Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C@@H:5]([C@@H:6]([OH:9])[CH:7]=[CH2:8])[CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([O:9][C@@H:6]([CH:7]=[CH2:8])[C@@H:5]1[O:3][CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C[C@H](O)[C@H]1CO1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C=C[C@H](OCc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
428 mg of sodium hydride (60% in oil) was suspended in 8 ml of THF, and a THF solution (5 ml) of 970 mg of (2R,3S)-1,2-epoxypent-4-ene-3-ol was dropwise added thereto under an argon atmosphere at -10° C. The mixture was stirred at room temperature for 20 minutes. Then, 360 mg of tetra-n-butylammonium iodide and 1.27 ml of benzyl bromide were added thereto at -10° C. The mixture was stirred at room temperature for two hours, and then poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 1.7 g of (2R,3S)-3-benzyloxy-l,2-epoxy-4-pentene as colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[NH:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[F:25][C:4]1[CH:3]=[C:2]([N:28]2[C@H:27]([CH3:26])[CH2:31][CH2:30][S:29]2(=[O:33])=[O:32])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)nc1C

Procedure:
To a mixture of (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (322 mg) described in Preparation Example 128, (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2, potassium carbonate (220 mg), copper(I) iodide (76 mg) and potassium iodide (132 mg) were added toluene (1 mL) and N,N′-dimethylethylenediamine (80 μL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (R)-[2-fluoro-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (140 mg) was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.08 mL) was added, and the precipitate was collected by filtration to give the title compound (166 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)=[CH:39][CH:38]=1>>[CH:45]1([CH2:44][O:43][C:40]2[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]4[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=4[C:22]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]4)=[O:23])=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:47]1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ClCc1ccc(OCC2CC2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OCC4CC4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-[3-(4-{[4-(cyclopropylmethoxy)benzyl]oxy}phenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-(cyclopropylmethoxy)benzene.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1)=[O:20]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 9 h

Procedure:
To a stirred slurry of 12.45 g (0.11 mole) of creatinine in 100 ml of dry DMF is added 16.41 g (0.1 mole) of m-nitrophenyl isocyanate (previously recrystallized from benzenepentane). After 9 hours, ice water is gradually added until crystallization occurres. A large excess of ice water precipitates the product as gummy crystals which then crystallize. The crude product is allowed to air dry for several days. Recrystallization from THF-H2O followed by THF gives pure product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea; m.p. 182°-188°C sl. dec.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[O:23]1[CH2:26][CH:25]([CH2:27][NH2:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:28][CH2:27][CH:25]4[CH2:26][O:23][CH2:24]4)=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NCC1COC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1C(=O)NCC1COC1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (55 mg) was reacted with oxetan-3-ylmethanamine similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-(oxetan-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 13 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(oxetan-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 443 (M)+. 1H NMR (400 MHz, DMSO) δ 11.37 (t, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 5.05-4.93 (m, 2H), 4.68-4.61 (m, 2H), 4.58-4.50 (m, 2H), 4.35 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.1 Hz, 2H), 3.21-3.13 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCCCC2C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of [1-tert-butoxycarbonyl-(2S)-octahydroindolyl]methanol (947 mg, 3.7 mmol), methyl 4-hydroxybenzoate (565 mg, 3.7 mmol), and Ph3P (1.2 g, 4.5 mmol) in THF (10 ml) was added DIAD (984 mg, 4.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (9/1, v/v) as eluent to give methyl 4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 50%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.10-2.25 (m, 11H), 1.45 (s, 9H), 3.88 (s, 3H), 3.70-4.20 (m, 3H), 4.36 (br s, 1H), 6.94 (d, J=8.8H z, 2H), 7.96 (d, J=8.5H z, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:28]3[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid amide (0.478 g, 2.4 mmol) according to the general procedure VI. Obtained as a white solid (0.180 g, 42%). MS (ISP) 475.2 [(M+H)+]; mp 215° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[CH2:12][N:13]=1.Cl[CH2:20][C:21]1[C:22]([CH3:27])=[N:23][O:24][C:25]=1[CH3:26]>CCCCCC.C1COCC1>[CH3:6][O:7][C:8]1[C@@H:9]([CH:16]([CH3:18])[CH3:17])[N:10]=[C:11]([O:14][CH3:15])[C@H:12]([CH2:20][C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[N:13]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: