Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[Br:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:21])=[CH:14][CH:13]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCc3ccc(Br)cc32)cc1
Temperature: 25 °C

Procedure:
6.4 ml (6.4 mmol) of a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (1M soln) are added dropwise to a solution of 0.9 g (4.26 mmol) of 6-bromo-1-indanone in 10 ml of absolute tetrahydrofuran under nitrogen at −20° C. The reaction solution is subsequently warmed to room temperature over the course of 12 hours, then 45 ml of 10% ammonium chloride solution are added, and finally the mixture is extracted twice with 20 ml of methylene chloride each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 4:1), giving 1.1 g of 6-bromo-1-(4-methoxyphenyl)indan-1-ol as pale-yellow oil. LC/MS: 302 (M+H-18 (water)). This oil is then dissolved in 20 ml of methylene chloride, the solution is cooled to −20° C., and, after addition of 0.8 ml (5 mmol) of triethylsilane, 0.53 ml (4.2 mmol) of boron trifluoride/diethyl ether complex is added. The reaction solution is subsequently warmed to room temperature, stirred at room temperature for four hours and then washed successively with 20 ml of saturated sodium hydrogencarbonate solution and 20 ml of saturated sodium chloride solution. After the methylene chloride solution has been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether/ethyl acetate 95:5), giving 0.52 g of 6-bromo-1-(4-methoxyphenyl)indane as colourless oil; 1H-NMR (d6-DMSO): δ 7.34 ppm (d, 1H, J=7.9 Hz), 7.26 ppm (d, 1H, J=7.9 Hz), 7.11 ppm (d, 2H, J=8.97 Hz), 6.93 ppm (s, 1H), 6.90 ppm (d, 2H, J=8.97 Hz), 4.31 ppm (t, 1H, J=8.27 Hz), 3.74 ppm (s, 3H, OCH3), 2.98 ppm (m, 1H), 2.85 ppm (m, 1H), 2.48 ppm (m, 1H), 2.0 ppm (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](CC(OC(=O)CC=O)=O)=[O:14]>C1(C)C=CC=CC=1>[CH:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])=[O:14]
Reactant: O=CCC(=O)OC(=O)CC=O
Reactant: COc1cc2cc[nH]c2cc1O
Solvent: Cc1ccccc1
Product: COc1cc2cc[nH]c2cc1OC=O
Yield: 29.9 %

Procedure:
A solution of 12 g (0.0735 mole) of 6-hydroxy 5-methoxy indole and 12.95 g (0.147 mole) of formyl acetic anhydride in 100 ml toluene is refluxed for 16 hours under nitrogen atmosphere. After cooling, 30 g of silica 60 is added to the reacting medium, and it is filtered and concentrated to half its volume. The white precipitate that is obtained is filtered and then recrystallized in 30 ml toluene. After vacuum-drying, 4.2 g of 6-formyloxy 5-methoxy indole is obtained (white powder, yield 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](C2C=CC=CC=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C(=O)CCC(O)=O)C=CC=1Cl.ClC1C=C(C(O)CCC(O)=O)C=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CCC(O)c1ccc(Cl)c(Cl)c1
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)O1

Procedure:
A novel three-step process for preparing 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid is disclosed, which involves (1) reducing 4-(3,4-dichlorophenyl)-4-ketobutanoic acid to 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid; (2) then converting the intermediate hydroxy acid formed in the first step to 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone, and (3) thereafter reacting the resulting gamma-butyrolactone compound with benzene in a Friedel-Crafts type reaction to form the desired final product. The latter compound is known to be useful as an intermediate leading to 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and ultimately, to cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalene amine (sertraline), which is known to be a preferred anti-depressant agent in the field of medicinal chemistry. The aforementioned 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone and 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid are both novel compounds. There is also disclosed a novel process for converting 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone directly to 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, as well as an alternate novel process for converting 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid directly to this same key intermediate.
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1>O.Cl>[Cl:9][C:8]1[CH:2]=[CH:3][C:4]([CH3:10])=[C:5]([CH:7]=1)[NH2:6]
Reactant: Cc1cc(Cl)c(Cl)cc1N
Agent: Cl
Solvent: O
Product: Cc1ccc(Cl)cc1N
Yield: 82 %

Procedure:
Following the general procedure I, 0.25 mol of 4,5-dichloro-2-methylaniline in 200 ml of water and 60 ml of concentrated hydrochloric acid are hydrogenated in the presence of the catalyst from Example 1 at 220° C. over the course of 30 minutes under a hydrogen pressure of 100 atmospheres gauge. 5-Chloro-2-methylaniline is obtained in a yield of 82% and a purity of 99%.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.O.NN>CCO>[NH2:18][C:14]1[CH:13]=[C:12]([NH:19][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[NH:3][N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N=C1NC(=O)c2ccccc21
Reactant: Nc1cccc(N)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(Nc2n[nH]c(=O)c3ccccc23)c1
Temperature: 80 °C

