Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][OH:24])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: OCc1ccccc1B(O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3CO)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-(hydroxymethyl)phenylboronic acid to give 478. MS(ESI+) 402.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41 (td, J=7.4, 1.1 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.02-5.83 (m, 1H), 5.16 (t, J=5.3 Hz, 1H), 4.56 (q, J=6.1 Hz, 4H), 4.45 (d, J=5.3 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][OH:32])=[CH:28][CH:27]=1>C(OCCO)C>[OH:32][CH2:31][CH2:30][C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:27][CH:28]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(CCO)cc3)c2cc1OC
Yield: 93.8 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 178.3 mg (1.3 mmol) of 4-aminophenethyl alcohol to give 327.8 mg (93.9%) of the product as an off white yellow solid, m.p. 208-210° C., mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C.O>ClCCl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH2:14][N:13]=[C:12]2[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:17][CH:18]=1)=[O:30]
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.7 %

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (80.0 mg, 0.15 mmol), 2,4-dichloro-benzoyl chloride (44.3 mg, 0.21 mmol), and triethyl amine (48.6 mg, 0.48 mmol) were dissolved in dichloromethane (2 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was purified by flash chromatography on silica gel using methylenchloride/MeOH 98:2→95:5 to give 2,4-dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-benzamide as a colourless oil (85.0 mg, 0.16 mmol, 84%).
Reaction SMILES: [C:1]1([CH:7]2[S:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:21]1([C:24]([N:17]2[CH2:16][CH2:15][C:14]3([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:20]3)[CH2:19][CH2:18]2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4, 0.4 g of cyclopropylcarbonyl chloride and 1.0 g of sodium bicarbonate in 20 ml of dichloromethane is stirred at ambient temperature for 16 hours. The well stirred mixture is filtered and the filtrate is concentrated to dryness. The residue is passed through a silica gel/ether column with an ether eluant to provide pure 1'-cyclopropylcarbonyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Fc1ncccc1-c1ccnc(C(F)(F)F)c1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(-c2cccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-2′-(trifluoromethyl)-3,4′-bipyridine (200 mg, 0.83 mmol), 4-(pyridin-2-ylamino)phenol (185 mg, 0.99 mmol) and cesium carbonate (323 mg, 0.99 mmol) in DMSO (3.3 mL) was heated to 80° C. for 4 h. The mixture was cooled to room temperature, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The solids were suspended in sat aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (EtOAc/Hexanes=0→40%) to give the title compound. MS (ESI, pos. ion) m/z: 409 (M+1). IC50 (uM) 0.022.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16]F>O.C(O)C>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[O:9][CH:15]=[CH:16][NH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: FCCBr
Reactant: NNC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc(C2=NNC=CO2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A solution of 2.9 g (0.07 mole) sodium hydroxide dissolved in 10 ml of water was added dropwise at room temperature to a mixture of 6.5 g (0.03 mole) 4-bromobenzoic hydrazide and 4.0 g (0.03 mole) 1-bromo-2-fluoroethane in 25 ml of ethanol. The resulting solution was refluxed for two and one-half hours. The mixture was cooled to room temperature, diluted with 150 ml of water and extracted several times with ether (100 ml). After separation and drying over anhydrous sodium sulfate, the solution was filtered and evaporated under reduced pressure leaving 4.6 grams of an oil (63.6% yield), which was purified by distillation. The product was characterized by IR and NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16]([N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[CH:15]=[CH:14][N:13]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=2)[N:31]=1.[H-].[Na+]>>[ClH:18].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16]([N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=3)[N:31]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CN(CCCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Product: CN(CCCOc1ccc2ncc([N+](=O)[O-])n2n1)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Product: Cl

Procedure:
Starting from 3-{[2-(1H-benzimidazol-2-ylsulfanylmethyl)-3-chloropyridin-4-yl]-methylamino}-propan-1-ol (3.0 g, 8.2 mmol) (see example D2.), 6-chloro-3-nitro-imidazo[1,2-b]pyridazine (1.72 g, 8.7 mmol) and sodium hydride (0.62 g 80% strength suspension) the title compound is prepared and purified according to the procedure given for example 27. Yield: 1.95 g, (42%). M.p. 202-03° C.
Reaction SMILES: CO[C:3](=O)[NH:4][CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][CH2:5][NH:4][CH3:3])=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: COC(=O)NCCC(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of [3-(1H-indol-5-yl)-3-phenyl-propyl]-carbamic acid methylester X (0.52 g, 1.7 mmol) in THF (35 ml), LiAlH4 (321 mg, 8.4 mmol) was slowly added. The mixture was refluxed for 1.5 hours, cooled to room temperature, and quenched by slow addition of freshly ground Na2SO4.10H2O The mixture was stirred at room temperature for 1 hour, filtered through celite with EtOAc. The filtrate was evaporated and purified via flash chromatography (DCM/MeOH/NH4OH) affording [3-(1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine (XI) as an off-white foam (408 mg, 91% yield). The amine compound was dissolved in a Et2O/THF mixture and HCl (2 M in Et2O, 0.772 ml) was added. The precipitate was filtered, washed with Et2O, and dried affording [3-(1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine hydrochloride salt (371 mg, 80% yield). MS (M+H) 265.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[O:74](C1C=CC(B(O)O)=CC=1)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35]([O:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)=[CH:36][CH:40]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: Nc1ccc(-c2ccc(Oc3ccccc3)cc2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (4-phenoxyphenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.29-7.18 (m, 1H), 7.10 (m, 2H), 7.01 (m, 5H), 6.82 (t, J=9.1 Hz, 4H), 6.56 (d, J=8.9 Hz, 1H), 6.43 (s, 1H), 6.19 (d, J=6.4 Hz, 2H), 5.30 (d, J=8.0 Hz, 1H), 3.52 (s, 2H), 2.97-2.85 (m, 1H), 2.75 (dd, J=14.0, 6.9 Hz, 1H). MS (m/z) 592.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].C(O[CH:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=O)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:26]1([CH:16]([C:5]2[C:3](=[O:4])[C:2]([CH3:1])=[C:8]([CH3:9])[C:7](=[O:10])[C:6]=2[CH3:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=O)OC(CCCCCCC(=O)O)c1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(CCCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Yield: 78.7 %

