Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:3]=1[CH3:23].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.[NH3:29]>C(O)(C)C.[OH-].[Na+].C([O-])(O)=O.[Na+].CO>[NH2:29][CH2:24][CH:26]([OH:28])[CH2:27][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:3]=1[CH3:23]
Reactant: N
Reactant: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1O
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: Cc1cc(CCC(=O)c2scc(CC(C)C)c2C)cc(C)c1OCC(O)CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-isobutyl-3-methyl-thiophen-2-yl)-propan-1-one (317 mg, 0.96 mmol) in isopropanol (10 mL), 3 N aq. NaOH (2.5 mL) followed by epichlorohydrine (284 mg, 3.07 mmol) is added. The dark red mixture is stirred at rt for 16 h before it is diluted with sat. aq. NaHCO3 and extracted twice with diethyl ether. The organic extracts are washed with water, dried over Na2SO4, filtered and evaporated to give crude 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(4-isobutyl-3-methyl-thiophen-2-yl)-propan-1-one (339 mg) as a yellow oil. The material is dissolved in 7 N NH3 in methanol (7.5 mL) and the resulting solution is stirred in an autoklave at 65° C. for 2.5 h. The solvent is removed in vacuo and the residue is dried under HV to leave rac-3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3-methyl-thiophen-2-yl)-propan-1-one (353 mg) as an orange oil; LC-MS: tR=0.88 min, [M+1]=404.20; 1H NMR (CDCl3): δ 7.06 (s, 1H), 6.88 (s, 2H), 3.98-3.90 (m 1H), 3.85-3.73 (m, 2H), 3.15-3.07 (m, 2H), 3.00-2.84 (m, 4H), 2.47 (s, 3H), 2.42 (d, J=7.6 Hz, 2H), 2.25 (s, 6H), 1.83 (hept, J=7.0 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H).
Reaction SMILES: [OH:1][O:2][S:3]([O-:5])=[O:4].[K+:6].[O:7]=O.[OH:9][S:10]([O-])(=[O:12])=[O:11].[K+]>O>[S:3]([O:2][O:1][S:10]([O-:12])(=[O:11])=[O:9])([O-:7])(=[O:5])=[O:4].[K+:6].[K+:6]
Reactant: O=S(=O)([O-])O
Reactant: O=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reaction time: 408 h
Yield: 11.2 %

Procedure:
Comparative Example A was prepared as for the “Conventional Complete Solution” described in Table 2 of Example 1 of U.S. Pat. No. 6,818,142. A 11.2% potassium monopersulfate solution was prepared by dissolving OXONE (12.6 g) potassium monopersulfate in deionized water (100 g) at a temperature of 22° C. The OXONE was mixed until completely dissolved. The resulting solution produced was prepared below the saturation limit expressed in Table 1 above. The resulting solution contained 0.51% active oxygen, 5.00% KHSO5, 2.54% KHSO4, pH=1.2, 10.56% total dissolved solids (TDS), and a 0.15:1 weight ratio of AO/SO4. A rate constant was derived from the data in Table 2 of U.S. Pat. No. 6,818,142 and found to be k=0.0062. Using Equation 1 above, the value of t10% was 17 days, where t10% is the time it takes to loose 10% of the active oxygen.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.O>[OH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:3]=2[CH:2]=1
Reactant: OCCCc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 14 g (103 mmol) of 3-phenyl-1-propanol and 18.2 g (123 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 15 g (113 mmol) of aluminum chloride. After the addition of aluminum chloride was complete, the reaction was heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature and 100 mL of water was added, followed by 100 mL of 1N HCl. The reaction mixture was stirred for 2 hours, filtered through a Celite pad and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 13.45 g (53%) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([O:15]C)[C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.B(Br)(Br)Br>C(Cl)Cl>[C:11]([C:9]1[CH:8]=[C:7]([OH:15])[C:6]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1-c1ccc(Cl)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(O)c(-c2ccc(Cl)cc2)c(C(C)(C)C)c1
Temperature: 0 °C

