Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.C(O[K])(C)(C)C.[CH:11]1(/[CH:17]=[CH:18]/B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1>ICCC.O>[CH:11]1(/[CH:17]=[CH:18]/[C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(Br)cc1F
Reactant: OB(O)/C=C/C1CCCCC1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(C)O
Solvent: CCCI
Product: Nc1ccc(/C=C/C2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
Isopropanol (60 mL) was added to PEPPSI™-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added trans-(2-cyclohexylvinyl)boronic acid (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g).
Reaction SMILES: FC(F)(F)S(O[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=O)=O.[NH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[C:29]([NH:28][C@@H:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:38]=[CH:37][CH:36]=1)=[O:33]
Reactant: Cc1cccc(C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc2ccccc2)c1
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(N[C@@H](Cc2cccc(C)c2)C(=O)OCc2ccccc2)c1

Procedure:
A solution of benzyl (R)-2-trifluoromethanesulfonyloxy-3-(3-methylphenyl)-propionate (0.59 g, 1.47 mmol) and methyl 3-aminobenzoate (0.44 g, 2.94 mmol) in CH2Cl2 (20 mL) is stirred overnight at room temp for 2 days. Solvent is evaporated, and the residue is chromatographed (silica, 33% CH2Cl2/hexane) to yield benzyl (S)-2-(3-methoxycarbonylphenylamino)-3-(3-methylphenyl)-propionate, as a clear oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.ClCCl>[N:28]1([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:39]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:40])[CH2:11]2)=[O:27])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 93 μl of cyclopentanecarbonyl chloride (0.762 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 133 mg (57% of theory)
Reaction SMILES: [CH3:1]C1C=C(C2N=C3N(CC4CCOCC4)C(=O)NC3=NC=2)C=CC=1C1N=CNN=1.C[C:31]1[CH:32]=[C:33]([C:48]2[N:53]=[C:52]3[N:54]([CH2:58][CH2:59][CH:60]4[CH2:65][CH2:64][O:63][CH2:62][CH2:61]4)[C:55](=[O:57])[NH:56][C:51]3=[N:50][CH:49]=2)[CH:34]=[CH:35][C:36]=1[C:37]1[N:41]=[CH:40][N:39](C2CCCCO2)[N:38]=1.Cl>O1CCOCC1>[CH3:1][C:32]1[CH:31]=[C:36]([C:37]2[N:41]=[CH:40][NH:39][N:38]=2)[CH:35]=[CH:34][C:33]=1[C:48]1[N:53]=[C:52]2[N:54]([CH2:58][CH2:59][CH:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[C:55](=[O:57])[NH:56][C:51]2=[N:50][CH:49]=1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CC4CCOCC4)c3n2)ccc1-c1nc[nH]n1
Reactant: Cc1cc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)ccc1-c1ncn(C2CCCCO2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2nc[nH]n2)ccc1-c1cnc2[nH]c(=O)n(CCC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one. 6-(3-Methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one (0.283 g, 0.578 mmol) was added to 6.0 M hydrogen chloride in dioxane (4.0 mL) and stirred at 25° C. for 2 h. The solution was condensed under reduced pressure and purified using reverse-phase semi-preparatory HPLC (20-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined, neutralized with ammonium hydroxide, concentrated, diluted with water (20 mL). The desired product was collected by filtration to afford the title compound as an off white solid, 99.5% pure, (0.061 g, 26%). 1H NMR (400 MHz, CD3OD-d4) δ 8.40 (br. s., 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=8.20, 1H), 7.55 (d, J=8.20, 1H), 4.04 (t, J=7.22, 2H), 3.90 (dd, J=11.32, 3.51, 2H), 3.34-3.42 (m, 3H), 2.49 (s, 3H), 1.70-1.87 (m, 4H), 1.58 (dddd, J=10.93, 7.32, 4.10, 3.81, 1H), 1.50-1.66 (m, 1H), 1.22-1.40 (m, 2H); MS (ESI) m/z 408.5[M+1]+; mp 258-260° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O.C(O)(=O)C>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cccc(Oc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 84.3 %

Procedure:
3-phenoxybenzaldehyde (1.0 g) and 1-acetylpiperazine (739 mg) were dissolved in 1,2-dichloroethane (10 ml) and sodium triacetoxyboro hydride (1.72 g) and acetic acid (300 mg) were added. The atmosphere was replaced with argon and the mixture was stirred at room temperature for 6.5 hours. Water (5 ml) and saturated sodium hydrogen carbonate (20 ml) were added and the aqueous layer was extracted 5 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate. Chloroform was removed and the residue was purified by silica gel column chromatography (ethyl adetate-ethyl acetate:methanol=20:1-10:1) to obtain 1.32 g of 1-acetyl-4-((3-phenoxyphenyl)methyl)piperazine. Yield: 84%.
