. Under heating and reflux, phosgene was blown at a rate of 930 ml/hr for 6 hours (0.25 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.5 g of 2-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.0% and 92.8%, respectively.
Reaction SMILES: CS(Cl)(=O)=O.[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].O[C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=3)[CH:25]=2)=[C:19]([CH3:40])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:23][C:21]1[CH:22]=[C:17]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:18]=[C:19]([CH3:40])[C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([CH:36]=[O:37])=[CH:38][CH:39]=2)[CH:25]=1
Reactant: O=C1CCCN1CCCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(OCCCN2CCCC2=O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride was dropwise added to a mixture of 1-(3-hydroxypropyl)pyrrolidin-2-one, triethylamine and ethyl acetate under ice-cooling, followed by stirring at 0° C. for 2 hours to obtain a colorless oil. 4-[(4′-Hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, cesium carbonate and DMF were added to the resulting oil, followed by stirring with heating at 60° C. for 19 hours to obtain 4-({2′,6′-dimethyl-4′-[3-(2-oxopyrrolidin-1-yl)propoxy]biphenyl-3-yl}methoxy)benzaldehyde.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([NH:9][C:10](=[O:27])[CH:11]([NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[OH:3][CH:1]([C:4]1[O:8][C:7]([NH:9][C:10](=[O:27])[CH:11]([NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)[CH3:2]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncc(C(C)=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncc(C(C)O)o1
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To a solution of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-acetyl-oxazol-2-yl)-amide (130 mg, 0.34 mmol) in a mixture of MeOH (5 ml) and THF (5 mL) was added NaBH4 (130 mg, 3.9 mmol) at room temperature. After stirring for 10 min, the mixture was concentrated to a small volume, quenched with water and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give 131 mg of the title compound as a colorless oil. LC-MS, RT=1.7 min, M+1=382.2, M−1=380.2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+]([O-])=O)[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:17].[K+].Cl.[CH3:20]O>>[CH3:20][O:17][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: CO
Reactant: [OH-]
Reactant: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [K+]
Product: COc1cc(C)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 60 %

Procedure:
2-Methyl-4,5-dinitrobenzoic acid (1.93 g, 8.5 mmol) was added to KOH (2.38 g, 42.5 mmol) in methanol (50 mL) and the mixture was heated to 70° C. for 1.5 h. The mixture was acidified with 2 M HCl(aq) and the solid was removed by filtration and dried to give 4-methoxy-2-methyl-5-nitrobenzoic acid (1.08 g, 60%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]−=210 at 3.23 min. 1H NMR (400 MHz, d6-DMSO): δ 8.40 (s, 1H), 7.36 (s, 1H), 4.02 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[SH:29])=[CH:4][CH:3]=1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:44])([F:43])[F:42])[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][C:41]([F:42])([F:43])[F:44])[CH:35]=2)=[CH:30][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S)n2Cc1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(SCc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-mercapto-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.216 mmol) in DMF (5 mL) was added 1-(bromomethyl)-3-(trifluoromethoxy)benzene (66 mg, 0.259 mmol), followed by potassium carbonate (89 mg, 0.645 mmol). The reaction was stirred at 80° C. for 2 h. The mixture was cooled, diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione (120 mg, 87.3%) as light yellow oil. LCMS retention time 2.106 min; LCMS MH+-THP 555.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:21]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A solution of 2-bromopyridine (5 g, 0.032 mol) in dry THF (150 mL) was cooled to −70° C. To this cooled solution was added n-BuLi (2.8 M, 12.4 mL, 0.034 mol) over a period of 20 min and allowed to stir for 2 h under N2 atmosphere. A solution of benzophenone (5.8 g, 0.032 mol) in dry THF (50 mL) was added to the solution at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 5 h at RT. The reaction mixture was concentrated under vacuum and the residue was washed with petroleum ether. The organic layer was filtered and the filtrate was concentrated under vacuum to give the title compound (8 g, 95%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)ccc1C
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1C
Yield: 87 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (320 mg) in acetonitrile (10 mL) were added ethyl 3-(5-hydroxy-2-methylphenyl)propanoate (230 mg) and cesium carbonate (546 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (427 mg) as a colorless oil.