Cc1noc(C)c1CCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1c(C)noc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.55M solution of butyllithium (10 ml, 15.5 mmol) in hexane was added by syringe to a stirred solution of (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2.85 g, 15.5 mmol) in THF (50 ml) at -78° C. and the solution stirred for 1 hour at -78° C. A solution of 4- chloromethyl-3,5-dimethylisoxazole (2.34 g, 16 mmol) in THF (10 ml) was added gradually and the stirring continued overnight. The solvent was removed under reduced pressure, the residue dissolved in ethyl acetate (50 ml) and extracted with phosphate buffer (pH 7). The water phase was extracted twice with ethyl acetate (2×20 ml). The organic layer was dried (MgSO4), solvent evaporated under reduced pressure and the residue purified by flash chromatography (diethyl ether/hexane 4/1, silica gel).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.N#N.[CH3:21][N:22]([CH2:42][CH:43]=[O:44])[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOCC>[CH3:21][N:22]([C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:42][CH:43]([C:11]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[N:8]=[CH:9][CH:10]=1)[OH:44]
Reactant: CN(CC=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cccn1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CC(O)c1ccnn1COCC[Si](C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -79 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (Heterocycles (1992), 34(2), 303-14)(0.80 g, 4.03 mmol) in 50 mL of THF/ether (3/2) was cooled to −78° C. and treated with 2.5M solution of n-BuLi (1.8 mL, 4.43 mmol) dropwise under N2 atmosphere. The resulting mixture was stirred for 30 min. [Methyl(trityl)amino]acetaldehyde (1.27 g, 4.04 mmol) in 5 mL of the THF/ether solution was added to reaction mixture and stirred for 1 h at −79° C. and warmed up to room temperature. The reaction was quenched by adding NH4Cl (sat. aq.) and water dropwise and the resulting suspension was extrcted into EtOAc (2×100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with 20% EtOAc in n-heptane, and those fractions with Rf=0.3 by TLC(EtOAc/hexane, 3/7) were combined and concentrated in vacuo to give 0.7 g of the product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH:23]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14])([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: CC(C)c1cc2c(cc1O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1C(C)C)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.4 g of 7-Hydroxy-6-isopropyl-1-tetralone was dissolved in 50 ml of N,N-dimethylformamide, followed by the addition of 7.3 g of potassium carbonate and 4.3 ml of 2-bromopropane. The obtained mixture was stirred for 8 hours under heating, cooled to room temperature by allowing to stand and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 6.0 g of the title compound as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][CH3:24]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][CH3:24])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCC(C)(C)N
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O
Solvent: CC#N
Product: CCC(C)(C)NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O

Procedure:
A mixture of 3-(benzo[1,3]dioxol-5-ylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile(0.800 g, 2.5 mmol) and 1,1-dimethylpropylamine (2.92 ml) in 10 ml of acetonitrile was stirred and refluxed for one week under nitrogen. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and trice with water. The organic phase was dried (sodium sulphate) and evaporated to afford the title compound as white crystals. Mp 86-88° C. 1H NMR (200 MHz, DMSO-d6): δ=0.90 (t, 3H), 1.34 (s, 6H), 1.70 (q, 2H), 3.04 (s, 3H), 6.66 (dd, 1H), 6.74 (d, 1H), 6.88 (d, 1H), 7.21 (s, 1H), 8.19 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.O1[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24]1>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:24][C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:14][C:12]2=[O:13])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC[C@@H]1CO1
Reactant: CCCCc1ccc(CC(=O)O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC[C@@H]1C[C@@H](c2ccc(CCCC)cc2)C(=O)O1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
4-Butylphenylacetic acid (5 g) was dissolved in THF (100 ml), followed by cooling the solution down to -60° C., dropwise adding a tetrahydrofuran solution of LDA (10.4 mmol) over 30 minutes, raising the temperature up to 0° C., agitating for 30 minutes, cooling down to -60° C., dropwise adding a mixed solution of (R)-1,2-epoxyoctane (3.4 g) with anhydrous THF (5 ml) over 10 minutes, gradually raising the temperature, agitating at room temperature overnight, pouring the reaction solution in ice water (100 ml) and toluene (200 ml), washing the resulting organic layer with 6N--HCl, 2N--NaOH and saturated NaCl aqueous solution in this order, drying over anhydrous magnesium sulfate, concentrating the organic layer under reduced pressure, placing the resulting concentrate in a 1 l three-necked flask, adding toluene (250 ml) and p-toluenesulfonic acid (1.1 g), heating the mixture under reflux for 4 hours, dehydrating with a Dien-Stark type drain tube, adding ice water (100 ml), washing the organic layer with 6N--HCl, 2N--NaOH and saturated NaCl aqueous solution in this order, drying over magnesium sulfate, concentrating the organic layer under reduced pressure, separation-purifying according to chromatography and recrystallizing from ethanol to obtain (αS,γR)-α-(4-butylphenyl)-γ-hexyl-γ-butyrolactone (trans-form) (0.8 g). m.p.: 37.