Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:13])=[CH:10][C:11]=1[OH:12])=[O:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19](Cl)=O.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]1[O:12][C:11]2[C:6]([C:4](=[O:5])[CH:3]=1)=[CH:7][CH:8]=[C:9]([OH:13])[CH:10]=2
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (18 mmol, 3.6 equivalents) is added in one portion to a well-stirred solution of 2,4-dihydroxyacetophenone (5 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at about 0° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 3,4-dimethoxybenzoyl chloride (5.9 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 3′,4′-dimethoxy-7-hydroxyflavone. 1H NMR (250 MHz, DMSO-d6): δ=3.85 (d, 6 H), 6.85–8.00 (m, 7 H), 10.72 (s, 1 H); 13C NMR (250 MHz, DMSO-d6): δ=56.08 (s), 56.22 (s), 102.95 (s), 105.82 (s), 109.76 (s), 112.11 (s), 115.19 (s), 116.51 (s), 119.38 (s), 123.97 (s), 126.80 (s), 149.40 (s), 152.10 (s), 157.79 (s), 162.41 (s), 162.94 (s), 176.70 (s); EI-MS (70 eV) m/e (rel. abund.)=298; UV (2-propanol): λ=236 nm, 332 nm.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C@@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:11][C@@H:10]1[CH2:33][OH:34])(C(C)(C)C)(C)C.N1C=CC=CC=1.Cl[S:42]([NH2:45])(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:34][CH2:33][C@H:10]1[CH2:11][C@H:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[O:31][CH3:32])[N:18]=[CH:17][N:16]=2)[CH2:13][C@H:9]1[OH:8])[NH2:45]
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](COS(N)(=O)=O)[C@H](O)C2)ncn1
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of {(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol (0.112 g, 0.231 mmol) (azetroped with toluene) and pyridine (0.0374 mL, 0.462 mmol) in anhydrous acetonitrile (2.3 mL) was cooled to 0° C. A 2 N solution of chlorosulfonamide in acetonitrile (0.116 mL) was added dropwise and the reaction was stirred for 3 h. Additional 2 N solution of chlorosulfonamide in acetonitrile (0.026 mL) and pyridine (0.0041 g, 0.052 mol) were added and the reaction was stirred for 1 h then quenched with methanol. The solution was concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound as a white solid (0.059 g, 57%). 1H NMR (CD3OD, 400 MHz, δ): 8.26 (s, 1H); 8.01 (s, 1H); 7.26-7.16 (m, 3H); 5.70 (s, 1H); 5.47-5.33 (bs, 1H); 4.35 (t, J=4.5 Hz, 1H); 4.31 (d, J=7.5 Hz, 1H); 4.28 (d, J=7.5 Hz, 1H); 4.25-4.21 (m, 1H); 4.15-4.11 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 3.36 (s, 3H); 3.16-3.00 (m, 2H); 2.54-2.45 (m, 1H); 2.26-2.19 (m, 1H); 2.10-1.98 (m, 1H); 1.87-1.78 (m, 1H); 1.77-1.69 (m, 1H). LC/MS: Rt=1.11 min, ES+ 450 (FA standard).
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:12](=[O:14])[N:11](COCC[Si](C)(C)C)[N:10]=[CH:9][C:8]=2[NH:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH:34]2[CH2:36][CH2:35]2)[CH:24]=1)[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[NH:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH:34]2[CH2:35][CH2:36]2)[CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Solvent: CCO
Product: CCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 95.2 %

Procedure:
Reaction was carried out in the same manner as in Example 6-(c) except for using 3.94 g (7.58 mmol) of 3-butyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 8-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-propyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and post treatment was carried out except for using ethanol in place of methanol, whereby 2.81 g of the title compound was obtained as a white solid. (Yield: 95%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH:22]([CH3:29])[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:30])[CH:22]([CH3:29])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 65 °C
Yield: 78.5 %

Procedure:
A mixture of 4-[4-(3-ethoxycarbonyl-2-methyl-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 189 step 2) (5.7 g, 14 mmol) and 1N NaOH (18 mL) in methanol was heated at 65° C. for 1 h. Methanol was evaporated at reduced pressure and diluted with water then cooled to 0° C. The aqueous layer was neutralized carefully with citric acid and extracted twice with methylene chloride to obtain a crude 4-[4-(3-carboxy-2-methyl-propionyl)phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.3 g, 81%), MS m/z 390 (M−1)
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 79.3 %