Procedure:
3-Imino-2,3-dihydro-isoindol-1-one (50 mg, 0.34 mmol) and benzene-1,3-diamine (110 mg, 0.102 mmol) were heated at 200° C. for 16 hrs. The resulting mixture was dissolved in EtOH (600 μL) and hydrazine hydrate (200 μL) was added. After heating for 2 hours at 80° C. the mixture was concentrated in vacuo and dissolved in 1500 μL DMSO and directly applied to preparative HPLC to afford 4-(3-amino-phenylamino)-2H-phthalazin-1-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].Cl[S:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>Cl>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([S:33]([NH:1][CH2:2][C:3]([O:5][C@H:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:18]=2)[CH2:7][C:8]2[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=2[Cl:16])=[O:4])(=[O:35])=[O:34])=[CH:44][CH:43]=1)([OH:42])=[O:41]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc(C(=O)O)cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
(S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner as described in Scheme 1, Step 1-2) (100 mg, 0.210 mmol) was dissolved in py (2.5 ml). 4-(chlorosulfonyl)benzoic acid (60.1 mg, 0.272 mmol) was added, and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give (S)-4-(2-(2-(4-carboxyphenylsulfonamido)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (120 mg, 87% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:15][O:14]C(C)(C)[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:12])[CH2:15][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CCOCc2ccccc2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: OC[C@@H](O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
In methanol (50 ml) were dissolved (S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1,3-dioxolane (2.06 g, 8.73 mmol) and p-toluenesulfonic acid hydrate (1.68 g, 8.8 mmol), and the solution was stirred at room temperature for 24 hours. After removal of methanol in vacuo, aqueous saturated sodium hydrogen carbonate was added to neutralize the solution. The solution was extracted with ethyl acetete and the extract was washed with saturated brine, dried on sodium sulfate, filtered, and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-benzyloxy-1,2-butanediol (1.70 g, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][C:25]=3[F:27])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 102.5 °C
Yield: 94.8 %

Procedure:
Bis(tricyclohexylphosphine)palladium (250 mg, 0.375 mmol) was added to a stirred solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (4.6 g, 12.5 mmol) and 2,4-difluorophenylboronic acid (3.92 g, 25 mmol) in 125 mL dioxane. Argon was bubbled through the solution for 5 min. H2O (12.5 mL) was then added followed by dried, powdered potassium carbonate (3.45 g, 25 mmol). The mixture was heated to 100-105° C. under argon for 1 hr, cooled and distributed between 100 mL ethyl acetate and 100 mL H2O. The ethyl acetate layer was washed with saturated NaCl, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient of 0-5% ethyl acetate in hexanes to yield 4.2 g of 3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]([CH3:17])[CH2:15]O.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)([CH3:17])[CH3:15]
Reactant: c1c[nH]cn1
Reactant: CC(CO)c1ccc2c(c1)Cc1ccccc1-2
Product: CC(C)(c1ccc2c(c1)Cc1ccccc1-2)n1ccnc1

Procedure:
Using 2-(9H-fluoren-2-yl)propanol and imidazole as starting compounds, the process of Example 1 was repeated to obtain 1-[1-(9H-fluoren-2-yl)-1-methylethyl]-1H-imidazole.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:19]([C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])[CH:18]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirring solution of diisopropylamine (56.4 g, 0.55 mol) in THF (500 mL) at −40° C., n-butyl lithium (200 mL, 2.66 M hexane solution) was added dropwise. The mixture was stirred at −40° C. for 1 hour and then cooled to −78° C. Then, a solution of 4-fluorobromobenzene (87.5 g, 0.50 mol) in THF (100 mL) was slowly added dropwise thereto such that the inner temperature of the reaction solution did not exceed −70° C. After the reaction solution was stirred at −78° C. for 1 hour, a solution of ethyl trifluoroacetate (65.4 mL, 0.55 mol) in THF (100 mL) was added thereto at the same temperature. After the temperature of the reaction solution was raised to 0° C. over 1 hour under stirring, a saturated aqueous ammonium chloride solution was added thereto, and the solution was diluted with ethyl acetate. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4), and the resulting yellow oily substance was purified again by distillation under reduced pressure (1 mmHg, 53° C.), whereby the objective compound (83.8 g, 61.8%) was obtained as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:22])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:21])[CH3:20])[NH2:5].C([O-])(=O)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:22][C:7]1[CH:6]=[C:4]([NH:5][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:3]=[C:2]([Cl:1])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(N)cc3Cl)cc12
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(Cl)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Yield: 17.5 %

