Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(O[CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31])(OP(OP(O)(O)=O)(O)=O)(=O)O.[Mg+2].[Cl-].[Cl-].N[C@H](C(O)=O)CCSC.[F-:44].[K+]>>[F:44][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[OH:31]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: [F-]
Agent: CSCC[C@H](N)C(=O)O
Agent: [Cl-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CF)[C@@H](O)[C@H]1O
Temperature: 90 °C

Procedure:
For purification of the organofluorine product, a cell-free extract (15 ml) was prepared as described before and incubated with ATP (5 mM), MgCl2 (15 mM), L-methionine (0.2 mM), potassium fluoride (10 mM) for one day at 26° C. After that time the biotransformation mixture was heated at 90° C. for 10 minutes and denatured protein was removed by centrifugation. The supernatant was lyophilised the resultant powder was dissolved in H2O (2 ml) and remaining solids were removed by centrifugation. The clear supernatant (100 μL) was applied to a Hypersil 5 μm C-18 column (250×10 mm, Phenomenex) and eluted isocratically (potassium phosphate buffer (50 mM)/acetonitrile, 95.5) at a flow rate of 5 ml/min. Detection was by UV at 260 nm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.COC(C)(C)C.CC(C)([O-])C.[Na+].[CH3:76][NH:77][CH:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[N:7]=[C:2]([N:77]([CH3:76])[CH:78]2[CH2:79][CH2:80][N:81]([C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[CH2:82][CH2:83]2)[CH:3]=[N:4][CH:5]=1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CN(c1cncc(-c2nn(C3CCCCO3)c3ccc(-c4c(F)cccc4F)cc23)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a glass microwave vial was added 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.200 g, 0.469 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 6.57 mg, 0.014 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dipropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (6.57 mg, 0.014 mmol), RuPhos precatalyst (10.28 mg, 0.014 mmol), and sodium tert-butoxide (0.144 mL, 1.174 mmol). The vial was placed under vacuum and flushed with argon. tert-Butyl 4-(methylamino)piperidine-1-carboxylate (0.121 g, 0.563 mmol, CNH Technologies) and THF (1.565 mL) were added and the reaction mixture was stirred at 85° C. overnight. Reaction was cooled to RT. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 100% EtOAc in hexane. The desired tert-Butyl 4-((6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate was obtained and then treated with 5-6 M HCl in IPA. The reaction mixture was heated at 80° C. for 1 h and then contracted to dryness. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 15% to 100% over 15 min. The title compound was obtained. MS (ESI, pos. ion) m/z: 421.1 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][C:15]1=[O:26].C(N(CC)CC)C>ClCCl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][C:15](=[O:26])[N:14]([CH2:13][CH:12]=[O:11])[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)N(CCO)C(=O)CO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CC=O)C(=O)CO2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in dichloromethane (10 mL) at −70° C. was added a solution of dimethyl sulfoxide (DMSO, 0.426 mL, 6.0 mmol) in dichloromethane (10 mL). After thirty minutes a solution of 4-(2-hydroxyethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 126, 550 mg, 2.5 mmol) in dichloromethane (3.5 mL) was added dropwise and it was stirred for 90 minutes. Triethyl amine (1.74 ml, 12.5 mmol) was added it was stirred at −70° C. for another 45 minutes. The reaction was quenched with water and warmed to 0° C. It was diluted with dichloromethane, the aqueous phase was extracted with dichloromethane (3×25 mL) and the combined organic phases were washed with 1N HCl (2×25 mL), water (25 mL), 1M sodium carbonate solution (2×25 mL), water, brine, dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with dichloromethane/methanol (96:4) gave the product as a yellow oil, 292 mg (53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25]C2CCCCO2)[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:32]C2CCCCO2)[CH2:12][C@H:11]1[Cl:39].C(O)(=O)C.O.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:25])[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:32])[CH2:12][C@H:11]1[Cl:39]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](Cl)C[C@H]1O