Procedure:
1.16 g (2.46 mmoles) of Z-Glp-Nle-Pro-NH2 are dissolved in 25 ml of methanol. 0.2 g of a 10% palladium-on-carbon catalyst is added to the solution, and hydrogen is bubbled through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated, and the solid, amorphous residue is triturated with ether. The resulting 0.72 g of crude product is dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.66 g (79.5%) of Glp-Nle-Pro-NH2 are obtained: Rf4 =0.43, [α]D25 =-77.1° (c=1%, in acetic acid). Amino acid analysis: Glu: 0.96 (1.0), Nle: 1.00 (1.0), Pro: 1.00 (1.0).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]([C@H:8]3[C@H:12]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:10](=[O:19])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1N[C@@H](c2cccc(Br)c2)[C@H](c2cccnc2)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](c2cccc(C#Cc3ccccc3)c2)[C@H](c2cccnc2)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To trans-4-(3-bromophenyl)-5-(pyridin-3-yl)oxazolidin-2-one (46 mg, 0.144 mmol) slurried in triethylamine (3 mL) was added ethynylbenzene (0.021 mL, 0.187 mmol), copper(I) iodide (2.74 mg, 0.014 mmol), and triphenylphosphine (26.5 mg, 0.101 mmol). The reaction mixture was cooled to −78° C. under nitrogen and subjected to three rounds of pump/nitrogen purge. The mixture was then warmed to ambient temperature and (Ph3P)2PdCl2 (10.12 mg, 0.014 mmol) was added. The vessel was fitted with a reflux condensor and placed in an oil bath at 93° C. for 18 h at which time the vessel was removed from the heat and the residue was solubilized in 1:1 dimethylformamide/methanol and purified via preparative HPLC method 4. Pooling and concentration of the fractions containing the peak eluting at 7.37 min provided 14.3 mg trans-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one as an indeterminate enantiomeric mixture. 1H NMR (500 MHz, MeOD) δ ppm 8.44 (1H, d, J=7.32 Hz), 8.16 (1H, br. s.), 7.57-7.63 (2H, m), 7.47-7.57 (4H, m), 7.44 (1H, d, J=7.63 Hz), 7.36-7.42 (4H, m), 5.68 (1H, d, J=6.41 Hz), 4.98 (1H, d, J=6.71 Hz). LC/MS (Analytical HPLC Method 6) 1.97 min, Anal. Calcd. for [M+H]+ C22H16N2O2: 341.12. found 341.29. HPLC retention time (Analytical HPLC method 3): 7.30 min. Further purification via preparative SFC method 5 provided 2.2 mg (4%) (4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (5.8 min retention time) as a colorless oil and 2.0 mg (4%) (4S,5S)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one as a colorless oil. HPLC retention time for (4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (Analytical HPLC method 3): 7.12 min. HPLC retention time for (4S,5S)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (Analytical HPLC method 3): 7.10 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([CH2:28]Br)=[O:27]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][C:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[O:27])=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g) in 5 mL of dimethylformamide was treated with 60% sodium hydride (0.112 g) and after 20 minutes, bromomethyl 2-naphthyl ketone (0.70 g) was added. The reaction mixture was stirred 3 hours at room temperature, was quenched with 0.1 mL of acetic acid and was diluted with ethyl acetate (75 mL). The mixture was washed with water (1 x 25 mL) and brine (1×25 mL), dried (MgSO4) and chromatographed over 100 g of silica gel, eluting with dichoromethane-ethyl acetate (50:1) to give 0.62 g of 4-[2-(2-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester, mp 120°-121° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[C:23](=O)([O-])[OH:24].[Na+]>CN(C=O)C>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]([CH:23]=[O:24])=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1H-Indol-6-yl)(morpholino)methanone (36.0 g, 156.5 mmol) in DMF (540 mL) was added drop wise at 0° C. to a solution of phosphoryl chloride (43.9 mL, 469 mmol) in DMF (884 mL) and the mixture was stirred at room temperature for 4 h. The reaction mixture was then neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate and evaporated. The residue was finally purified by column chromatography [100-200 mesh silica; dichloromethane with 10% methanol]. White solid. Yield: 36 g (89% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:30]3[CH2:31][CH2:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 1,2,3,4-tetrahydroisoquinoline (0.95 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 9 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20). The residue was further purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (90:10) gradually changing to pentane:ethyl acetate (70:30) to afford the title compound (343 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]=2)[NH:3]1.O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])[CH:8]=2)[NH:3]1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 80 °C
Reaction time: 12 h
Yield: 1114.7 %

Procedure:
4 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)acetic acid are dissolved in 100 ml of ethanol, and 300 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h, and the solvent is subsequently removed in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate and stirred at 60° C. for a further 12 h. The mixture is neutralised using sodium hydrogencarbonate, and the organic phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo, giving 4.1 g of ethyl 2-(2,3-dioxoindolin-5-yl)acetate;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH2:13])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH:33]3[CH2:35][CH2:34]3)[C:31](=[O:36])[N:30]([CH2:37][C:38](O)=[O:39])[N:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([NH:13][C:38](=[O:39])[CH2:37][N:30]3[C:31](=[O:36])[N:32]([CH:33]4[CH2:34][CH2:35]4)[C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)=[N:29]3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NC1(c2cccc(Cl)c2)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)NC1(c2cccc(Cl)c2)CCC1
Reaction time: 0.17 h

