Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1O.S(=O)(=O)(O)O>O>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:18]3[C:19]([CH3:23])=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[C:17]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Temperature: 115 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a mixture of hydroxy(4-isopropylphenyl)acetic acid synthesized in Reference Example 1 (11.8 g, 60.8 mmol) and 2,3,5-trimethylphenol (12.4 g, 91.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature, and the mixture was stirred at 115° C. for 12 hours. The mixture was added to water and was extracted with diisopropyl ether. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane ethyl acetate=8:1) to obtain 10.9 g (yield 65%) of the title compound. Melting point: 107-108° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)(=[O:4])=[O:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:5]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(NS(C)(=O)=O)oc23)c1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O

Procedure:
This compound is prepared in the manner of Step F, Example 1, with 4.3 grams (10 mmole) of 3-(2-methylsulfonylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 1.5 grams (11 mmole) of potassium carbonate, 1.7 grams (12 mmole) of methyl iodide, and 25 mL of acetone as reagents.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.C([BH3-])#[N:14].[Na+].C([O-])(=O)C.[NH4+]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[CH:7]([NH2:14])[CH2:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: O=C1CCc2cc(Br)cc(F)c21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCc2cc(Br)cc(F)c21

Procedure:
In analogy to the procedure described for the preparation of intermediates A-4 [A], 5-bromo-7-fluoro-indan-1-one was reacted with sodium cyanoborohydride and ammonium acetate in 2-propanol at reflux to yield the title compound as light yellow oil. MS: 228 (M−H−, 1Br).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[O:19]=[C:20]1[C:28]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:27]2[C:22](=[C:23]([C:40]#[N:41])[CH:24]=[CH:25][CH:26]=2)[NH:21]1>>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][C:23]=3[C:40]#[N:41])[C:28]3([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]3)[C:20]2=[O:19])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(C#N)c32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile was obtained (74%) as a colorless solid: mp=162-163° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.66 (dd, J=8.0, 1.2 Hz, 1H), 7.52 (dd, J=7.4, 1.2 Hz, 1H), 7.39 (s, 1H), 7.19 (dd, J=7.7, 7.7 Hz, 1H), 6.72 (s, 1H), 6.42 (s, 1H), 5.94 (s, 2H), 5.25 (ABq, 2H), 4.80 (ABq, 2H), 3.28-3.15 (m, 1H), 1.26 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.9, 155.4, 149.7, 148.6, 144.0, 141.8, 133.8, 133.1, 128.4, 123.4, 119.0, 116.5, 114.3, 103.1, 101.5, 93.3, 93.1, 79.4, 56.5, 40.9, 32.4, 22.7; MS (ES+) m/z 446.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]1[CH2:27][CH2:26][CH:25](O)[CH2:24]1)[CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:25]2[CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CCN1CCC(O)C1
Product: CCN1CCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-Ethyl-3-pyrrolidinol.
Reaction SMILES: NCC(O)=O.[CH2:6]([OH:17])[C@H:7]([OH:16])[C@H:8]1[O:13][C:11](=[O:12])[C@@H:10]([OH:14])[C@@H:9]1[OH:15]>C(O)C>[O:12]=[C:11]1[O:13][C@H:8]([C@H:7]([CH2:6][OH:17])[OH:16])[C:9]([OH:15])=[C:10]1[OH:14]
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@@H](O)[C@@H]1O
Agent: NCC(=O)O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 24 h

Procedure:
A 4.0 liter laboratory scale airlift fermentor was filled with sterile glycine medium, pH 4.1, containing 2.75% w/v ethanol, 0.7% glycine and 0.5% L-galactono-gamma-lactone. The fermentor was inoculated with a 24 hour suspension of the C. norvegensis KCC MF-42 cells washed from G-Agar (2.5%) flasks. The viable cell count at 0 hour was 5.5×106. Aeration of the fermentor was adjusted to 1.9 liters of air per liter of fermentation medium per minute [V/V/minute]which provided a cycle rate of 5.0 m-1. After 24 hours at 30° C., the viable cell count rose to 1.1×108, and at 48 hours was 3.0×108, at 72 hours the viable cell count was 2.8×108. The count declined to 1.7×108 after 91 hours of cultivation. A level of 0.72 gL-1 of L-ascorbic acid was produced.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]([OH:24])(=O)[CH:21]=[CH2:22].[NH2:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1O.[OH-].[Na+]>O.ClCCl.C(OCC)C>[Br:32][C:30]1[CH:29]=[CH:28][C:27]2[O:24][C:20]([CH:21]=[CH2:22])=[N:25][C:26]=2[CH:31]=1
Reactant: C=CC(=O)O
Reactant: Nc1cc(Br)ccc1O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C=Cc1nc2cc(Br)ccc2o1
Temperature: 78 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
A mixture of 12 g of methanesulfonic acid and 1.8 g of phosphorus pentoxide (P2O5) was stirred 12 hours. To this well stirred suspension was added 0.346 g (4.8 mmol) of acrylic acid and 0.808 g (4 mmol) of 2-amino-4-bromo-phenol. The reaction was heated at 78° C. for 5 hours, then cooled to room temperature. The reaction was then slowly poured into a well-stirred slurry of 15 mL of 50% aqueous NaOH in 200 g of ice and water. The mixture was then poured into a separatory funnel and shaken with 300 mL water, 200 mL of diethyl ether, and 75 mL of dichloromethane and shaken vigorously. A small quantity of solid was removed by suction filtration, and the filtrate again shaken vigorously in a separatory funnel. The organic phase was collected, dried over Na2SO4, and concentrated in vacuo to a thick syrup that crystallized to give large yellow stars. Purification by flash chromatography on silica gel (eluting with 1:1 hexane:dichloromethane) gave 0.404 g (45%) of 5-bromo-2-vinyl-benzooxazole as a white powder, mp 55-56° C. 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=1.8 Hz, 1H), 7.46 (dd, J=8.7, 1.8 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 6.76 (dd, J=17, 10.5 Hz, 1H), 6.50 (d, J=17 Hz, 1H), 5.90 (d, J=10.5 Hz, 1H); Mass spectrum: [M+H]+ at 224.0 & 226.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][NH2:12].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:12][CH3:11])[C:5]#[N:6]
Reactant: CN
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1Cl
Temperature: 65 °C
Yield: 95 %