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]#[N:36])=[CH:34][C:28]=3[N:27]=2)([CH3:25])[CH3:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[CH:6]2.[OH-].[K+].C(N)CC(C)C>CCO>[CH3:1][O:2][C:3]1[C:4]([C:23]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]#[N:36])=[CH:34][C:28]=3[N:27]=2)([CH3:25])[CH3:24])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(C)c1nc2cc(C#N)ccc2[nH]1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(C)c1nc2cc(C#N)ccc2[nH]1

Procedure:
A solution of 2-(2-(5-methoxy-7-methyl-1-tosyl-1H-indol-4-yl)propan-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (43 mg, 0.086 mmol) and KOH (48.4 mg, 0.862 mmol) and isoamylamine (150 μL, 1.29 mmol) in EtOH (1.2 mL) was heated at 100° C. under microwave irradiation for 2 h. The reaction mixture was loaded onto silica gel and was purified by silica gel flash chromatography (0-50% EtOAc:DCM), and then SFC using a 2-ethylpyridine column with 12% MeOH+0.2% DEA in CO2. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (s, 1H) 10.88 (br. s., 1H) 8.08 (m) 7.66-7.76 (m) 7.37-7.53 (m) 7.04-7.18 (m, 1H) 6.73 (s, 1H) 5.89 (m) 5.83 (m) 3.45 (m) 3.43 (m) 2.43 (s, 3H) 1.90 (s, 6H). HRMS calcd. for C21H20N4O (M+H)+ 345.1715. found 345.1724.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[CH:7]=1.[B:15](OC)([O:18]C)[O:16]C.C([Li])CCC.Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.CCCCCC>[F:12][C:11]([F:14])([F:13])[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([B:15]([OH:18])[OH:16])=[CH:7][N:6]2[CH:8]=1
Reactant: FC(F)(F)c1cn2cc(Br)ccc2n1
Reactant: COB(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc2nc(C(F)(F)F)cn2c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a cooled (−78° C.) solution of 6-bromo-2-trifluoromethyl-imidazo[1,2-a]pyridine p (5.66 mmol, 1.50 g) and trimethyl borate (1.2 equiv., 6.79 mmol, 0.706 g) in diethyl ether (7 ml) under N2-atmosphere was added dropwise butyllithium (1.2 equiv., 6.79 mmol, 2.72 ml of a solution 2.5 M BuLi in hexane) over a period of 10 minutes. After 30 min, the solution was warmed to −20° C. and 2N hydrochloric acid (7.5 ml) was added dropwise. The mixture was partitioned between water (50 ml) and diethyl ether (50 ml). The aqueous layer was isolated and the pH of the solution was adjusted to pH=7 by the addition of sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated under reduced pressure affording 2-trifluoromethyl-imidazo[1,2-a]pyridine-6-boronic acid q (0.23 g, yield=11.4%, purity (LC)=67%).
Reaction SMILES: [C:1]1([CH2:6][S:7][C:8]([N:10]2[C@@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:26]([S:28][CH2:29][C:30]4[S:34][CH:33]=[CH:32][CH:31]=4)=[S:27])[C:12]=3[CH2:11]2)=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:37])=[N-]>CCOCC>[C:1]1([CH2:6][S:7][C:8]([N:10]2[C@@H:22]([C:23]([O:25][CH3:37])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([C:26]([S:28][CH2:29][C:30]4[S:34][CH:33]=[CH:32][CH:31]=4)=[S:27])[C:12]=3[CH2:11]2)=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)[C@H]1Cc2c(n(C(=S)SCc3cccs3)c3ccccc23)CN1C(=S)SCc1cccs1
Solvent: CCOCC
Product: COC(=O)[C@H]1Cc2c(n(C(=S)SCc3cccs3)c3ccccc23)CN1C(=S)SCc1cccs1
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A mixture of (3R)-2,9-di[(2-thenylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (0.3 g), diazomethane [prepared from N-nitrosomethylurea (1.55 g) and 40% KOH (4.5 ml)] and ether (30 ml) is allowed to stand at 0° C. overnight. Undissolved substances are removed by filtration and the filtrate is concentrated to give the title compound (150 mg, 50%) as pale yellow powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Cl[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: Cc1ccnc(Cl)c1
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](Nc2cc(C)ccn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation, see Intermediate 44) (115 mg, 0.268 mmol) and 2-chloro-4-methylpyridine (102 mg, 0.803 mmol) in toluene (2.5 mL) were successively added sodium tert-butoxide (129 mg, 1.338 mmol), tris(dibenzylideneacetone)dipalladium(0) (245 mg, 0.268 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (211 mg, 0.535 mmol). The resulting mixture was stirred at 100° C. for 1 h then cooled to room temperature. The insoluble material was washed with 5% MeOH in DCM. The combined filtrate and washings were concentrated in vacuo and the residue was dissolved in a 1:1 MeOH/DMSO mixture and purified via MDAP (modifier; formic acid). The appropriate fractions were combined and the solvents evaporated using a blow down apparatus to give 2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(4-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-1,2,3-triazol-1-yl)ethanol (18.5 mg, 0.046 mmol, 17%) as a colourless oil.