Procedure:
A solution of 4.9 g (14.8 mmol) of the product of Step A in 30 mL of CH2Cl2 was placed in an external cooling bath containing dry ice and acetone and stirred under a nitrogen atmosphere. A 1.0 M solution of boron tribromide (20 mL, 20.0 mmol) in CH2Cl2 was added dropwise. After the addition was complete, the reaction mixture was stirred an additional 5 min then allowed to warn to room temperature. After stirring 1 h the reaction mixture was poured into 500 mL ice water and was stirred for 30 min. The aqueous layer was separated and extracted with 100 mL CH2Cl2. The organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 3% EtOAc-hexanes. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(Cl)Cl>[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:2][OH:3])=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)NO)cc1
Yield: 10.8 %

Procedure:
To a cold, stirring suspension of 1.2 gms hydroxylamine hydrochloride and 1.7 gms sodium carbonate in 40 ml CH2Cl2 was added dropwise 4.2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The mixture was stirred for 1/2 hr in the cold, then 2 ml water was added, and the reaction was stirred at room temperature overnight. The suspension was then diluted with CH2Cl2, washed three times with water and once with NaCl solution, then dried over MgSO4. The drying agent was filtered off and the solvent was removed in vacuo to give a solid which was crystallized from CHCl3 :hexanes and then hexanes. Impurities were still present by thin layer chromatography, so the solid was dissolved in 3:1 benzene:hexanes, shaken with 150 gms silica gel, and the silica gel washed with ethyl acetate. The solid remaining on evaporation of the solvent was purified by column chromatography on silica gel with 30% ethyl acetate:CHCl3. The main fraction had Rf=0.4 by thin layer chromatography. The residue from the collected fractions was crystallized twice from CH2Cl2 to give 0.45 gms product of m.p. 94°-6°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[CH:7]2.[H-].[Na+].[CH3:19]I>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:19])[N:8]=[CH:7]2
Reactant: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ncc2cccc(Br)c2n1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
8-Bromo-N-(tert-butyl)quinazolin-2-amine (374a) (40 mg, 0.14 mmol) in THF (4 mL) at 0° C. was treated with NaH (60% dispersion in mineral oil, 8.6 mg, 0.21 mmol) and stirred at 0° C. for 30 min. MeI (10.71 μl, 0.17 mmol) was added and the solution was warmed to RT overnight (16 h). The reaction mixture was treated with brine and extracted with EtOAc (50 mL), dried over MgSO4, filtered and concentrated. Purification on a silica gel column (0-50% EtOAc in hexanes) afforded the title compound (34 mg, 0.12 mmol, 82% yield) as yellow viscous oil. m/z (ESI, +ve ion) 294.0/296.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.75 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), tetrahydrofuran (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml tetrahydrofuran. The cis to trans ratio is 85 to 87/15 to 13. The amount of dehalogenated byproduct is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.75 to 0.78%].
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccn2)c2ccccc12
Product: O=Cc1c(N2CCNCC2)n(-c2ccccn2)c2ccccc12
Yield: 72 %

Procedure:
2-Chloro-1-(pyridin-2-yl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 2-(piperazin-1-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxaldehyde (72% yield) as an orange solid. ESI/MS 307 (M+H); RT 2.23 min; NMR 10.30 (1H, s); 8.75 (1H, m); 8.26 (1H, d, J=9 Hz); 7.98 (1H, m); 7.46 (5H, m); 3.30 (4H, m); 2.81 (4H, m).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1>ClCCl>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 22 h
Yield: 96.2 %

