Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:62])([CH3:61])[C@H:3]([N:45]1[CH2:49][CH2:48][N:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([N+:57]([O-])=O)[CH:52]=2)[C:46]1=[O:60])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5]>C(O)C.[Pd]>[NH2:57][C:53]1[CH:52]=[C:51]([CH:56]=[CH:55][CH:54]=1)[CH2:50][N:47]1[CH2:48][CH2:49][N:45]([C@@H:3]([C:2]([CH3:61])([CH3:1])[CH3:62])[C:4]([NH:6][C@@H:7]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:8]([OH:37])[CH2:9][C@@H:10]([NH:24][C:25]([C@@H:27]([NH:32][C:33](=[O:36])[O:34][CH3:35])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:17]=2)=[O:5])[C:46]1=[O:60]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc([N+](=O)[O-])c2)C1=O)C(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(N)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution containing the product from Example 125C (0.077 g, 0.091 mmol) in ethanol (2 mL) was treated with 10% Pd on carbon (0.029 g), stirred under an atmosphere of hydrogen (balloon pressure) at 25° C. for 3 hours, filtered and concentrated under reduced pressure. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA. The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.035 g, 47% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.89(s, 9H), 1.60-1.49(m, 2H), 2.38-2.28(m, 1H), 2.62-2.53(m, 1H), 2.68-2.66(m, 2H), 2.86-2.76(m, 2H), 2.98-2.89(q, J=9.19 Hz, 1H), 3.20-3.14(m, 1H), 3.50(s, 3H), 3.70-3.62(m, 1H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.07(s, 1H), 4.14(s, 2H), 4.25-4.10(m, 2H), 4.55-4.53(d, J=7.35 Hz, 1H), 5.03(s, 2H), 6.42-6.39(d, J=7.35 Hz, 1H), 6.48-6.66(m, 2H), 6.62-6.59(d, J=9.93 Hz, 1H), 7.01-6.96(t, J=7.91 Hz, 1H), 7.11-7.04(m, 5H), 7.24-7.21(d, J=8.09 Hz, 2H), 7.33-7.28(m, 1H), 7.40-7.37(d, J=9.19 Hz, 1H), 7.91-7.80(m, 5H), 8.64-8.63(d, J=4.41 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH2:11]([C@H:13]1[O:15][CH2:14]1)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C@@H:13]2[O:15][CH2:14]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: ClC[C@@H]1CO1
Reactant: COc1cc(Cl)ccc1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 36 h
Yield: 81.7 %

Procedure:
To a reaction vessel were added 4-chloro-2-methoxyphenol 20.0 g (126 mmol), (S)-epichlorohydrin 23.3 g (252 mmol), benzyl trimethylammonium chloride 0.585 g (3.15 mmol), toluene 40 mL and water 40 mL. To this mixture was dropped an aqueous 24% NaOH solution 31.5 g (189 mmol) in an ice bath, and the mixture was stirred at room temperature for 36 hours. The water layer was removed and the organic layer was washed with an aqueous 5% HCl solution and a 5% NaCl solution successively. The organic layer was taken and the solvent was evaporated to give crude (R)-glycidyl 4-chloro-2-methoxyphenyl ether 22.1 g (yield 87%, chemical purity 93%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:10][O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][O:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(N)CO1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A solution of 4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic acid tert-butyl ester (694 mg, 1.86 mmol) and PhSH (0.142 ml, 1.1 equiv) in MeCN (10 ml) under argon at room temperature was treated with K2CO3 (386 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (10/0 then 9/1) afforded 336 mg of the title amine (1.8 mmol, 96%). 1H-NMR (CDCl3, 400 MHz): 4.03-3.92 (m, 3H), 3.89-3.76 (m, 1H), 3.70 (dd, 1H), 3.37 (dd, 1H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].C(O[CH:14]=[C:15]([C:21](=[O:32])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([Cl:30])[C:23]=1F)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O>C(Cl)(Cl)Cl>[Cl:30][C:24]1[C:25]([F:29])=[C:26]([F:28])[CH:27]=[C:22]2[C:23]=1[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=1)[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]2=[O:32]
Reactant: COc1cc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) with ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate synthesized from ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (2.8 g) in accordance with a method known per se in the art dissolved therein. The reaction mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (2.7 g) and N,N-dimethylformamide (6 ml) were added to the residue, followed by stirring at 90° C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (80 ml) and distilled water (300 ml) were added to the reaction mixture, thereby conducting liquid separation. A chloroform layer was washed twice with distilled water (300 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.98 g) as a colorless powder.
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:15]([NH:23][C:24](=[O:46])[NH:25][C:26]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([O-:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Pd].C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:15]([NH:23][C:24](=[O:46])[NH:25][C:26]1[CH:41]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)O
Reaction time: 3 h