Procedure:
319 mg of methane sulfonic acid chloride is added at 0° C. to a solution of 1.00 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis-(tetrahydropran-2-yloxy)-4,13-prostadienic acid methyl ester in 10 ml of pyridine. It is stirred for 4 hours at 20° C. and the solution is added to a suspension of 9.99 g of tetrabutylammonium chloride in 10 ml of toluene. After 15-hours stirring at 0° C., it is stirred for another 7 hours at 40° C. Then it is added to 100 ml of ice water and extracted three times with 50 ml each of ether. After the organic phase is washed twice with 20 ml of brine, dried over MgSO4 and is concentrated by evaporation in a vacuum a residue is obtained which is chromatographed on silica gel with hexane/0-40% ether. 839 mg of oily (4Z,13E)-(9R,11R,15R)-9-chloro-16,16-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester is obtained. For cleavage of the protecting groups, the resulting ester is stirred with 31 ml of a mixture of acetic acid/water/ tetrahydrofuran (65/35/10) for 24 hours at 20° C. After addition of toluene and concentration of the solution by evaporation in a vacuum the residue is chromatographed on silica gel. With toluene/0-10% isopropanol as eluant, 326 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.25-3.29 (m, 4H), 3.73-3.77 (m, 4H), 4.16 (s, 3H), 6.55-6.59 (m, 3H), 7.21-7.43 (m, 3H), 7.78-7.83 (m, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([CH3:39])[CH:38]=2)=[CH:29][CH:28]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:40]#[N:41])=[CH:35][CH:36]=[C:37]([CH3:39])[CH:38]=4)=[CH:29][CH:28]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: Cc1ccc(C#N)c(-c2ccc(CO)cc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(hydroxymethyl)-5-methylbiphenyl-2-carbonitrile (1.5 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (2 g, 85%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12](=O)[NH:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.N>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:15]2=[CH:16][CH:17]=[CH:18][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Agent: BrBr
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 53.5 %

Procedure:
(S)-tert-Butyl (4-(benzyloxy)-1-oxo-1-((2-(phenylcarbamoyl)-1H-pyrrol-1-yl)amino)butan-2-yl)carbamate (1.57 g, 3.19 mmol) was treated with triphenylphosphine (1.17 g, 4.46 mmol), bromine (229 μl, 4.47 mmol), triethylamine (1.78 mL, 12.77 mmol) and a solution of ammonia solution (7M in methanol, 150 mL, 1000 mmol) according to the method of Preparation 5b. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 0.81 g (53.5%) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][C:34](=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH:34]([OH:36])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1
Reactant: O=C1CC(c2ccccc2Cl)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccccc1Cl)O2

Procedure:
2-(2-Chlorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.12 g of 2(2-chlorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 7.63 (dd, 1H, J 7.7, 1.8 Hz), 7.49 (dd, 1H, J 7.8, 1.4 Hz), 7.45-7.36 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.8 Hz), 6.56 (dd, 1H, J 8.9, 2.9 Hz), 5.39 (dd, 1H, J 11.7, 1.5 Hz), 4.90 (m, 1H), 2.33 (m, 1H), 1.82 (m, 1H).
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH:7]([N+:10]1[CH2:14][CH2:13][CH2:12][C:11]=1OC)([CH3:9])[CH3:8].[CH3:17][NH:18][CH3:19]>C1C=CC=CC=1>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:17][N:18]([CH3:19])[C:11]1[CH2:12][CH2:13][CH2:14][N+:10]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CNC
Reactant: COC1=[N+](C(C)C)CCC1
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)[N+]1=C(N(C)C)CCC1
Reaction time: 1.5 h

Procedure:
161 g of 1-isopropyl-2-methoxy-1-pyrrolinium methyl sulfate are added dropwise, with stirring, to a solution of 43.8 g of dimethylamine in 283 ml of benzene. Subsequently, boiling under reflux is effected for 1.5 hours; the heavy phase is separated off and washed 4 times with, in each case, 50 ml of diethyl ether. After drying under a high vacuum, 154 g (91% of theory) of the title compound (as a reddish oil) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].[H-].[Na+].CN(C=O)C.[N+:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl.CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:36][C:35]1[CH:38]=[CH:39][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Yield: 92.9 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one, 0.132 g of sodium hydride as a 60% dispersion in oil, 5 ml of DMF and 0.741 g of 4-nitrobenzyl bromide. Chromatography on silica using a DCM/hexane mixture (80/20; v/v) and then DCM as the eluent gives 1.32 g of the expected product after crystallization from a DCM/ iso ether mixture. M.p.=189°-193° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH2:21]([O:25][C:26]1[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1)[C:22]#[C:23][CH3:24]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH2:21][C:22]#[C:23][CH3:24])=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: CC#CCOc1cnc(C(=O)O)cn1
Product: CC#CCOc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid [G. Csjernyik et al. WO2012087237 (2012)] following General Procedure F yielded the title compound as a white solid. MS: m/z=466.5 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH:23]([C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)[OH:24]>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:21][CH2:22][CH:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[OH:24])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: NCC(O)c1ccco1
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Product: CC(C)(C(=O)NCC(O)c1ccco1)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 75 %