Procedure:
100 mg of 3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]aniline (Example IV) are heated to reflux with 49 mg of sodium acetate and 50 mg of ethyl bromoacetate in 5 ml of ethanol for 17 hours. A further 21 mg of ethyl bromoacetate are added and the mixture is refluxed for 2 hours. The solvent is removed in vacuo, the residue is taken up with water and dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried and the solvent is removed in vacuo. Chromatographic purification (cyclohexane/ethyl acetate) affords 22 mg of ethyl N-{3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl}glycinate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>Cl.O1CCOCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(CC2CCN(CC3CCCCN3)CC2)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
(+/−)-N-(t-butoxycarbonyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-piperidine (340 mg, 0.87 mmol) was dissolved in 4M HCl in dioxane (10 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was partioned between 10% NaOH and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, and conc. in vacuo to a white solid yielding 250 mg of product. MS (ESI) 291 (M+H).
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:3][NH:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1
Reactant: Cc1nc2ccc(N(C)C(=O)C(F)(F)F)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNc1ccc2nc(C)oc2c1
Yield: 81.2 %

Procedure:
To a solution of crude 2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (16.5 g, 63.0 mmol) in MeOH (440 mL) and water (73 mL) was added K2CO3 (35.3 g, 25.5 mmol). The reaction mixture was stirred at reflux for 3 h, then concentrated under vacuum, diluted with water (50 mL), extracted with EtOAc (2×50 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to obtain crude N,2-dimethylbenzo[d]oxazol-6-amine (8.3 g), (MS: ESI +ve, 163.12 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 2.51 (s, 3H), 2.56 (s, 3H), 5.87-5.85 (m, 1H), 6.57-6.53 (m, 1H), 6.65-6.64 (d, J=2.4, 1H), 7.31-7.28 (t, 1H).
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][CH2:5]2)[CH2:3]1.[CH2:22]([O:24][C:25]1[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH3:23]>CO>[CH2:22]([O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][CH2:5][C@:4]2([OH:6])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)([CH3:1])[CH2:3]2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: CCOc1ccc(N)cn1
Solvent: CO
Product: CCOc1ccc(NC[C@]2(O)CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)cn1
Temperature: 120 °C

Procedure:
A 5 mL microwave vial was charged with 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.533 mmol),6-(ethyloxy)-3-pyridinamine (221 mg, 1.599 mmol) and MeOH (4 mL). The reaction mixture was stirred and heated to 120° C. for 24 h. The reaction mixture was concentrated down to afford an oil. The oil was purified by silica gel (40 g) loading and initially elluting in DCM through to 6% MeOH/DCM over 18 column volumes to afford 1-{[(1S,3S)-3-({[6-(ethyloxy)-3-pyridinyl]amino}methyl)-3-hydroxy-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile as an colorless oil. MS (m/z) 420 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[CH3:12][O:13][CH2:14][C:15](=[O:17])[CH3:16]>O1CCCC1>[CH3:12][O:13][CH2:14][C:15]([CH3:16])([OH:17])[C:5]#[C:4][C:2]([CH3:3])([OH:6])[CH3:1]
Reactant: COCC(C)=O
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC(C)(O)C#CC(C)(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.3 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and to this solution, n-butyl lithium (1.6 molar solution in hexanes, 372 ml, 0.59 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of methoxyacetone (38 g, 0.43 mol) in tetrahydrofuran (50 ml) is added. The reaction mixture is stirred at −78° C. for one hour, allowed to come to ambient temperature, and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with ethyl acetate (3×250 ml), and the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-methoxy-2,5-dimethylhex-3-yne-2,5-diol (15 g) as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]2[N:11]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:9]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:8]=2[C:7](=[O:33])[N:6]([CH3:34])[C:5]1=[O:35].Cl.[CH3:37][NH:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:9]2[C:8]3[C:7](=[O:33])[N:6]([CH3:34])[C:5](=[O:35])[N:4]([CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])[C:12]=3[N:11]=[C:10]2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[CH:27][CH:28]=1
Reactant: CNC
Reactant: Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(CCBr)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)n(C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 14.5 %

Procedure:
To a solution of 3-(2-bromoethyl)-7-(4-chlorobenzyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 0.192 mmol) in DMF (3 mL) was added dimethylamine hydrochloride (150 mg, 1.84 mmol), followed by potassium carbonate (100 mg, 0.725 mmol). The mixture was stirred at 40° C. for 16 h; then it was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 7-(4-chlorobenzyl)-3-(2-(dimethylamino)ethyl)-1-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 13.3% yield) as white solid.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[C:17]=1[CH3:38])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:18]1[C:17]([CH3:38])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:39])([OH:33])=[O:32]
Reactant: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)O)cccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 300 mg (0.55 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 226 mg (95%) of the title compound as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 3-bromopropylcarbamate (0.5 g, 2 mmol) and 3,4-dichlorophenol (0.38, 2.3 mmol) in DMF (10.5 mL) was added Cs2CO3 (1.02 g, 3.10 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaCl and water (1:1), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to provide Intermediate 3A (543 mg, 56% yield). HPLC/MS (Method B) RT=3.85 min, [M+H]+ 320.2.