Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH2:8][CH2:9][OH:10])([CH3:7])[CH2:4][O:3]1.CCN(CC)CC.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:10][CH2:9][CH2:8][C@@:5]2([CH3:7])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OC[C@](C)(CCO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@]2(C)COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 4 and Et3N in DCM was added TsCl dropwise. The resulting mixture was stirred at 0° C. for 30 min. The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 5.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:4].O>C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([Br:1])[CH:14]=1)[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1ccc(OC)c(Br)c1

Procedure:
87.5 g of bromine are added dropwise at 25° C. over 3 hours to a solution of ethyl3-(4-methoxyphenyl)propanoate (113.9 g; 0.545 mol) in 900 ml of chloroform. The mixture is poured into water and the organic phase is separated out by settling of the phases and washed with 10% sodium hydrosulfite solution. After drying and evaporating off the solvents, a yellow oil is collected (154 g; 98%).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(#N)C>[N:20]1([C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][CH2:16]2)=[O:19])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(CCc1ccccc1)N1CCNCC1
Agent: Cl
Solvent: CC#N
Product: O=C(CCc1ccccc1)N1CCN(C(=O)n2ccnc2)CC1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
1-(3-Phenylpropanoyl)piperazine hydrochloride (1.0 g) was dissolved in acetonitrile, and 1,1′-carbonyldiimidazole (950 mg) was added thereto at room temperature, followed by stirring at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.13 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[N:18]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[C:17](=[O:26])[C@@H:16]2[CH2:27][CH2:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[OH:30])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([NH2:41])[C:39]#[CH:40].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[NH2:41][CH2:38][C:39]#[C:40][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)[C@@H:16]([CH2:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[OH:30])[C:17]2=[O:26])=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Reactant: C#CCN
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 8 mg (0.013 mmol, 1 equiv.) (3R,4S)-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)azetidin-2-one (intermediate step A) in 0.5 mL DMF was added 2.2 mg (0.002 mmol, 0.15 equiv.) tetrakistriphenylphosphine palladium(0) and 0.8 mg (0.004 mmol, 0.3 equiv) copper(I) iodide. The solution was deoxygenated by a slow stream of anhydrous nitrogen delivered by a needle through a rubber septum. To the resulting solution was added by syringe 0.012 mL (0.177 mmol, 14 equiv.) propargyl amine and 0.012 mL (0.09 mmol, 7 equiv.) triethylamine. The resulting solution was stirred at room temperature for 1.25 hr at which time the solvent was removed under vacuum. The residue was purified by prep. Tlc eluting with CH2Cl2/MeOH (9/1) to afford the title compound. m/z (ES) 559.3 (MH+), 542.3 (MH−NH3+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[N:16][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nnn(Cc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.6 %

Procedure:
A solution of 438 mg (1.7 mmol) of 1-(t-butoxycarbonyl)-4-(1H-tetrazol-5-yl)piperidine (from Step B) in 2 mL of DMF at 0° C. was treated with 83 mg (0.50 mmol) of sodium hydride (60% in mineral oil) and 0.41 mL (3.4 mmol) of benzyl bromide. The resulting mixture was warmed to rt and stirred for 2.5 h. The mixture was partitioned between 50 mL of ether and 50 mL of water and the layers were separated. The organic layer was washed with 50 mL sat'd brine, dried over magnesium sulfate and concentrated. Flash chromatography using 2:1 v/v methylene chloride/ether, then 1:2 v/v methylene chloride/ether afforded 85 mg (15%) of 1-(t-butoxycarbonyl)-4-(2-(benzyl)-(2H)tetrazol-5-yl)piperidine. Elution with 2:1 v/v ethyl acetate/methylene chloride afforded 95 mg (17%) of 1-(t-butoxycarbonyl)-4-(1-(benzyl)-(1H)-tetrazol-5-yl)piperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35]>>[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH3:35]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc2cc(O)ccc2n1C
Product: COc1cc2c(Oc3ccc4c(c3)cc(C)n4C)ncnc2cc1OCCCN1CCOCC1
Yield: 73.4 %

Procedure:
Using an analogous procedure to that described in Example 120 OR 121 PER PP, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.48 mmol), (prepared as described for the starting material in Example 1), was reacted with 1,2-dimethyl-5-hydroxyindole (92 mg, 0.57 mol), (Tetrahedron 1994, 50, 13433), to give 4-(1,2-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (163 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: CC(=O)N1CSC[C@@H]1C(=O)O
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 331 mg (0.85 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 8.5 ml of dichloromethane, 149 mg (0.85 mmol) of (S)-3-acetylthiazolidin-4-carboxylic acid, 376 mg (0.85 mmol) of BOP reagent and 0.16 ml (0.95 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 305 mg of 2-(((S)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C(OC(=O)C)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[O:14][C:12](=[O:13])/[C:11](=[C:16](/[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)\[CH3:15])/[N:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CNC(=O)c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: C/C(=C1/N=C(c2cccnc2Cl)OC1=O)c1ccc([N+](=O)[O-])cc1
Yield: 20.8 %