Procedure:
To a mixture of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4] benzodiazepine (1.44 g) and triethylamine (0.95 g) in dichloromethane (40 mL) cooled in an ice bath, was added dropwise a solution of the crude 4-bromo-2-chlorobenzoyl chloride (2.42 g) in dichloromethane (20 mL). The cooling bath was removed and after stirring for 22 hours, the reaction mixture was sequentially washed with water, saturated aqueous sodium bicarbonate, 0.5 N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered and then evaporated to dryness to yield an off-white foam. Purification by flash chromatography on silica gel Merck-60 eluting with hexane-ethyl acetate (2:1) resulted in a white solid (3.02 g), m.p. 77-80° C.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1C)(=O)C.[O:20]1[CH2:24][CH2:23]CC1.[OH2:25].O.[OH-].[Li+]>CO>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:23][C:24]([OH:20])=[O:25])=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)cc1C
Reactant: O
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of methyl-4-benzyloxyphenyl acetate (Compound 16, 12.08 g, 47.2 mmol) in a mixture of methanol (45 mL), tetrahydrofuran (40 mL) and water (15 mL) was treated with lithium hydroxide monohydrate (5 g, 119 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The precipitated solid in the reaction mixture was filtered and washed well with diethyl ether. The white solid was then dissolved in dilute, aqueous hydrochloric acid and the solution was extracted with ethyl acetate (×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (11 g, 96%).
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:29]N=[C:27]([CH3:30])[N:26]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:4])[CH3:3].FC(F)(F)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.[C:45]([O-])(O)=O.[Na+]>>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:29][C:30]([CH3:45])=[CH:27][N:26]=4)[CH2:22][N:21]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:3])[CH3:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])O
Reactant: Cc1noc(C2CNCC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)n1
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)o1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
A mixture of (4-isopropoxy-3-methyl-phenyl)-[10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt (28 mg, 0.06 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (14 μL, 0.09 mmol) and NaHCO3 (21 mg, 0.23 mmol) was heated at 80° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to room temperature, microfiltered and purified by Waters mass directed LC/MS: (10-99% ACN/H2O (5 mM HCl)) and concentrated to yield (4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (3 mg, 10%) as a white solid. ESI-MS m/z calc. 496.5. found 497.7 (M+1)+; Retention time: 1.99 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.27-7.06 (m, 2H), 6.96 (d, J=9.1 Hz, 1H), 5.17 (dd, J=13.6, 4.2 Hz, 1H), 4.63 (dt, J=12.1, 6.2 Hz, 1H), 3.31-3.19 (m, 5H), 2.92-2.81 (m, 1H), 2.67 (dd, J=12.0, 10.1 Hz, 1H), 2.43-2.27 (m, 6H), 2.15 (s, 3H), 1.70-1.40 (m, 4H), 1.29 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+].[OH-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:19])=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)O
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the commercially available 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (CAS No. 950-81-2) (51.6 g) in tetrahydrofuran (THF) (1 L) at 0° C. was added a solution of sulfamic acid (48.5 g) in water (640 mL). A solution of sodium chlorite (43.7 g) in water (500 mL) was added slowly maintaining the temperature below 8° C. The reaction mixture was allowed to warm to room temperature. After 5 hours, the pH of the reaction was adjusted to 8 with a 6 N aqueous solution of sodium hydroxide (NaOH). The mixture was extracted with ethyl acetate (EtOAc). The aqueous layer was acidified to pH 4 with a 6N solution of hydrochloric acid (HCl) and extracted with dichloromethane (DCM). The combined DCM extracts were washed sequentially with 5% aqueous sodium sulfite and saturated brine, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude solid was triturated with methanol (MeOH) to give the title compound (17 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.C(OC([NH:34][C@H:35]([C:39](O)=[O:40])[C@@H:36]([CH3:38])[OH:37])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C1COCC1>[NH2:34][C@@H:35]([CH:36]([OH:37])[CH3:38])[C:39]([N:23]1[CH2:22][CH2:21][N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)[N:19]=2)[CH2:25][CH2:24]1)=[O:40]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCNCC4)n3)ccc21
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(O)[C@H](N)C(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
200 mg (0.57 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]piperazine, 138 mg (0.629 mmol) of N-(tert-butoxycarbonyl)-L-threonine, 105 mg (0.69 mmol) of HOBt, 132 mg (0.69 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 291 μl (1.72 mmol) of DIPEA are dissolved in 5 ml of THF and stirred at room temperature for 18 h. The crude product was purified by column chromatography and silica gel, dissolved in dioxane, and an excess of 4N HCl in dioxane was added. The reaction mixture is stirred at room temperature for 12 h, evaporated and purified by means of preparative HPLC. The product is converted into the hydrochloride using methanolic HCl.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[Sn:13](Cl)([CH3:16])([CH3:15])[CH3:14].N#N>C1COCC1>[CH3:14][Sn:13]([CH3:16])([CH3:15])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)Cl
Agent: CC(C)[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cccnc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To anhydrous THF (100 ml) containing 3-bromo-pyridine (3.29 g, 20.82 mmol), were added 1.2 eq of iPrMgCl (12.49 ml, 2M in THF) and the resulting mixture was stirred for 2 hours under N2 (10° C.). Subsequently 1.2 eq of (CH3)3SnCl were added and the reaction mixture was stirred for 18 hours at room temperature (under N2). The reaction mixture was quenched with a saturated NH4Cl solution, diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-trimethylstannanyl-pyridine (71) (3.32 g, 66%). LCMS (method A): Rt: 2.09 min, ([M+H]+=242). 1H-NMR (400 MHz, CDCl3): δ 8.62 (bs, 1H), 8.52 (dd, J=5 Hz, 2 Hz, 1H), 7.76 (dt, J=8 Hz, 2 Hz, 1H), 7.25-7.21 (m, 1H), 0.33 (s, 9H), with Sn satellites at 0.41 and 0.27.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH3:27][C:20]([C:28]1[CH:29]=[C:30]([S:34]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)c1

