Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37].CN1CCOCC1>C(Cl)(Cl)Cl>[C:36]([S:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The benzyl ester (D8) (41 g, 0.088 mole) was dissolved in thiolacetic acid (170 ml) and left to stand at room temperature under nitrogen for 19 days. Volatile material was removed in vacuo and the residue chromatographed on silica gel with initially ether, rising slowly to ethyl acetate. After removal of high Rf impurities the title compound was obtained as a mixture of diastereomers as a pale yellow foam (29.76 g, 62.4%). (Found: C, 64.29; H, 7.16; N, 4.86. C29H38N2SO6 requires C, 64.18; H, 7.06; N, 5.16%). Later fractions contained olefinic material (D8). However, more complete reaction can be obtained by addition of a suitable base, for example triethylamine. An aliquot (2 ml) was removed from the above reaction mixture after 14 days, treated with triethylamine (3 drops) and left to stand for a further 5 days at room temperature under nitrogen. The same work-up procedure as for the bulk of the reaction mixture described above gave only the diastereomer mixture (E3) with no olefinic material remaining. 3-Mercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E4, Isomer A, 2.0 g 0.004 mol) was dissolved in chloroform (100 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and acetic anhydride (2.04 g, 0.02 mol) was added followed by N-methylmorpholine (2.02 g, 0.02 mol). The reaction mixture was allowed to warm to room temperature, then stirred under nitrogen for 3 days.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([OH:29])=O)[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([NH:31][CH3:30])=[O:29])[CH:3]=1
Reactant: CN
Reactant: Cc1nc(N)cc(OCC(=O)O)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-(6-amino-3-((1-benzyl-1H-pyrazole-4-carboxamido)methyl)-2-methylpyridin-4-yloxy)acetic acid (35 mg, 0.051 mmol) was dissolved in DMF (1 ml), CDl (16.65 mg, 0.103 mmol) was added. After stirring for 15 min at rt Methylamin 2M in THF (0.257 ml, 0.513 mmol) was added and the reaction mixture was stirred 6 h at rt. Purification by prep HPLC (Nucleosil C18, 250×40 mm 5 to 100% ACN and 0.1% TFA, flow 40 mml/min.) offered the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.71 (d, 3H), 4.37 (d, 2H), 4.67 (s, 2H), 5.34 (s, 2H), 6.20 (s, 1H), 7.24 (m, 5H), 7.79 (s, 2H), 7.89 (s, 1H), 8.25 (d, 2H), 8.28 (s, 1H), 8.35 (t, 1H). HPLC/MS (Method B) Rtb=0.46 min, MS [M+H]+=409.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:22]Br.CO>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ncccc1C(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncc(Br)cc1C(=O)c1cccnc1
Reaction time: 2 h

Procedure:
(2-Amino-pyridin-3-yl)-pyridin-3-yl-methanone (0.13 g, 0.65 mmol) is dissolved in glacial acetic acid (6 ml). Na2CO3 (0.075 g, 0.72 mmol) is added. After evolution of gas has finished, a solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml) is added dropwise. Na2CO3 (0.075 g, 0.72 mmol) is added, followed by a second solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml). The resulting yellow suspension is left to stir for 2 hour. The reaction is quenched by pouring onto ice water (150 ml), and neutralised using NaHCO3. The product is extracted with EtOAc and dried (MgSO4). Concentration in vacuo affords an oil, which is trituatuted with methanol to yield the title compound [M+H]+ 277.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[Cl-].[Ca+2].[Cl-].N1C=CC=CC=1.[S:22](Cl)(Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:22]1(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: OCCNCc1ccccc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1(=O)OCCN1Cc1ccccc1Cl
Temperature: -50 °C
Yield: 18.5 %