Procedure:
A mixture of benzhydrol 2-[2[3-(octyl)ureido]-4-trifluoromethylphenoxy)-benzoate (290 mg, 0.00047 mol) and 10% palladium on carbon (100 mg) in ethyl acetate was hydrogenated in a parr bottle, at 55 psi for three hours. The mixture was diluted with chloroform, filtered through Celite and the filtrate evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to give the title compound. 1H NMR (250 MHz, CD3OD) δ8.52 (d, 1H), 7.95 (dd, 1H), 7.6 (tt, 1H), 7.35 (tt, 1H), 7.14 (dd, 2H),6.7 (d, 1H), 3.15 (t, 1H), 1.3 (s, 14H) 0.85 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:11]2[C:19]3[O:18][CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]([F:20])[CH:12]=2)[OH:10])=[CH:4][N:3]=1>C(OC(=O)C)C.[O-2].[Mn+2]>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[C:19]3[O:18][CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]([F:20])[CH:12]=2)=[O:10])=[CH:4][N:3]=1
Reactant: OC(c1cnc(Cl)nc1Cl)c1cc(F)cc2ccoc12
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=C(c1cnc(Cl)nc1Cl)c1cc(F)cc2ccoc12
Reaction time: 3.5 h
Yield: 908.9 %

Procedure:
At 20° C., a solution of (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanol (0.9 g, 0.29 mmol, Step D) in ethylacetate (110 mL) was treated with a slurry of manganese oxide (9.0 g, Aldrich) in ethyl acetate (110 mL). After stirring for 3.5 hours, the reaction was filtered through celite and solvent removed in vacuo to give 0.82 g of (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanone as a foam and taken to the next step.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:49][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)(=[O:46])=[O:47]
Reactant: c1ccc(OC2CCCCO2)c(CNc2ccc(OCCN3CCCC3)cc2)c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccccc2OC2CCCCO2)c2ccc(OCCN3CCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.5 %

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[2-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.19 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.43 mmol) and 2-mesitylene sulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g), PS-trisamine resin (0.050 g), and 1.5 mL methylene chloride were added and the mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford the title compound of Step A (0.039 g). MS 579.3 (M+1)+
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN.[CH3:31]O>[Ni]>[NH2:25][C:21]1[CH:20]=[C:19]2[C:24]([C:16]([C:13]3[CH2:14][CH2:15][CH:10]([N:2]([CH2:1][CH3:31])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:11][CH:12]=3)=[CH:17][NH:18]2)=[CH:23][CH:22]=1
Reactant: CO
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(N)ccc23)CC1

Procedure:
A solution of compound 127 (0.2 g, 0.518 mmol) in dry MeOH (3 mL) was treated with Ra—Ni (0.02 g) followed by hydrazine hydrate (0.16 mL, 5.188 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 2 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2×15 mL). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to obtain compound 130 as a foam. 1H NMR (DMSO-d6) δ 1.08 (t, 3H, J=6.9 Hz), 1.41 (s, 9H), 1.72-1.89 (m, 2H), 2.18-2.60 (m, 4H), 3.10-3.20 (m, 2H), 4.01 (brs, 1H), 4.71 (s, 2H), 6.02 (brs, 1H), 6.39 (dd, 1H, J=1.5, 8.5 Hz), 6.51 (d, 1H, J=1.8 Hz), 6.99 (d, 1H, J=2.1 Hz), 7.43 (d, 1H, J=8.4 Hz), 10.44 (s, 1H); ESI-MS (m/z, %): 378 (M+Na, 8), 356 (MH+,4), 300 (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.C=O.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37]1>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[NH:36][CH:37]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: c1ccc2[nH]ccc2c1
Agent: C=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccccc34)CC1)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
A mixture of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (170 mg, 0.564 mmol, Intermediate 1 free base), AcOH (0.039 ml, 0.67 mmol), and HCHO (35% in H2O, 0.055 ml, 0.67 mmol) in MeOH (8 ml) and dioxane (2 ml) was stirred at RT for 20 min and then treated with indole (94 mg, 0.80 mmol). The resulting solution was stirred at RT overnight and then further HCHO (0.02 ml) was added. After heating at 50° C. for 4 h, the solvent was evaporated and the residue was dissolved with DCM and washed with 5% aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, evaporated and the crude product was purified by column chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.4) to give (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester as a white solid (140 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[OH:21])[CH:17]=[CH:16][N:15]=1.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH2:39][S:40][CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])([CH3:35])([CH3:34])[CH3:33].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[OH:21][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:3]2[CH:4]=[C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:45]([C:44]2[CH:43]=[C:42]([CH:50]=[CH:49][CH:48]=2)[CH2:41][S:40][CH2:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:51])=[O:46])[CH:19]=1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of mg of (2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)(3-(trifluoromethyl)phenyl)-methanol 5.2c, and 41 mg of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c, 67 mg of diisopropylethylamine in 1.5 mL of DMF was treated with 57 mg of HATU. After stirring at 60° C. for 2 h the mixture was diluted with ethyl acetate and washed once with a saturated aqueous solution of sodium bicarbonate, three times with water, and once with brine. After drying (Na2SO4) the solvent was evaporated to give 107 mg of product. MS (ES, m/z) 706.2 [M+H]+.
Reaction SMILES: CN(C)CCCNS([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH:27]=[CH2:28])[C:20](=[O:29])[N:19]([CH2:30][CH:31]=[CH2:32])[C:18]=3[N:17]=2)=[CH:12]C=1)(=O)=O.Cl>>[CH:13]1([C:16]2[NH:24][C:23]3[C:22](=[O:25])[N:21]([CH2:26][CH:27]=[CH2:28])[C:20](=[O:29])[N:19]([CH2:30][CH:31]=[CH2:32])[C:18]=3[N:17]=2)[CH2:12][CH2:10][CH2:15][CH2:14]1
Reactant: C=CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCCN(C)C)cc3)nc2n(CC=C)c1=O
Agent: Cl
Product: C=CCn1c(=O)c2[nH]c(C3CCCC3)nc2n(CC=C)c1=O

