Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47]Cl)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C>CC#N>[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][N:11]([CH2:10][CH2:9][CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21)C(=O)OC(C)(C)C
Yield: 76.5 %

Procedure:
Using the General Procedure for N-alkylation: A solution of (2S)-2-(tert-butoxycarbonylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoic acid tert-butyl ester (0.700 g, 1.67 mmol), 1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.690 g, 2.59 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) in CH3CN (16 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (50:1 CH2Cl2—MeOH) provided 0.830 g (77%) of 2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a tan foam.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]#[N:19]>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][CH2:17][C:18]#[N:19])[CH3:2]
Reactant: CCc1c(O)cc(C)c2sccc12
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(OCC#N)cc(C)c2sccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
4-Ethyl-7-methyl-benzo[b]thiophen-5-ol (438 mg, 2 mmol) was dissolved in 10 ml DMF, and the reaction mixture was cooled to zero degrees C. Sodium hydride (66 mg, 3 mmol) was added and the reaction mixture was stirred 30 minutes at zero C. Bromoacetonitrile (170 ul, 3 mmol) was added, and the reaction mixture was stirred 10 minutes at zero degrees C., then allowed to warm to room temperature. The reaction was quenched after 1 hour at room temperature with water, diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. Solvent was removed in vacuo, and the residue chromatographed (10% ethyl acetate in hexanes) to give 422 mg of (4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-acetonitrile as an oil, 80%.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]O)=[CH:4][CH:3]=1.[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)(Cl)(Cl)[Cl:29]>>[Br:1][C:2]1[O:6][C:5]([CH2:7][Cl:29])=[CH:4][CH:3]=1.[C:22]1([P:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCc1ccc(Br)o1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(Br)o1
Temperature: 75 °C

Procedure:
To a solution of (5-bromo-2-furanyl)methanol (Example 310A) (144 mmol) in dry carbon tetrachloride (30 mL) was added triphenylphosphine (6.0 g, 228 mmol) at rt. The reaction is heated at 75° C. for 1 h. Concentration and purification by radial chromatography (0-10% EtOAc-hexanes gradient) afforded the title compound with contamination of triphenylphosphine. The product is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:4][CH2:3]1
Reactant: CC1=CC[C@@H](C(C)(C)O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCC(C(C)(C)O)CC1
Yield: 94.9 %

Procedure:
α-Terpineol (6.17 g) in ethanol (130 ml) was hydrogenated for 1 h at atmospheric pressure using 10% Pd-C catalyst (290 mg). The catalyst was then removed by filtration through Kieselguhr and the solvent was removed under reduced pressure to leave the title compound as an oil (5.93 g). Distillation gave an oil (4.56 g) b.p. (13 mm) 98°; νmax (film) 3375, 2940, 1445, 1160, 1140, and 910 cm-1 ; δH (60 MHz, CDCl3) 0.6-2.0(m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[N:8]([C:10]([O:12][CH3:13])=[O:11])[NH:9][C:41](=[O:42])[NH:14][C:6]=2[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1
Reactant: COC(=O)N(N)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1NC(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 60 °C
Reaction time: 5 h
Yield: 42.1 %