Procedure:
Prepared in a similar manner to Example 3 starting from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and 2-amino-1-(furan-2-yl)ethanol. Yield: 75%. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 6H), 3.26 (m, 1H), 3.41 (m, 1H), 4.63 (t, 1H), 5.45 (br-s, 1H), 6.21-6.22 (d, 1H), 6.35 (t, 1H), 7.34 (t, 3H), 7.35-7.37 (dd, 2H), 7.54-7.55 (d, 1H), 7.71-7.73 (dd, 2H), 8.61 (t, 1H), 8.97-8.98 (d, 1H), 9.15-9.16 (d, 1H). MS (M+H, 358).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCCCNC(=O)OCc2ccccc2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(O)c2ccccc12)OCc1ccccc1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
Tetrabutylammoniumfluoride (1.0 M in THF, 1.1 mL) was added to a solution of benzyl 4-[4-(tert-butyldimethylsilyloxy)naphthalen-1-yl]butylcarbamate (19, 500 mg, 1.1 mmole) in THF (5 ml) at room temperature. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, 3:1 hexanes/EtOAc) to afford carbamate 20 (230 mg, 61%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.25 8.21 (m, 1H), 7.91 (dd, J=6.6, 1.8 Hz, 1H), 7.52-7.43 (m, 2H), 7.35-7.27 (m, 5H), 7.05 (d, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 5.10 (s, 2H), 4.75 (br s, 1H), 3.23 (q, J=6.6 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 1.76-1.56 (m, 4H).
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:18]([NH:20][C:21]([C:24]([O:26]C)=[O:25])([CH3:23])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>C1COCC1.O>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:18]([NH:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C(=O)O
Temperature: 22 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A solution containing about 260 mg of compound 7 and 91.5 mg of LiOH monohydrate in 7.5 ml of THF/H2O (2:1) was stirred at 22° C. for about 3 hours. The organic solvent was evaporated and the aqueous solution was extracted with Et2O (2×10 ml) and then acidified to a pH of less than 1 with 1 N HCl. The mixture was extracted again with Et2O (3×10 ml) and the combined organic extracts were dried over Na2SO4 and evaporated to yield about 240 mg of Boc-Tyr(OBn)-Aib-OH. A solution containing about 200 mg of Boc-Tyr(OBn)-Aib-OH in 10 ml of dry CH3CN was treated at 0° C. with 95 mg of DCC and stirred for about 2 hours. After filtration through florosil, the solution was evaporated to dryness. The resulting crude product (8) was dissolved in 2 ml of dry THF and added at -78° C. to a mixture of 130 mg of compound 4 and 165 μM of a 1.5 M solution of N-BuLi in hexanes in 4 ml of dry THF. After addition of about 13 mg of DMAP, the cold bath was removed and the reaction mixture stirred at 22° C. for about 2 hours. The solvent was evaporated and 4 ml of water added. After extraction with CH2Cl2 (3×10 ml), the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on SiO2 (EtOAc/hexanes, 1:1) to yield about 285 mg of compound 9.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][C:33]2[CH:32]=[CH:31][C:28]3[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=3[N:34]=2)[C@H:3]([OH:23])[CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CN[C@H]3CCN(CCn4c(=O)ccc5c(F)cc(F)cc54)C[C@H]3O)nc2N1
Yield: 70.9 %

Procedure:
Cis(±)1-{2-[4-amino-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (175 mg, 0.54 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (96 mg, 0.54 mmol) and sodium triacetoxy borohydride (344 mg, 1.6 mmol) were reacted as described for Example 1 to give 186 mg (71%) of the free base of the product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27]([N:29]3[CH2:34][CH2:33][S:32](=[O:43])[CH2:31][CH2:30]3)=[O:28])[CH2:11]2)[O:7][N:6]=1
Reactant: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COCCc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 39.8 %

Procedure:
113 mg (0.227 mmol) of the compound from Example 47A were reacted according to General Method 1 with 70.4 mg (0.204 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 108 mg of the racemate according to Method 9D gave 37.1 mg of the title compound from Example 46 (Enantiomer 1) and 41.8 mg of the title compound from Example 47 (Enantiomer 2).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1>CO.[H][H].[C].[Pd]>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: [H][H]
Reactant: N=C(N)n1nc(C=Cc2ccccc2)cc1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)n1nc(CCc2ccccc2)cc1N
Yield: 62.9 %

Procedure:
0.1 g of 10% palladium-carbon were added to a solution of 0.6 g of 5-amino-3-(2-phenylethenyl)-1H-pyrazole-1-carboxamidine hydrochloride in 40 ml of methanol and stirred for 30 minutes in hydrogen atmosphere of normal pressure at room temperature. The reaction solution was filtered to remove the insoluble solids therefrom, and the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from ethanol-ether to obtain 0.38 g of 5-amino-3-(2-phenylethyl)-1H-pyrazole-1-carboxamidine hydrochloride.