Procedure:
2,3,5-Trimethylhydroquinone (3.1 g, 0.02 mole) and 8-acetoxy-8-phenyloctanoic acid (6.0 g, 0.021 mole) were added to toluene (80 ml), and boron trifluoride ethyl etherate (0.3 ml) was added dropwise to the mixture at room temperature, with stirring. The reaction solution was stirred at room temperature for 4 days, and then the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), and a 10% aqueous solution of ferric chloride was added to the solution to conduct oxidation to the quinone derivative. The reaction product was extracted twice with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting crude product was chromatographed on a silica gel column, followed by elution with isopropyl ether, and the quinone derivative was recrystallized from isopropyl ether to give 8-phenyl-8-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)octanoic acid (5.8 g, 78%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 10 to 19, 50 and 51 were prepared.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2].FC1C=C(F)C=CC=1N.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>>[C:1]([C:3]1[C:4](=[O:18])[N:5]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2]
Reactant: N#Cc1cn(-c2ccc(F)cc2F)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: Nc1ccc(F)cc1F
Product: N#Cc1cn(-c2ccc(F)cc2F)c(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
In like manner, 5-cyano-1-(2,4-difluorophenyl)uracil is prepared, starting with 2,4-difluoroaniline, and is then reacted with trichloromethanesulfenyl chloride, giving 5-cyano-1-(2,4-difluorophenyl)-3-trichloromethanesulfenyluracil, m.p. 196°-198°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[C:16]([C:17](=[O:19])[CH3:18])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Product: COc1ccc(C=C(C(C)=O)C(C)=O)cc1OC
Reaction time: 8 h

Procedure:
3-(3,4-dimethoxybenzylidene)-2,4-pentanedione (hereinafter “Compound 2”) was prepared by the condensation of 3,4-dimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of Compound 2 is about 67% with a purity, as determined by GC, of about 99.5%. Compound 2 is an off-white free-flowing powder having a melting point of 104-108° C. with a λmax at 335 nm.
Reaction SMILES: [CH2:1]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(O)=[O:19].[Na+].C1C(=O)N(Br)C(=O)C1.N1C=CC=CC=1>CC(C)=O.O>[O:19]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])/[CH:17]=[CH:16]/[CH:15]=[O:14]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCc1ccco1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCC(=O)/C=C/C=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A mixture of 2-dodecylfuran (1.00 g, 4.24 mmol) and NaHCO3 (712 mg, 8.48 mmol) in acetone/H2O (10:1, 2 ml) was treated at −20° C. with NBS (905 mg, 5.11 mmol) dissolved in acetone/H2O (10 ml). After the mixture had been stirred for 1 h at −20° C., it was treated with pyridine (0.69 ml, 8.48 mmol). Thereafter, the reaction mixture came to RT, and stirring was continued for 2 h. The solution was washed with 1 N HCl, followed by extraction with ethyl acetate (2×50 ml). The organic phase was dried over NaSO4 and concentrated in order to obtain the crude product. The latter was purified by column chromatography (DCM) to give the product as a pale yellow oil (642 mg, 2.55 mmol, 60%). 1H NMR (300 MHz, CDCl3) δ 1H ppm: 0.88 (t, 3H, J=6.7 Hz, H-16), 1.19-1.36 (m, 18H), 1.59-1.71 (m, H-5), 2.69 (t, 2H, J=7.8 Hz, H-5), 6.73-6.92 (m, 2H, H-2.3), 9.78 (d, CHO, J=7.0 Hz, H-1); 13C NMR (75.5 MHz, CDCl3) δ 13C ppm: 14.2 (C-16), 22.8, 23.7, 29.2, 29.3, 29.4, 29.5, 29.5, 29.6, 29.7, 32.0, 41.3 (C-5), 137.2 (C-2), 144.8 (C-3), 193.2 (C-1), 199.9 (C-4); (−)-ESI-CID-MS: 251 [M−H]−; ESI-FT-ICR-MS: m/z 251.20137 (calculated for C16H27O2−, m/z 251.20165).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[Cl:17]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:8])=[CH:12][C:11]=1[Cl:17]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1Br
Temperature: 90 °C
Yield: 85.4 %