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C=C(C(O)=O)C=CC=3N=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=C(C(OC)=O)C=CC=3N=2)C=CC=CC=1.[Li+].[OH-].[ClH:40]>C1COCC1.CO.O>[C:7]([Cl:40])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Phenyl-benzooxazole-6-carboxylic acid, 1v. A mixture of methyl 2-phenyl-benzooxazole-6-carboxylate 1u (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1t (0.34 g).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC(=O)[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1)(C)(C)C.C(OC(=O)NC1CCCC(B2OC(C)(C)C(C)(C)O2)=C1)(C)(C)C>>[NH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][C:33]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[C:5]=3[O:4][CH:3]=2)=[CH:32]1
Reactant: CC(C)(C)OC(=O)NC1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)(C)OC(=O)NC1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CC(N)CCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting material 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and the mixture of [3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester and [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-2-enyl]-carbamic acid tert-butyl ester. 1H-NMR (CD3OD, 400 MHz): δ=1.48-1.82 (m, 2H), 1.88 (d, 3H), 1.91-2.16 (m, 2H), 2.38 (d, J=5.3 Hz, 2H), 3.72 (br. s., 1H), 6.21 (br. s., 1H), 6.48 (qd, J=6.7, 2.5 Hz, 1H), 7.02-7.14 (m, 1H), 7.38 (dd, J=8.8, 4.8 Hz, 1H), 7.63 (s, 1H), 8.22 (s, 1H). MS (ES+): m/z 436.03 (MH+, 35Cl, 37Cl), 437.96 (MH+, 37Cl, 37Cl). HPLC: tR=2.38 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]#N.CC(O)C.[OH-:23].[K+].[OH2:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]([OH:25])=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC#N)c1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC(=O)O)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of (2-chloro-5-(Boc-amino)phenyl)acetonitrile (5.2 g; 20 mmol; from step (iii) above) in water:i-PrOH (37 mL; 2:1) was added KOH (5 g; 89 mmol), and the solution was refluxed overnight. The mixture was subsequently concentrated, water:THF (50 mL; 1:1) and Boc2O were added, and the mixture was stirred overnight. The THF was evaporated, the water phase was washed with ether (1×50 mL), made acidic with HCl (dilute) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, dried (Na2SO4) and concentrated, yielding 2.8 g (50%) of the sub-title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]([F:28])([F:27])[C:13]1[C:14]([N:19]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32].Cl>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:25][C:24]([C:22]1[CH:21]=[N:20][N:19]([C:14]2[C:13]([C:12]([F:11])([F:27])[F:28])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:23]=1)=[O:26]
Reactant: CC(=O)c1cnn(-c2ncccc2C(F)(F)F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cnn(-c2ncccc2C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 201.4 %

Procedure:
Alternatively, lithium bis(trimethylsilyl)amide (1.0M solution in THF, 1.1 mL, 1.1 mmol) was slowly added to a solution of 1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone (240 mg, 0.94 mmol) in 2 mL anhydrous THF at −78° C. under nitrogen. The mixture was then allowed to warm to −20° C. and kept at −20° C. to −5° C. for 3 hrs. After this period of time the mixture was cooled to −78° C. and to it was added ethyl trifluoroacetate (200 mg, 0.41 mmol). The mixture was next allowed to warm to ambient temperature overnight. 1N aqueous HCl was carefully added to adjust the pH 2. Two layers were separated and the aqueous layer was extracted with chloroform three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 4,4,4-trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione as a yellow solid (290 mg, 88% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 6.35 (s, 1H), 7.59 (dd, 1H, J=4.80, J=7.83), 8.21 (s, 1H), 8.28 (dd, 1H, J=1.77, J=3.80), 8.75 (dd, 1H, J=4.80, J=1.77), 8.76 (d, 1H, J=0.51)