Procedure:
57.2 mg (0.262 mmol) of 1-(3-chlorophenyl)cyclobutanamine hydrochloride are placed in 2 ml of dimethylformamide and treated with 26.5 mg (0.262 mmol) of triethylamine. After 10 mins' stirring, 70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 38.7 mg (0.286 mmol) of HOBt are added. After a further 10 mins' stirring, the mixture is treated with 59.4 mg (0.310 mmol) of EDC hydrochloride and stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1) and thus yields 66 mg (61% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1ccc(-c2nc(Cl)ncc2F)cc1
Temperature: 85 °C
Yield: 29 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (0.50 g, 3.0 mmol) and 4-carboxyphenyl boronic acid (0.5 g, 3.0 mmol) were dissolved in dimethoxyethane (20 mL) in a screw cap test tube and 6 mL 2M Na2CO3 was added followed by 80 mg (0.069 mmol) tetrakis(triphenylphosphine)palladium. Argon was bubbled through the reaction mixture for 5 minutes and then the reaction mixture was heated to 85° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a solid, which was purified by chromatography on silica (MeOH 5%/CH2Cl2) to give 0.22 g (0.87 mmol, 29% yield) of 4-(2-chloro-5-fluoropyrimidin-4-yl)-benzoic acid as a white solid. 1H NMR 500 MHz (MeOH-d4): 8.85 (m, 1H), 8.20 (m, 4H).
Reaction SMILES: N.[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[Li].C(O)C>C(OCC)C>[CH2:2]([O:6][C:7]1[CH2:12][CH:11]=[C:10]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]2)[CH2:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OCCCC)cc2)CC1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](CCC2=CCC(OCCCC)=CC2)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
1306 ml of liquid ammonia were placed in a sulphonation flask and then a solution of 38.4 g of 4-butyloxy-1-[2-(trans-4-pentylcyclohexyl)ethyl]benzene in 1.1 l of diethyl ether was added dropwise within 40 minutes while cooling. 23.3 g of lithium wire were subsequently added within 35 minutes and the mixture was stirred for 2 hours. 420 ml of ethanol were then added dropwise to the mixture within 70 minutes and the ammonia was allowed to evaporate overnight under nitrogen. The mixture was cooled to 10° C. and 1.5 l of water were then added dropwise within 35 minutes in such a manner that the temperature did not rise above 10° C. The mixture was extracted three times with 0.5 l of diethyl ether each time. The organic phases were washed twice with 0.5 l of water each time, dried over potassium carbonate, filtered and concentrated, there being obtained 39.0 g of 4-butyloxy-1-[2-(trans-4-pentylcyclohexyl)ethyl]-1,4-cyclohexadiene as a colourless crystallizing oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][N:30]2[CH2:31][CH2:32][CH:27]([C:23]3[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=3)[CH2:28][CH2:29]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccsc1Sc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccsc3Sc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-[(4-chlorophenyl)sulfanyl]-3-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:16]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccco1

Procedure:
Using 2-amino-benzothiazole and furan-2-carboxylic acid chloride in pyridine the title compound was obtained as a white solid (83% yield), MS: m/e=244 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=4)[C:21]4([CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Br:39]N1C(=O)CCC1=O>C(#N)C>[Br:39][C:24]1[N:23]=[C:22]2[C:21]3([CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:20][N:19]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:7]=3[CH3:18])[C:27]2=[CH:26][C:25]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(Br)c(N3CCOCC3)cc21
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (250 mg, 0.489 mmol) in acetonitrile (6 mL) at 0° C. was added dropwise via syringe over 5 min a solution of N-bromosuccinimide (87 mg, 0.489 mmol) in acetonitrile (4 mL). The reaction was stirred at this temperature for 15 min. After this time the reaction was partitioned between EtOAc (40 mL) and water (15 mL). The separated organic layer was washed with NaHCO3 (15 mL, saturated aqueous solution) and Na2S2O3 (15 mL, saturated aqueous solution) and then it was dried over MgSO4, filtered and evaporated in vacuo to give 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dt, J=4.8, 1.4 Hz), 7.83-7.99 (3H, m), 7.70 (1H, dd, J=9.2, 5.9 Hz), 7.42 (1H, ddd, J=6.8, 4.7, 2.2 Hz), 7.28-7.34 (1H, m), 5.97 (1H, s), 4.10-4.20 (2H, m), 3.94-4.06 (2H, m), 3.74-3.84 (4H, m), 3.49-3.64 (2H, m), 2.78-2.94 (4H, m), 2.28-2.46 (5H, m), 1.72-1.88 (2H, m). Mass Spectrum (ESI) m/e=590.0 [(M+1) (79Br)] and 592.0 [(M+1) (81Br)]