Procedure:
Add NBS (5.266 g, 23.9 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol) in carbon tetrachloride (49 mL) and heat overnight at 90° C. Cool to 0° C. and filter the mixture. Concentrate the filtrate in vacuo to obtain the desired intermediate as a yellow oil (5.807 g, 85%).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH3:33][I:34]>>[I-:34].[CH:18]1([CH2:17][N+:14]2([CH3:33])[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[C@:7]([C@@H:4]3[CH2:5][CH2:6][C:2]([F:1])([F:32])[CH2:3]3)([OH:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:16][CH2:15]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CI
Reactant: O=C(OC1CCN(CC2CCCCCC2)CC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Product: C[N+]1(CC2CCCCCC2)CCC(OC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Product: [I-]
Reaction time: 12 h

Procedure:
A solution formed by dissolving 1-(cycloheptylmethyl)piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 0.3 ml of methyl iodide at room temperature was allowed to stand for 12 hours at the same temperature, and excessive reagent was distilled off under reduced pressure. The diastereomers in the residue were separated on preparative thin layer chromatography (Kieselgel™60F254 Art5744 (Merck), chloroform/methanol=5/1) to provide the title compound respectively as 3.8 mg (low polar substance) and 2.8 mg (high polar substance) of colorless oily substances.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:25][O:24][C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([CH3:23])[CH:14]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1>CS(C)=O>[ClH:33].[CH3:26][C:2]1([CH3:1])[N:3]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:4][C:5]2([CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([CH3:23])[CH:14]=3)=[O:12])[CH2:9][CH2:10]2)[O:24][CH2:25]1
Reactant: Clc1ncccn1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNC(C)(C)CO3)ccc1OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(c2ncccn2)C(C)(C)CO3)ccc1OC(C)C
Product: Cl
Yield: 39.3 %

Procedure:
A solution of (9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (11.0 mg, 0.0305 mmol), potassium carbonate (4.2 mg, 0.031 mmol) and 2-chloropyrimidine (3.7 mg, 0.031 mmol) in DMSO (90 μL) was heated at 90° C. for 2 h. The reaction was filtered and purified by HPLC (1-99% CH3CN/5 mM HCl) to provide (3,3-dimethyl-4-(pyrimidin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone hydrochloride (6.0 mg, 0.012 mmol, 38%). ESI-MS m/z calc. 438.3. found 439.3 (M+1)+; Retention time: 1.92 minutes (3 min run).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[CH:35][CH:34]=3)=[N:11][N:10]=2)=CC=1.[OH-].[K+].COC1C=CC(CNC2SC(C3C=C4C(=CC=3)NC=C4C3N=C(N4CCN(C)C(=O)C4)C=CC=3)=NN=2)=CC=1.C(O)(C(F)(F)F)=O>O1CCOCC1.O>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[C:33]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]3)[CH:36]=[CH:35][CH:34]=2)=[N:11][N:10]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(N6CCN(C)C(=O)C6)n5)c4c3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2cccc(-c3c[nH]c4ccc(-c5nnc(N)s5)cc34)n2)CC1=O
Temperature: 80 °C
Yield: 42.1 %

Procedure:
A glass microwave reaction vessel was charged with 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (350 mg, 0.515 mmol) in p-dioxane (6 mL) followed by aq. 1 M KOH (2.5 mL, 2.500 mmol). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 80° C. for 15 min. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 526 (M+1). A glass microwave reaction vessel was charged with crude 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (271 mg, 0.516 mmol) and TFA (5.00 mL, 67.3 mmol). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 40 min, then the solvent was removed. The residue was purified with RP-HPLC to give 4-(6-(5-(5-amino-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (88.0 mg, 0.217 mmol, 42.1%). MS (ESI, pos. ion) m/z: 406 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (1H, d, J=2.0 Hz), 8.79 (1H, d, J=1.6 Hz), 8.11 (1H, d, J=2.5 Hz), 7.71 (1H, dd, J=8.4, 1.8 Hz), 7.59 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=8.6 Hz), 7.27 (2H, s), 7.22 (1H, d, J=7.4 Hz), 6.62 (1H, d, J=8.2 Hz), 4.12 (2H, s), 4.06 (2H, t, J=5.4 Hz), 3.58 (2H, t, J=5.3 Hz), 2.96 (3H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:20])[CH3:2]
Reactant: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a DMF solution of methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate were added potassium carbonate and methyl iodide, and the whole was stirred at an oil bath temperature of 70° C. for 2 hours to obtain methyl 6-(3-ethyl-4-methoxyphenyl)pyridine-2-carboxylate, which was then stirred in methanol and a 1M aqueous sodium hydroxide solution at an oil bath temperature of 60° C. for 1 hour to obtain an objective compound.