Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH:33]([C:37]#[N:38])[C:34]([NH2:36])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:37]#[N:38]
Reactant: N#CC(N)C(N)=O
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)C(N)=O
Reaction time: 1 h
Yield: 28.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-2-cyanoacetamide (4.59 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.4 min) to provide N-(2-amino-1-cyano-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.013 mmol, 28.6% yield) as a mixture of diastereomers. LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.50-7.80 (7 H, m), 5.40-5.63 (1 H, m), 5.27 (1 H, s); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4=[N:1][O:2][N:3]=[C:4]4[CH:9]=3)=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:15])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1Oc1ccc2nonc2c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.23) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[2,1,3]oxadiazol-5-yloxy)-nicotinic acid and (+)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6]CO.[CH2:10]1[O:18][C:17]2[C:12](=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=2)[O:11]1>C(O)(=O)C>[N+:19]([C:15]1[C:14]([N+:22]([O-:24])=[O:23])=[CH:13][C:12]([OH:11])=[C:17]([O:18][CH2:10][CH2:6][O:5][CH2:4][CH2:3][OH:9])[CH:16]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
0.4 mol (26.4g) of 85% pure potassium hydroxide pellets is added at 70° C. to 200 ml of diethylene glycol. 0.2 mol (42 4g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to this solution. The heating is maintained for 31/2 hours After dilution with ice-cold water and neutralization with 22 ml of acetic acid, the expected product precipitates. After being dried, it is recrystallized from 96° strength alcohol. It melts at 135° C. Analysis of the product gives the following results:
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=O)[CH2:5]1)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
To a solution of trans 3-azidocyclobutanecarboxylic acid (0.58 g, 4.1 mmol) in dichloromethane (10 ml) was added oxalyl chloride (0.45 ml) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (~2 h) and the solvent was evaporated in vacuo leaving a slightly yellow oil; 0.63 g, 95%, ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C--O of acyl chloride); 1Hmr (CDCl3) δ: 4.12 (1H, m, H-1), 3.6 (1H, m, H-3) and 3.1-2.1 ppm (4H, H-2, H-4).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=O)C.O.[NH2:14][NH2:15]>>[OH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([NH:14][NH2:15])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Reactant: NN
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](O)CC1

Procedure:
A mixture of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (5.0 g, 29 mmol) and hydrazine hydrate (1.4 g, 29 mmol) was heated at reflux for 24 h. Residual water was removed by azeotropic distillation with toluene. The residue was triturated from tert-butyl methyl ether. The precipitate was collected by filtration and dried in vacuo to give the title compound as white solid in 91% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17].[C:18]([OH:21])(=[O:20])[CH3:19].O>CCOCC.C([O-])(=O)C.[Ag+]>[C:18]([O:21][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)C2
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Temperature: 105 °C
Reaction time: 16 h