Procedure:
(S)-Arginine (12.6 g) and K2CO3 (12.03 g) are suspended in 50% water/dioxan (250 ml) with vigorous stirring and the reaction mixture is cooled to <5° C. 3-(α,α-Dimethylbenzyl)benzenesulphonyl chloride (21.4g) is added in 6 portions over 30 minutes at <5° C. The mixture is stirred at 20° C. for 2 hours. A colourless solid precipitates. The dioxan is removed by evaporation and the aqueous residue is acidified with cone. HCl. The mixture is extracted with ethyl acetate (3×50ml) and the aqueous phase and all solid materials are combined and neutralised (4M NaOH). The suspension is stirred for 16 hours at 20° C. The solid precipitate is collected by filtration and stirred for 16 hours with a little water. The solid is collected by filtration and dried (NaOH pellets) to give Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-arginine, m.p. 122°-124° C. (Found: C, 53.49; H, 6.81; N, 11.92; S, 6.93. C21H28N4O4S.2.3H2O requires C, 53.22; H, 6.93; N, 11.82; S, 6.77%).
Reaction SMILES: C(OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.[CH:37]1([CH2:40][N:41]([CH2:74][CH2:75]O)[C:42]([C:44]2[C:49]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[C:48]([OH:58])[N:47]=[C:46]([CH2:59][C:60]3([N:65]4[C:69]5=[N:70][CH:71]=[CH:72][CH:73]=[C:68]5[CH:67]=[CH:66]4)[CH2:64][CH2:63][CH2:62][CH2:61]3)[N:45]=2)=[O:43])[CH2:39][CH2:38]1>>[CH2:51]([O:50][C:49]1[C:48](=[O:58])[N:47]=[C:46]([CH2:59][C:60]2([N:65]3[C:69]4=[N:70][CH:71]=[CH:72][CH:73]=[C:68]4[CH:67]=[CH:66]3)[CH2:64][CH2:63][CH2:62][CH2:61]2)[N:45]2[CH2:75][CH2:74][N:41]([CH2:40][CH:37]3[CH2:39][CH2:38]3)[C:42](=[O:43])[C:44]=12)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1CC1CC1

Procedure:
9-Benzyloxy-2-cyclopropylmethyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (415) was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (414) (130 mg, 0.24 mmol) and was obtained as white solid (56 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:10](=[O:12])[CH:11]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 1) (7.56 g, 19.6 mmol) in dioxane (30 mL) was added 2N NaOH (14.7 mL). Stirred at ambient temperature for 1 h. Concentrated to −20 mL under reduced pressure. Cooled to 0° C. and added 5% citric acid to precipitate solid, filtered the precipitate, rinsed with water, and dried in vacuo overnight. Obtained product as an orange solid (6.62 g, 91%). Used without further purification. 1H NMR (CD3OD/400 MHz) δ8.28 (s, 1H), 8.04 (m, 1H), 7.88 (s, 1H), 7.56 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 6.99 (m, 2H), 5.87 (s, 1H), 5.39 (s, 2H), 2.19 (s, 3H). ESHRMS m/z 373.1001 (M+H calculated for C19H15F2N2O4 requires 373.0994).