Procedure:
A mixture of 2-{[(2-chloro-3-pyridinyl)carbonyl]amino}acetic acid (6.44 g, 30 mmol, prepared from glycine and 2-chloronicotinoyl chloride), 4-nitroacetophenone (2.48 g, 15 mmol), lead (IV) acetate (3.33 g, 7.5 mmol) and acetic anhydride in THF (30 ml) was heated at reflux for 4 days. The mixture was poured onto crushed ice, the solid filtered off, washed with water and dried. The brown solid was triturated twice with boiling ethanol and filtered off to give the title compound as a brown solid (1.07 g). δH (CDCl3), 8.57 (1H, dd, J 4.8, 2.1 Hz, PyH), 8.34-8,29 (3H, m, ArH+PyH), 8.05 (2H, d, J 9.1 Hz, ArH), 7.41 (1H, dd, J 7.9, 4.8 Hz, PyH) and 2.84 (3H, s, Me).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: CCc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (461 mg, 1.2 mmol)[prepared according to Preparation 6] and diisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317 mmol) in one portion. The solution was stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:11]([O-:14])(=[S:13])[CH3:12].[K+].O>CN(C)C=O>[C:11]([S:13][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])(=[O:14])[CH3:12]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)CCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)CCCSC(C)=O
Yield: 96.7 %

Procedure:
Allyl 4-bromobutyrate (19.7 g) was treated with potassium thioacetate (10.9 g) in dimethyl formamide (100 ml) at 20° C. for 2 hours. Water (500 ml) was added and the mixture extracted with diethyl ether. The ethereal solution was washed with dilute aq. HCl, brine, dried (MgSO4) and evaporated to give the title compound as an oil (18.6 g, 97%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(N(C(C)C)C(C)C)C>C1COCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=3)[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 53.6 %

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-acetamide (419) (3 g, 11.72 mmol) and Fmoc-Cl (3.1 g, 12 mmol) were combined and dissolved in THF (60 mL). iPr2EtN (18 mmol, 1.2 equiv.) was added and the mixture was heated to 80° C. for 15 minutes while stirring. TLC indicated complete reaction at this point. The mixture was poured into ice-water (500 mL) and a white solid precipitated. The solid was collected by filtration under reduced pressure followed by drying under high vacuum to give the desired product (420) as a white powder (3 g, 6.28 mmol, 54% yield). LC-MS (ESI): (exact mass: 478.19) m/e=479.2 [M+1]+ (70%), 957.6 [2M+1]+ (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[C:4]([F:14])[CH:3]=1.S(OC)(O[CH3:19])(=O)=O.N.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:19])[N:9]=2)=[C:4]([F:14])[CH:3]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2F)n[nH]1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: N
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
50 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole from Example 1.1 were initially charged in 1500 ml of toluene. 35.5 g of dimethyl sulfate were then added, and the mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was made alkaline using ammonia, stirred overnight and acidified by addition of hydrochloric acid. The mixture was then cooled to 0° C., and the precipitated solid was filtered off. After drying, 49.4 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole were obtained as crude product (purity according to NMR about 80%, impurity essentially starting material), which was purified by recrystallization from toluene to >95% purity. Yield 49.4 g, 74.1%. M.p.: 204° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15]C(=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][F:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.O.[OH-].[Na+]>[NH2:15][C@@H:14]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:10]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:11]([CH2:19][F:20])[CH2:12][C@@H:13]1[OH:17]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](CF)C[C@@H]1O
Yield: 96.7 %

Procedure:
A mixture of (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-6-(fluoromethyl)hexahydrobenzo[d]oxazol-2(3H)-one (410 mg, 1.065 mmol) in ethanol (8 mL), water (8 mL) and 5 N NaOH (4 mL) was heated at reflux for 2 h. After cooling, the reaction was diluted with water (50 mL), extracted with DCM (3×25 mL) and dried with Na2SO4. The solvent was evaporated to give (1S,2S,3R,4R,5S)-2-amino-3,4-bis(benzyloxy)-5-(fluoromethyl)cyclohexanol as a white solid (370 mg, 97%) which was pure enough for next reaction. MS m/z 382.2 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.29-7.39 (m, 10H), 5.03 (d, J=11.4 Hz, 1H), 4.91 (d, J=10.9 Hz, 1H), 4.78 (ddd, J=48.0 Hz, 9.0 Hz, 3.0 Hz, 1H), 4.67 (d, J=10.9 Hz, 1H), 4.65 (d, J=11.4 Hz, 1H), 4.37 (ddd, J=47.4 Hz, 9.1 Hz, 2.0 Hz, 1H), 3.88 (br s, 1H), 3.58 (t, J=9.4 Hz, 1H), 3.48 (t, J=9.9 Hz, 1H), 2.11-2.26 (m, 1H), 1.95 (dt, J=14.3 Hz, 3.1 Hz, 1H), 1.63 (t, J=13.6 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.CS(C)=O.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>O>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)nc1
Temperature: 80 °C
Yield: 88.4 %