Procedure:
2-(2-Chloroethyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one (18.14 gm, 0.0619 mole), silver acetate (22.74 gm, 0.136 mole), acetic acid (225 ml) and water (2 ml) was stirred and heated at 105° C. internal temperature for 9 hours, then at ambient temperature for 16 hours. The mixture was diluted with ether, filtered and the solid washed with ethyl acetate. The combined filtrate and washing was evaporated in vacuo and the reside suspended in water then extracted first with a mixture of ether and tetrahydrofuran, then with methylene chloride and finally with ethyl acetate. The combined organic extracts were washed with water, then with brine and finally dried over MgSO4. The solvents were removed by evaporation in vacuo to give 12.9 g of residual solid. The solid was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 8.1 g of product, m.p. 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.CO>[Pd].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium on carbon (10% wt., 0.59 mg, 5.53 mol). The reaction was stirred at room temperature under a hydrogen balloon for 12 h after which the reaction was purged with nitrogen and filtered through Celite™. The remaining palldium was washed with DCM (30 mL) and the resulting solution was concentrated in vacuo to afford tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate (27 mg, 0.06 mmol, 100% yield) which was used without further purification. LC/MS (m/z, MH+): 491.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1C(=O)N([I:20])C(=O)C1>S(O)(C(F)(F)F)(=O)=O>[Br:1][C:2]1[C:11]([I:20])=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cc2ccc(Br)cc2cn1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: Clc1cc2ccc(Br)c(I)c2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 7-Bromo-3-chloroisoquinoline (1.5 g, 6.19 mmol) was added NIS (1.4 g, 6.9 mmol). The flask was placed in an ice bath and treated with TfOH (40 mL) and stirred at RT overnight. The reaction mixture was carefully poured into ice, and the aqueous layer was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (Hexanes:DCM→1:1) to provide the title product.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2cccc(Cl)c2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Temperature: 115 °C
Yield: 117.1 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(2, 3-dichlorophenyl)cyclohexen-3-one (1.5 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2 g) and granulated potassium hydroxide (330 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (70 mg), 30 minutes later; 1 hour later; and 1.5 hours, respectively. The reaction solution was stirred at the same temperature for 1 hour, cooled and concentrated under reduced pressure, and to the residue were added ethyl acetate (50 ml) and water (20 ml). The mixture was shaken and separated ethyl acetate layer was washed with brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.05 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][F:39]>C(#N)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:37][CH2:38][F:39])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH2:16][CH2:15]1
Reactant: FCCBr
Reactant: Fc1ccc(O[C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccc(F)cn3)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(5-fluoro-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and potassium carbonate (67 mg, 0.48 mmol) in acetonitrile (1.2 ml) was treated with 1-bromo-2-fluoroethane (37 mg, 0.29 mmol) at 0° C. The cooling bath was removed and the reaction mixture was heated at 70° C. over night. The mixture was filtered and concentrated in vacuo. Purification by flash column chromatography gave the title compound (17 mg, 15%) as white solid. MS m/e: 460 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:24][C@@H:23]([OH:25])[CH2:22][N:8]2[C:9](=[O:21])[N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:11]3=[O:12])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:24][C:23](=[O:25])[CH2:22][N:8]2[C:9](=[O:21])[N:10]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:11]3=[O:12])=[CH:26][CH:27]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of (6R,7aS)-7a-(4-bromobenzyl)-2-(3,5-dichlorophenyl)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (Preparation 4), (0.2 g, 0.42 mmol) in dichloromethane (5 mL) was added Dess-Martin periodane reagent (0.216 g, 0.504 mmol) in one lot at room temperature. The reaction mixture was stirred at room temperature for one hour and partitioned between dichloromethane (15 mL) and 1N NaOH (15 mL). The dichloromethane layer was washed with brine (2×20 mL), dried over sodium sulfate and concentrated to yield the title compound as a foamy solid (0.185 g). Retention time=3.84 min; column: YMC S5 Combiscreen ODS 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O and 0.2% H3PO4.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=O.B.C1COCC1.[NH4+].[Cl-].CCOCC>C1COCC1>[F:14][C:13]([F:15])([F:16])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][CH2:3][C:2]([F:1])([F:23])[F:22])=[CH:11][CH:10]=1)([OH:21])[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)C(F)(F)F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.5 %

Procedure:
A solution of 4.2 g (11.8 mmol) of 2,2,2-trifluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide in 30 mL of THF was treated with 24.2 mL of a 1M BH3.THF-complex solution in THF. The mixture was stirred for 72 hours at RT and then refluxed for 2 hours. After cooling to RT, the mixture was distributed between a saturated aqueous solution of NH4Cl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silicagel with n-heptane/EtOAc 4:1 yielded 3.0 g (74%) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol, light brown oil, MS: 342 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[F:15])=[O:5].[O:21]1CCOC[CH2:22]1>>[Br:20][C:18]1[CH:19]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:22](=[O:21])[NH:1]2)=[CH:16][CH:17]=1
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccc(I)cc1F
Reactant: C1COCCO1
Product: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(I)cc1F

Procedure:
A mixture of 2-amino-4-bromo-N-(2-fluoro-4-iodobenzyl)benzamide (3.80 g), N,N'-carbonyldiimidazole (5.5 g) and 1,4-dioxane (30 ml) was refluxed for 2 hours. The resulting crystals were collected by filtration, washed with 1,4-dioxane and dried over phosphorus pentoxide to give 7-bromo-3-(2-fluoro-4-iodobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.85 g).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:14])=[C:4]([S:15]([NH:18][CH:19]2[CH2:21][CH2:20]2)(=[O:17])=[O:16])[CH:3]=1.[C:22]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:8]1([CH2:7][N:6]2[C:2]([C:28]3[CH:27]=[C:26]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=3)=[CH:3][C:4]([S:15]([NH:18][CH:19]3[CH2:21][CH2:20]3)(=[O:17])=[O:16])=[C:5]2[CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Reactant: Cc1c(S(=O)(=O)NC2CC2)cc(Br)n1CC1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1c(S(=O)(=O)NC2CC2)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Yield: 9 %