Reaction SMILES: [C:1]1([P:7](N=[N+]=[N-])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2.C1(C)C=CC=CC=1>O1CCCC1.O>[C:1]1([P:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
Alternatively, compounds of formula (16) can be (a) treated with diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as, but not limited to toluene, at a temperature of about 0° C. to about 50° C.; and (b) treated with the asides obtained from step (a) with triphenylphosphine in a mixture of tetrahydrofuran and water and at about the reflux temperature of the solvent, to provide compounds of formula (18).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nnc2ccc3nc(O)c(O)nc3c21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c21
Yield: 65 %

Procedure:
Finely powdered potassium nitrate (0.71 g, 7 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-1-methyl-lH-1,2,3-triazolo[4,5-f]quinoxaline (1.52 g, 7 in 28 ml of conc. sulfuric acid at 0° C. After about 1 h the ice bath was removed and stirring was continued over night at room temperature. Then an additional amount of potassium nitrate (0.7 g) was added and the mixture was stirred for 4 h at room temperature. Now the solution was poured into 150 ml of ice/water and the precipitated yellow solid was isolated by filtration and washed with water. Recrystallization from water/ethanol (1:1) afforded 1.2 g (65%) of the pure nitro compound; m.p. >300° C.; IR (KBr): 3600-2500, 1720 cm-1 ; lH-NMR (DMSO-d6) 4.62 (s,3H, CH3), 8.07 (s, lH, ArH), 12.4 (broad s, lH, OH, only one exchangeable proton could be seen).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].N12CCCN=C1CCCCC2.[F:22][CH:23]([F:42])[O:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32](C2C=CC=CC=2)[C:33](=O)[O-:34])[N:26]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:33]([NH:32][C:27]1[N:26]=[C:25]([O:24][CH:23]([F:42])[F:22])[CH:30]=[C:29]([CH3:31])[N:28]=1)=[O:34])(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccccn1
Reactant: Cc1cc(OC(F)F)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2ccccn2)n1
Reaction time: 6 h
Yield: 42.3 %

Procedure:
To a solution of 0.52 g of 2-pyridinylsulfonamide and 0.55 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of absolute dioxan is added 1 g of N-(4-difluoromethoxy-6-methylpyrimidin-2-yl)-phenylcarbamate. The reaction mixture is stirred for 6 hours at 20°-25° C., then taken up in water and acidified with 2N hydrochloric acid. The precipitate is isolated, washed with water and recrystallised from a mixture of acetone/ether, affording 0.5 g (42.4%) of N-(2-pyridinylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 1.1) with a melting point of 150°-151° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:19]2[CH2:18][C@H:17]3[N:20]([CH2:22][CH2:23][C@@:9]45[C@H:16]3[CH:15]=[CH:14][C@H:12]([OH:13])[C@@H:10]4[O:11][C:7]([C:8]=25)=[C:5]([OH:6])[CH:4]=1)[CH3:21].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].II>O.CO>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:6][C:5]2[CH:4]=[CH:3][C:19]3[CH2:18][C@H:17]4[N:20]([CH3:21])[CH2:22][CH2:23][C@:9]56[C:8]=3[C:7]=2[O:11][C@H:10]5[C@@H:12]([OH:13])[CH:14]=[CH:15][C@@H:16]46)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.5 g (37.5 mmol) of NaH (60% dispersion in mineral oil) was rinsed with 2×25 mL of hexanes to remove the oil. To the reaction mixture was added 140 mL of anhydrous DMF followed by 10.1 g (35 mmol) of morphine. This mixture was allowed to stir at room temperature for 30 minutes under nitrogen atmosphere, and 14.5 g (53 mmol) of N-(3-bromopropyl) phthalimide was added. The reaction mixture was allowed to stir 18 h at room temperature. The reaction was monitored by thin layer chromatography (silica, 7:2:1:1, MeOH:EtAc:NH40H:H2O, I2 visualization), which showed that the reaction was incomplete. To the reaction mixture 0.15 g (3.75 mmol) of NaH (60% in oil) was added, and the mixture was allowed to stir for an additional 1.5 h. The mixture was poured into 350 mL of ice-water and extracted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2×250 mL of ethyl acetate. The organic layers were combined and washed with 2×150 mL of water, 150 mL of 1N NaOH and 2×150 mL of water. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized with diethyl ether to give 12.9 g (27.3 mmol, 77%) of the desired product 13 as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][NH:29][CH3:30].C1COCC1>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([N:29]([CH3:30])[CH3:28])[S:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Reactant: CNC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(N(C)C)n3)n2)ccc(C#N)c1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide (0.247 g, 0.531 mmol) was added into a microwave test tube with dry pyridine. The mixture was bubbled with nitrogen and dimethylamine 2 M in THF (1.329 ml, 2.66 mmol) was added. The reaction mixture was heated with microwaves at 120° C. for 10 h. The crude product was evaporated, diluted with DCM, washed with 1M Na2CO3 and water. The product was purified with Flash-chromatography. Yield 63.2%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.53 (s, 3H), 3.00 (s, 6H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.55 (m, 1H), 6.41 (d, 1H), 7.30 (d, 1H), 7.52 (m, 3H), 7.74 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH2:14][C@@H:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([CH2:22][C@@H:13]([NH:12][C:8]([C:5]2[O:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=2)=[O:10])[CH2:14][C@@H:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1ncc(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)o1

Procedure:
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 22, (68 mg, 0.47 mmol) in DMF (2 mL) and DCM (2 mL) is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (150 mg, 0.43 mmol), HATU (246 mg, 0.65 mmol), and triethylamine (180 μL, 1.29 mmol). After stirring the reaction for 2 hours at room temperature, the reaction is quenched with H2O, and the crude is diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxyoxazole-5-carboxamido)-2-methylpentanoate (175 mg). HPLC retention time=1.71 minutes (condition A); MS 437.5 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J=7.1 Hz, 3H) 1.25 (t, J=7.1 Hz, 3H) 1.65 (ddd, J=14.3, 10.0, 4.3 Hz, 1H) 1.96-2.10 (m, 1H) 2.63 (ddd, J=9.4, 7.1, 4.2 Hz, 1H) 2.92 (dd, J=13.9, 6.3 Hz, 1H) 2.99 (dd, J=13.9, 6.3 Hz, 1H) 4.11 (s, 3H) 4.12-4.18 (m, 2H) 4.34-4.54 (m, 1H) 6.15 (d, J=8.8 Hz, 1H) 7.28 (d, J=8.3 Hz, 2H) 7.31-7.37 (m, 1H) 7.40-7.47 (m, 3H) 7.54 (d, J=8.3 Hz, 2H) 7.59 (dd, J=8.3, 1.26 Hz, 2H)
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[BH3-][C:15]#N.[Na+].C=O.Cl>CO.O>[CH3:15][N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCc2c([nH]c3ccccc23)C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-β-carboline (0.50 g, 2.9 mmol) and NaCNBH3 (0.44 g, 7.0 mmol) were added to a round bottomed flask, dissolved in MeOH (35 mL), and treated with 3.23 mL of a 27% solution of formaldehyde in water. This mixture was stirred for 2 h, after which, 2N HCl (50 mL) was added, followed by stirring for 15 min. The mixture was taken to pH=11 by addition of concentrated, aqueous NaOH and extracted with methylene chloride (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The product was purified by MPCC (0-10% gradient of MeOH in CH2Cl2), giving the title compound (511 mg, 95%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.39 (d, 1H, J=7.7 Hz), 7.27 (d, 1H, J=8.0 Hz), 7.05 (t, 1H, J=7.5 Hz), 6.96 (t, 1H, J=7.7 Hz), 3.68 (s, 2H), 2.86 (m, 4H), 2.53 (s, 3H). 13C NMR APT (100 MHz, CD3OD): δ 136.1 (up), 131.7 (up), 127.2 (up), 121.2 (down), 119.2 (down), 117.9 (down), 110.8 (down), 107.8 (up), 53.0