Procedure:
To a solution of 4-[2-(pteridin-4-ylamino)ethyl]phenol (270 mg, 1.0 mmol) and dry DMSO (5 mL) was added 2-chloro-5-trifluoromethylpyridine (155 mg, 0.85 mmol) and K2CO3 (280 mg, 2.0 mmol). This mixture was heated to 80° C. for 3 h, cooled to ambient temperature, poured into H2O (20 mL) and extracted with CH2Cl2 (20 mL). The CH2Cl2 solution was washed with H2O (2×10 mL), dried with Na2SO4, and the solution was filtered. The solution was concentrated in vacuo, redissolved in a minimum volume of CH2Cl2 and treated with hexane to precipitate a solid. The solid was collected by filtration and dried under vacuum to afford pteridin-4-yl-{2-[4-(5-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine (310 mg) as an off-white solid: mp 147-150° C.; 1H NMR (300 MHz, CDCl3) δ 9.04 (d, J=1.9 Hz, 1H), 8.85 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.40-7.29 (m, 3H), 7.22 (dd, J=5.2, 0.8 Hz, 1H), 7.19-7.05 (m, 3H), 4.01 (dd, J=13.3, 7.0 Hz, 2H), 3.10 (t, J=7.1 Hz, 2H); ESIMS m/z 413 ([M+H]+).
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]([CH2:29][CH2:30][S:31]([N:34]1[CH2:39][CH2:38][NH2+:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])=[O:28].[Cl-]>>[CH3:25][O:26][C:27](=[O:28])[CH2:29][CH2:30][S:31]([N:34]1[CH2:35][CH2:36][N:37]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C@H:18]3[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]3)=[O:9])=[N:15][CH:14]=2)[CH2:38][CH2:39]1)(=[O:32])=[O:33]
Reactant: COC(=O)CCS(=O)(=O)N1CC[NH2+]CC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: [Cl-]
Product: COC(=O)CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)[C@H]3CC[C@H](C)CC3)s2)CC1

Procedure:
Prepared in 60% (342 mg) yield as described in general procedure (B) from trans-1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea (349 mg, 1.0 mmol) and 4-(2-methoxycarbonyl-ethanesulfonyl)-piperazin-1-ium; chloride (273 mg, 1.0 mmol).
Reaction SMILES: ClCCl.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([OH:11])=[O:10].Cl.C(N=C=NCCCN(C)C)C.[OH:24][CH:25]([CH3:29])[C:26](=O)[CH3:27]>O>[O:24]=[C:25]([CH3:29])[CH:26]([C:6]1[CH:7]=[CH:8][O:4][C:5]=1[C:9]([OH:11])=[O:10])[CH3:27]
Reactant: CC(=O)C(C)O
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)C(C)c1ccoc1C(=O)O
Yield: 99.9 %

Procedure:
The dichloromethane (150 mL) solution of furan-2-carboxylic acid (11.2 g, 100 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (28.8 g, 150 mmol), N,N-dimethylaminopyridine (1.2 g, 10 mmol), and acetoin (9.69 g, 110 mmol) was stirred at room temperature for 5 hrs. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 3-oxobutan-2-yl furan-2-carboxylic acid (18.2 g, 100%) as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[CH2:19][CH2:20][CH3:21])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:37])[CH3:36].N1C=CC=CC=1>ClCCl>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([CH:2]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:34][N:33]=[N:32][N:31]=4)[CH:25]=3)[NH:1][C:35](=[O:37])[CH3:36])=[CH:4][CH:5]=2)=[C:10]([CH2:19][CH2:20][CH3:21])[C:11]=1[OH:18])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of 1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (80 mg, 0.175 mmol), acetyl chloride (15 μL, 0.211 mmol) and dichloromethane (1.5 mL) is stirred at room temperature. Pyridine (50 μL, 0.62 mmol) is added and the mixture is stirred at room temperature 24 hr. An additional portion of acetyl chloride (20 μL, 0.28 mmol) is added and the reaction is stirred an additional 24 hr. The reaction mixture is purified as is via reversed phase C18 preparative chromatography eluting with 4:6 acetonitrile:water (0.1% trifluoroacetic acid) to 8:2 acetonitrile:water (0.1% trifluoroacetic acid) to give the title compound (53 mg, 61%), as a white solid. 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 8.92 (d, 1H), 8.03 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.36-7.61 (m, 6H), 6.73 (d, 1H), 6.23 (d, 1H), 5.25 (s, 2H), 2.59-2.62 (m, 5H), 1.97 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1=498.