Procedure:
The solution of compound 3d (600 mg, 1.60 mmol), (3,5-di-tert-butylphenyl)boronic acid (700 mg, 3.00 mmol), Pd(dppf)Cl2 (80 mg) and K2CO3 (483 mg, 3.50 mmol) in DMF (30 mL) was heated at 120° C. under N2 for 16 h. The resulting solution was concentrated, diluted with water and extracted with EA twice. The combined organic layers were washed with water (3×) and brine (3×) consecutively, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=10/1) to give compound 3 (70 mg, 10%) as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 0.58-0.66 (m, 6H), 0.95-1.00 (m, 3H), 1.34 (s, 18H), 1.30-1.35 (m, 3H), 1.40-1.55 (m, 3H), 2.32-2.35 (m, 1H), 2.54 (s, 3H), 3.73 (d, J=7.2 Hz, 2H), 4.69 (s, 11-1), 6.44 (s, 1H), 7.15 (s, 2H), 7.40 (s, 1H). MS Calcd.: 484; MS Found: 485 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[NH:5][C:6]2[NH:7][CH2:8][CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[NH:10][C:11]=2[C:12](=[O:14])[N:13]=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([N:10]1[CH:9]([CH:15]([OH:19])[CH:16]([OH:18])[CH3:17])[CH2:8][NH:7][C:6]2[NH:5][C:4]([NH2:3])=[N:13][C:12](=[O:14])[C:11]1=2)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Agent: Cl
Solvent: c1ccncc1
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
2-Amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (1.63 g, 5.2 mmol) was dissolved in 50 mL of pyridine under a nitrogen atmosphere. To this solution was added benzyl chloroformate (1.93 ml, 13.5 mmol). The reaction mixture was degassed under vacuum and placed under an atmosphere of nitrogen. The mixture was stirred for 12 h at room temperature. The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-titled compound as a white solid (0.93 g, 48% yield). 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 7.41-7.30 (m, 5H), 6.84 (s, 1H), 6.12 (s, 2H), 5.10-4.99 (m, 2H), 3.93 (d, J=6.0 Hz, 1H), 3.66 (dd, J=2.4 Hz, J=6.3 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=12 Hz, 1H), 3.25 (d, J=10.5 Hz, 1H), 3.03 (dd, J=4.5 Hz, J=12.4 Hz, 1H), 1.26 (d, J=6.3 Hz, 1H). MS: ESI (positive): 376 (M+H).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:17]1([C:22](=O)[CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([C:22](=[N:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)C1CCCC1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=N[C@H](C)c1ccccc1)C1CCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-1-Phenylethanamine (1.36 ml, 1.2 mmol) and triethylamine (7.46 ml, 53.5 mmol) were dissolved in DCM (30 ml) and cooled to 0° C. Titanium tetrachloride (0.49 ml, 4.46 mmol) was added, followed by the solution of 1-cyclopentyl-ethanone (1 g, 8.92 mmol) in DCM (5 ml). The reaction mixture was stirred 3 h at reflux temperature. After cooling to rt diethylether was added (130 ml) and the reaction mixture was filtered. The filtrate was collected and the solvents were evaporated at reduced pressure to give the product as yellow, viscous oil (2.04 g, crude quantitative). [1H-NMR (DMSO-d6, 600 MHz) δ 7.35 (d, 2H), 7.28 (t, 2H), 7.17 (t, 1H), 4.61 (q, 1H), 2.67-2.62 (m, 1H), 1.81 (s, 3H), 1.71-1.50 (m, 8H), 1.27 (d, 3H); LCMS RtL=2.706 min; [M+H]+=216.2]
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(Cl)cc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-chlorophenyl)propan-2-ol (1 g, 2.57 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.65 (d, 2H), 7.55 (s, 1H), 7.45 (d, 2H), 7.22 (s, 2H), 7.05 (s, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.86 (m, 1H), 3.60 (m, 1H), 3.16(m, 2H), 3.12 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[NH:34][C:35]([CH:38]([NH:41][C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])[CH2:39]O)=[N:36][CH:37]=4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].O1CCNC1.[CH:59]1([CH:62]2CN[C@H](C(O)=O)C2)[CH2:61][CH2:60]1.Cl>O1CCOCC1>[CH3:51][O:50][C:48](=[O:49])[NH:47][CH:43]([C:42]([N:41]1[CH:38]([C:35]2[NH:34][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:53])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:26][CH:25]=4)=[CH:32][CH:31]=3)=[CH:37][N:36]=2)[CH2:39][C:59]2([CH2:61][CH2:60]2)[CH2:62]1)=[O:52])[CH:44]([CH3:46])[CH3:45]
Reactant: COC(=O)NC(C(=O)NC(CO)c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: O=C(O)[C@@H]1CC(C2CC2)CN1
Agent: C1COCN1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
was prepared in a similar fashion to (1-{2-[5-(4′-{2-[2-Hydroxy-1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-ethyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, replacing the oxazolidine derived carboxylic acid with the corresponding 4-cyclopropyl-proline derivative and using HCl in dioxane for the Boc deprotection.