Procedure:
56 mg (0.132 mmol) of the compound obtained in example 56A were initially charged in 3 ml of dimethylformamide, and 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added. After 5 h at RT, another 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added and the mixture was heated to 60° C. The next day, another 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added and the mixture was heated to 60° C. for 2 further days. The reaction mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 25 mg of the title compound were obtained (42% of theory).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][P:4]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)([O:5][CH2:6][CH3:7])=[O:3])[CH3:10]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29; Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @0.05 Torr) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[O:21]=[C:22]1[CH2:27][CH2:26][C:25]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[C:3]([NH:34][C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22](=[O:21])[CH2:27][CH2:26]1)=[O:4]
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz).
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.CON(C)C([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)=O>C1COCC1>[CH3:21][S:20][C:16]1[N:17]=[C:18]([C:7](=[O:6])[CH3:8])[CH:19]=[CH:14][N:15]=1
Reactant: CON(C)C(=O)c1ccnc(SC)n1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CSc1nccc(C(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in diethyl ether (3.0 M, 6.10 mL, 18.3 mmol, 3.0 equiv) was added to a solution of N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1-2, 1.30 g, 6.10 mmol, 1 equiv) in THF at −78° C. The reaction mixture was warmed to 0° C., stirred for 30 minutes, then partitioned between brine and ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1-[2-(methylthio)pyrimidin-4-yl]ethanone (1-3) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, 1H, J=4.9 Hz), 7.51 (d, 1H, J=4.9 Hz), 2.70 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[S:41][C:22]3=[N:23][C:24]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:25][C:26](=[O:27])[N:21]3[N:20]=2)[CH:16]=[N:17][CH:18]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([C:19]2[S:41][C:22]3=[N:23][C:24]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:25][C:26](=[O:27])[N:21]3[N:20]=2)[CH:14]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cncc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1cncc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-(5-(2-(tert-butoxycarbonylamino)acetamido)pyridin-3-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (20 mg, 0.034 mmol) in DCM (2 ml) is added TFA (0.5 ml). The mixture is stirred for 2 h, concentrated in vacuo and the residue is directly purified by preparative HPLC to give the desired product 2-Amino-N-(5-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)pyridin-3-yl)acetamide: 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.10-8.90 (br.s., 2H), 8.94 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.67 (t, J=2.0 Hz, 1H), 8.35-8.15 (br.s., 3H), 5.62 (s, 1H), 3.89 (s, 2H), 3.85 (t, J=5.2 Hz, 4H), 3.20 (t, J=5.2 Hz, 4H); LC/MS: tR=1.908 min; HRMS: m/z (M+H+)=387.1344 (Calculated for C16H19N8O2S=387.1352).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)N)=[CH:5][CH:4]=1.C(O[CH:23](OCC)[CH2:24][CH2:25][CH2:26][NH:27][CH3:28])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:23]=[C:24]2[CH2:25][CH2:26][NH:27][CH3:28]
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12
Temperature: 90 °C
Yield: 74.3 %

Procedure:
28% aqueous HCl (0.07 mL, 0.54 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(3-phenyl-propyl)-hydrazine (261 mg, 1 mmol) in ethanol (1 mL) and water (0.5 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (175 mg, 1 mmol) was added. The reaction was heated to 90° C. and 28% aqueous HCl (0.08 mL, 0.61 mmol) was added. The reaction was heated at reflux for 6 h. More 4, 4-diethoxy-N-methylbutan-1-amine (90 mg, 0.51 mmol) was added at 60° C. and more 28% aqueous HCl (0.19 mL, 1.46 mmol) was added at 90° C. The reaction was heated to reflux for a further 8 h. The reaction was cooled and concentrated under reduced pressure. The red-brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give a brown oil (243 mg, 74%).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:25]1[N:30]=[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[N:28]=[C:27]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[N:26]=1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:25]1[N:30]=[C:29]([O:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[N:28]=[C:27]([N:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[N:26]=1)[CH:12]=[C:11]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]([OH:5])=[O:21]
Reactant: Clc1nc(OC2CCCC2)nc(N2CCCc3ccccc32)n1
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)c1c[nH]c2ccc(Cl)cc12
Product: O=C(O)CCC(=O)c1cn(-c2nc(OC3CCCC3)nc(N3CCCc4ccccc43)n2)c2ccc(Cl)cc12

Procedure:
Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid 2-trimethylsilanyl-ethyl ester with 1-(4-chloro-6-cyclopentyloxy-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline and subsequent hydrolysis as outlined previously yielded the titled compound. Rf 0.30 (5% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.97 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.18 (1H, d, J=2 Hz, ArH), 7.81 (1H, d, J=8 Hz, ArH), 7.35-7.10 (4H, m, ArH), 5.44 (1H, m, CH), 4.08 (2H, t, J=6 Hz, CH2), 3.22 (2H, t, J=6 Hz, CH2), 2.78 (2H, t, J=6 Hz, CH2), 2.58 (2H, t, J=6 Hz, CH2), 2.01-1.61 (10H, m, CH2); ESI-LCMS e/z calculated for C29H28ClN5O4 545.183, found 546 (M+H)+, 568 (M+Na)+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1(C)C=CC=CC=1.O>[CH2:39]([O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80 %