Procedure:
To a solution of N-hydroxyethyl-2-chlorobenzylamine (1.86 g, 10.0 mmole) in dry methylene chloride (6 ml) in a reaction vessel fitted with a calcium chloride (CaCl2) drying tube was added dry pyridine (1.66 ml, 20.5 mmole). The solution was stirred and cooled to -50° C. Sulfuryl chloride (1.35 g, 10.0 mmole) dissolved in dry methylene chloride (4 ml) was added dropwise over 20 minutes while the temperature of the solution was maintained between -45° C. and -50° C. The solution was stirred at -50° C. for 90 minutes and then allowed to warm to 8° C. over 90 minutes. The entire reaction mixture was poured onto a silica gel bed (30 g), slurry-packed in a 60 ml Type "C" sintered glass funnel. The bed was eluted with methylene chloride while collecting 40 ml fractions. Fractions containing the product were combined and the solvent removed by evaporation under vacuum at 40° C. yielding N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine as a clear oil (0.40 g, 1.85 mmole), which crystallized. Characteristic analytical data are mp. 61°-62.5° C.; and NMR spectra similar to those of Example 2A (above).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH2:44])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([NH:44][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCCCNCCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 16.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and butylamine (6.8 mg) according to an analogous synthetic method to Example 806, the title compound (4.6 mg) was obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[CH2:9]([NH:16][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC(C)NCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
Ru(OCOCH3)2((R)-dm-binap)(20.5 mg, 0.0215 mmol), methyl acetoacetate (500 mg, 4.305 mmol), benzylamine (461 mg, 4.305 mmol) and methanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature, and acetic acid (259 mg, 4.305 mmol) was added thereto. The mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=75/25/5) to give the objective methyl (−)-3-(benzylamino)butanoate (141 mg) as a colorless oil in 15.8% yield. The enantiomeric excess of the resulting methyl (−)-3-(benzylamino)butanoate was determined to be 44.5% ee by HPLC analysis using a CHIRALCEL OD-H column.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCN(CC)CCSc1nnc(N)s1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(C(C)(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.7 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Tert-butylbenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.7 g of the aimed compound.
Reaction SMILES: C([O:4][P:5]([O:12][CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[C:16]([P:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])[O:12][CH:13]([CH3:14])[CH3:15])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)OP(OC(C)C)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)OP(=O)(C(=O)C(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
158 parts of diisopropoxyphenylphosphine are added slowly to 84 parts of pivaloyl chloride at 50°-60° C., with thorough stirring. Stirring is then continued for two hours, after which the mixture is fractionated under reduced pressure. Isopropyl pivaloyl-phenylphosphinate distils at 119°-121° C./0.5 mm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][C:12]1([CH3:30])[O:16][N:15]=[C:14]([S:17][CH2:18][C:19]2[C:20]([C:26]([F:29])([F:28])[F:27])=[N:21][N:22]([CH3:25])[C:23]=2F)[CH2:13]1.O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([C:26]([F:28])([F:27])[F:29])[C:19]=1[CH2:18][S:17][C:14]1[CH2:13][C:12]([CH3:30])([CH3:11])[O:16][N:15]=1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: Oc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1Oc1ccccc1Cl
Reaction time: 1 h
Yield: 68.2 %

Procedure:
0.2 g (8.3 mmoles) of sodium hydride (purity: 60%) was added, with ice-cooling, to a solution of 0.44 g (3.4 mmoles) of 2-chlorophenol dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto was added 0.7 g (2.2 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline. The resulting mixture was stirred at 120 to 130° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.63 g (yield: 66.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41](Br)=[CH:40][C:39]=2[N:38]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([CH:2]=[CH:1][S:3]([CH3:6])(=[O:5])=[O:4])=[CH:40][C:39]=2[N:38]=1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c21
Temperature: 120 °C
Yield: 44.1 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (15 mg, 0.07 mmol), acetonitrile (50 mL), methyl vinyl sulfone (268 mg, 2.52 mmol), triethylamine (1.00 mL, 7.17 mmol), tri-o-tolylphosphine (45 mg, 0.21 mmol) and 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (800 mg, 2.39 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 12 hours, cooled to ambient temperature, and then concentrated under reduced pressure to yield a dark brown oil. The oil was partitioned between chloroform (75 mL) and a solution comprised of a 1:1 combination of 10% aqueous potassium carbonate and 10% sodium hydroxide. A precipitate formed. The mixture was filtered and the recovered solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 20% methanol in dichloromethane. The filtrate was also concentrated and the residue purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane). The two lots of purified product were combined to provide 380 mg of 1-{4-amino-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a pale yellow solid. MS (APCI) m/z 361 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:51])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:51])[CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Reactant: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1