Procedure:
N-[3-(dimethylamino)propyl]-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-di-2-propenyl-1H-purine-8-yl)benzenesulfonamide, or the monohydrochloride salt thereof and
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[N:11]([CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(I)c(CBr)cn1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Combine 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.45 g, 1.4 mmol), sodium azide (370 mg, 5.7 mmol), and 18-crown ether (45 mg, 0.17 mml) in dimethylformamide (10 mL) in a round bottom flask. Stir the mixture for 4 hours at room temperature. Dilute the reaction mixture with chloroform, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent in vacuo to give a crude product. Purify the crude with flash column chromatography (eluted with 20% methyl acetate in hexane) to give the title compound (colorless oil, 0.0.32 g, 82%). MS (ES) m/z 279 [M+1]+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]([OH:27])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:48][CH2:47][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:45][CH2:44]1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:25]([N:43]2[CH2:44][CH2:45][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:48]2)=[O:27])=[CH:15][CH:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
11.14 g (30 mmol) of N-(benzyloxycarbonyl)-O-(1,1-dimethylethyl)-L-tyrosine were dissolved in 65 ml of ethyl acetate while warming to 40°. The solution was treated at 20° with 0.1 g (0.9 mmol) of N-hydroxysuccinimide. Subsequently, a solution of 7.5 g (36 mmol) of dicyclohexylcarbodiimide in 40 ml of ethyl acetate was added dropwise at 22° within 25 minutes. A white suspension formed during the addition and this was stirred for 30 minutes. A solution of 7.8 g (36 mmol) of t-butyl (4-piperidinyloxy)acetate in 100 ml of ethyl acetate was then added dropwise to the suspension within 30 minutes. A suspension formed and this was stirred at 22° for 3 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 2N hydrochloric acid, water and semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. The residue was a viscous oil and weighed 18.5 g. The oil was diluted with a mixture of 10 ml of ethyl acetate and 60 ml of hexane and warmed to 50°. The insoluble solid was filtered off under suction and the filtrate was treated with 20 ml of hexane and seeded with a small amount of crystalline product at 30°. The mixture was cooled to 0° within one hour and stirred at this temperature for 30 minutes. The crystals were then filtered off under suction and washed on the filter with 20 ml of hexane. 14.5 g (85%) of benzyl [(S)-p-t-butoxy-α-[[4-[(t-butoxycarbonyl)methoxy]-piperidino]carbonyl]phenethyl]carbamate were obtained in this manner. Its content was 96% according to HPLC.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.[C:20]([O:24][C:25]([C:27]1([CH2:30][CH:31]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:20]([O:24][C:25]([C:27]1([CH2:30][CH2:31][N:14]2[CH2:13][CH2:12][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:17][C:7]=4[S:8][CH:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)csc2c1
Reactant: CC(C)(C)OC(=O)C1(CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a solution of 4.2 g (14.7 mmol) of 1-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazine in 100 mL of dichloromethane under nitrogen was added 3.5 g (19.1 mmol) of 1-(2-Oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester. After stirring 10 minutes at room temperature 6.5 g (30.7 mmol) of sodium triacetoxyborohydride was added portion-wise. After 30 minutes 100 mL of 0.5 N aqueous sodium hydroxide was added and the reaction was stirred for 15 minutes. The organic layer was separated, dried and concentrated to deliver a paste. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 6.6 g (13.4 mmol) of the desired product as a white powder mp=187-9° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]2[O:16][CH2:17][O:18][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([NH2:13])=[CH:11][C:10]2[O:16][CH2:17][O:18][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1cc2c(cc1N)OCO2
Yield: 98.8 %

Procedure:
The solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (0.8 g, 3.13 mmol) in ethyl acetate (25 mL) was subjected to catalytic hydrogenation using 10% palladium on carbon (100 mg) at 50 psi for 30 min. The catalyst was filtered and the solvent was removed under reduced pressure to give 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethane as a solid (0.69 g, 98% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].Cl.[CH3:20][C:21]1[CH:25]=[C:24]([NH2:26])[S:23][N:22]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:26][C:24]1[S:23][N:22]=[C:21]([CH3:20])[CH:25]=1)#[N:18]
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Cl
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C#N)sn1
Reaction time: 20 h
Yield: 128.9 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (86 mg, 0.323 mmol), 3-methylisothiazol-5-amine hydrochloride (70 mg, 0.464 mmol), K2CO3 (130 mg, 0.942 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. EtOAc and H2O were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (143 mg).