Procedure:
9.1 g (0.05 mole) of L-tyrosine was used, 11.4 g (0.06 mole) of p-toluenesulfonic acid hydrate was used, and 11.79 g (0.055 mole) of myristyl alcohol was used as an alcohol. After 200 ml of toluene was added thereto as a solvent, these materials were stirred and mixed well. The resulting reaction mixture was heated at the reflux temperature of toluene to carry out the esterification reaction. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with toluene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7-15 hours. After being cooled to room temperature, the reaction mixture was poured into a separating funnel and treated with 200 ml of a mixture of 0.2N NaOH and 3M NaCl solutions. This treatment was repeated three times. Thereafter, the toluene layer was isolated and washed thoroughly with water. After washing with water, the toluene layer was isolated and dried overnight over anhydrous sodium sulfate. After drying, the toluene layer was filtered and the resulting toluene solution was evaporated to remove the solvent. Thus, there was obtained 15.1 g (80% yield) of purified free L-tyrosine myristyl ester in the form of an oily material.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>C1COCC1>[Cl:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 270 %

Procedure:
Anhydrous CeCl3 (16 g, 64.9 mmol) was stirred vigorously in 100 mL THF for 2 h 15 min. The suspension was then cooled to −78° C. and a 1 M solution of vinylmagnesiumbromide (62 mL, 62.3 mmol) was added. After 1.5 h at −78° C., a solution of 3-chloropropiophenone (7 g, 14.5 mmol) in 20 mL THF was added dropwise via cannula. The reaction mixture was stirred for 1 h, then gradually warmed to room temperature and quenched by the addition of saturated aqueous NaHCO3. Extraction into EtOAc (3×) followed by purification by silica gel chromatography (4:1 hexanes:EtOAc) afforded the 5-chloro-3-phenylpent-1-en-3-ol (7.7 g, 94%) as a yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.45-7.34 (m, 4H), 7.28 (m, 1H), 6.18 (dd, 1H, J=17.2, 10.6 Hz), 5.34 (d, 1H, J=17.2 Hz), 5.23 (d, 1H, J=10.8 Hz), 3.59 (td, 1H, J=10.6, 5.5 Hz), 3.41 (td, 1H, J=10.5, 5.5 Hz), 2.40 (m, 2H), 2.0 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:25][CH:26]=1
Reactant: Cn1cc(I)cn1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: Cn1cc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)cn1

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 4-iodo-1-methyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)=[C:3]([CH3:17])[CH:4]=2)[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: Cc1cc(N2CCN(C(C)C)CC2)ncc1Br
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(-c2cnc(N3CCN(C(C)C)CC3)cc2C)c1
Temperature: 100 °C

Procedure:
To a solution of 1-(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine (0.59 g, 2 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added 3-acetylamino-phenylboronic acid (430 mg, 2.4 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol) and TEA (404 mg, 4 mmol). The resulting mixture was degassed and heated at 100° C. for 4 h under a nitrogen atmosphere. The mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by chromatography on silica gel eluting with CH2Cl2/MeOH (100:1). This afforded 138 mg (15%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH:20][CH2:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:12]
Reactant: CN1CCCC1CCN
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2[nH]1
Yield: 58.3 %

Procedure:
Experimental condition analogous to Example 5, from 1H-indole-2-carbaldehyde 0.14 g (2 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.3 g (2.4 mmol), and sodium triacethoxyborohydride 0.87 g (1.87 mmol), in 20 mL Dichloromethane. The compound was purified using silica gel chromatography elution, ethyl-acetate-methanol-amonium hydroxide: 9-1-0.1 to 8-2-0.2, yield to 0.3 g light brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([N:2]1[CH:3]=[C:4]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:21]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:1]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: c1cc(-c2cn[nH]c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)n1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of [5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.128 mmol) in dichloromethane (1 ml) was added triethylamine (23 μl, 0.166 mmol) followed by methanesulfonyl chloride (12 μl, 0.154 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The product was purified by preparatory HPLC to yield the desired product. RT: 2.41 min, MI: 468, Method: 2; 1H NMR (DMSO, 300 MHz): 9.56 (s, 1H), 9.47 (s, 1H), 8.94 (s, 1H), 8.18 (s, 2H), 7.69-7.54 (m, 3H), 6.93 (d, 2H), 4.06 (t, 2H), 3.72 (s, 3H), 2.92 (t, 2H), 2.67 (s, 4H), 1.74 (s, 4H).