Procedure:
97 mg (0.19 mmol) of the compound of Example 30 is reacted overnight analogously to the synthesis of the compound of Example 6 with 48 mg (0.19 mmol, 70%) of meta-chloroperbenzoic acid. After the crude product is filtered by a Millipore spray filter and the residue is subsequently purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 82 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70].CO>C(Cl)Cl>[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[C:59]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:60][C:61]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:25]=3)[C:10]3[C:11](=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=3)[C:62]=2[CH:63]=1
Reactant: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 988 %

Procedure:
In 40 mL of methylene chloride, 5.70 g (10 mmol) of 3,3′,4,4′-tetrakishexyloxybiphenyl and 15.3 g (31 mmol) of 1-(16-bromohexadecyl)-2-hexyloxybenzene were dissolved. Under argon, 10.0 g (62 mmol) of FeCl3 was added to the solution, and the solution was stirred at ambient temperature for three hours. The resulting reaction mixture was put into 800 mL of methanol and filtered to obtain 102 g of a solid. The solid was purified by silica-gel column chromatography to obtain a yellow solid. The yellow solid was recrystallized from ethanol and 8.2 g of a white solid was obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([O:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a solution of (S)-methyl 2-hydroxypropanoate (1.00 g, 9.61 mmol) in DMF (10 mL) at rt, were added imidazole (0.981 g, 14.41 mmol) and TBS-Cl (1.737 g, 11.53 mmol). The mixture was stirred at rt for 3 h. The reaction mixture was diluted with hexanes. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% ethyl acetate/hexanes) to give 17A (1.73 g, 7.92 mmol, 82% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 4.34 (q, J=6.7 Hz, 1H) 3.72 (s, 3H) 1.40 (d, J=6.8 Hz, 3H) 0.90 (s, 8H) 0.09 (d, J=10.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)CCC.CN(C=O)C>C(OCC)(=O)C.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>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing tert-butyl 5-bromopicolinate 41-1 (1.55 g, 6.0 mmol), 2-(tributylstannyl)pyrazine 41-2 (2.21 g, 6.0 mmol) and Pd(PPh3)4 (426 mg, 0.6 mmol) under argon was added DMF (15 mL). The mixture was stirred at 120° C. for 10 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 5-(pyrazin-2-yl)picolinate 41-3 as a pale yellow solid. MS m/z 258.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][NH2:24].C(OC(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.4.). Starting with 2.20 g (5.91 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, and 14.80 ml (29.55 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after crystallization from diisopropyl ether, 1.974 g of pure product are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][CH2:10][C:11](=[O:13])[NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)OC(C)(C)C
Yield: 20 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.30 mL, 0.40 g, 3.18 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with glycine tert-butyl ester (H-GlyOtBu) (0.53 g, 3.18 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.16 g (20% yield) of the title compound (34) as a semi-solid material. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.95-6.69 (m, 2H), 6.63 (br. m, 1H), 4.73 (s, 2H), 3.99 (d, J=4.8 Hz, 2H), 3.83 (s, 3H), 1.48 (s, 9H). MS (ESI): m/z 324.05 (M+Na+)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[NH4+].[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].Cl>ClCCl>[C:11]([N:14]1[CH2:15][CH2:16][CH:17]([C:20](=[O:21])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:18][CH2:19]1)(=[O:13])[CH3:12]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
67 g of 1,3-difluorobenzene and 133 g of ammonium chloride were added to 150 ml of dichloromethane, and then the mixture was cooled to room temperature. 98 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml of dichloromethane was added thereto dropwise, and then the mixture was stirred at an elevated temperature for 3 hours. The reaction mixture was poured to a mixture of ice and hydrochloric acid, and the resulting mixture was extracted with 200 ml of dichloromethane. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed from the filtrate to obtain 55.9 g of the title compound (yield: 41%).