Procedure:
A mixture of 3-chloro-4-fluorobenzonitrile (5.2 g, 33 mmol), THF (55 mL), and 40% methylamine in water (25 mL, 290 mmol) in a sealed tube was heated to 65° C. for 1.5 hours, cooled to room temperature. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting solid was dried for about 16 hours under high vacuum in the presence of P2O5 to provide 6.3 g (95%) of the desired product. MS (DCI/NH3) m/z 184, 186 (M+H+NH3)+; 1H NMR (DMSO-d6) δ 7.72 (d, 1H), 7.55 (dd, 1H), 6.70 (d, 1H), 6.52 (br q, 1H), 2.80 (d, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:15](=[O:16])[C:14](=[C:17]2[S:21][CH:20]=[CH:19][S:18]2)[C:13](=[O:22])[CH:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]I.O>CN(C)C=O>[CH2:3]([N:10]1[C:15](=[O:16])[C:14](=[C:17]2[S:18][CH:19]=[CH:20][S:21]2)[C:13](=[O:22])[C:12]([CH3:28])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)C(=O)C(=C2SC=CS2)C1=O
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 175 mg) is suspended in dimethylformamide (10 ml), and thereto is added dropwise a solution of ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (1.3 g) in dimethylformamide (30 ml) under ice-cooling. The mixture is stirred at the same temperature for 20 minutes. Methyl iodide (0.7 ml) is added to the mixture, and the mixture is stirred under ice-cooling for 1.5 hours and then at room temperature for 1.5 hours. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane to give ethyl 1-benzyl-5-(1,3-dithiol-2-ylidene)-3-methyl-4,6-dioxopiperidine-3-carboxylate (1.15 g, 85.2%) as pale yellow needles, m.p. 111°-113° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-])=O)=[CH:4][N:3]=1.CC([O-])=O.[K+]>C(O)C.[Pd]>[C:8]1([C:7]2[CH:6]=[C:5]([NH2:14])[CH:4]=[N:3][CH:2]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-c2ccccc2)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1cncc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 68.3 %

Procedure:
A mixture of 2-chloro-5-nitro-3-phenylpyridine (0.43 mmol, 0.1 g), KOAc (0.43 mmol, 0.042 g) and Pd/C 10% (0.03 g) in ethanol (4 ml) was stirred for 24 hours under hydrogen atmosphere. The catalyst was filtered off and the solid thoughtfully washed with warm ethanol. The solid residue was purified by chromatography over SiO2 eluting with dichloromethane/methanol mixtures affording 5-phenylpyridin-3-amine (0.05 g, yield 69%) of the expected product.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH:6]1([S:9](Cl)(=[O:11])=[O:10])[CH2:8][CH2:7]1>C1COCC1>[C:1]([NH:5][S:9]([CH:6]1[CH2:8][CH2:7]1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1CC1
Temperature: -20 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a round-bottom flask equipped with a stir bar was added tert-butylamine (32.9 mL, 313 mmol) and dry THF (330 mL). The solution was cooled to −20° C. and to the stirred solution was added dropwise cyclopropanesulfonyl chloride (14.5 mL, 142 mmol). The solution was allowed to warm to room temperature with stirring for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM, washed with 1N HCl; water; and then brine. The organic solution was dried over MgSO4, filtered, and then concentrated in vacuo. The resulting solid was recrystallized from hexanes:EtOAc (5:1) to afford N-(tert-butyl)cyclopropanesulfonamide as a colorless crystalline solid (20.95 g, 83%). 1H NMR (400 MHz, CDCl3) δ 4.22 (br. s., 1H), 2.47 (tt, J=8.0, 4.9 Hz, 1H), 1.40 (s, 9H), 1.22-1.16 (m, 2H), 1.04-0.97 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]3[N:28]([CH3:29])[C:27](=[O:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[CH3:31])[N:20]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[CH3:29][N:28]1[C:27](=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:31])[N:20]=[C:19]1[CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:33][CH:32]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(C=Cc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 2-[2-[4-(4-acetoxybenzoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (631 mg) in THF-ethyl acetate-methanol (1:1:1) (50 ml) was added 10% Pd/C (50% hydrous) (126 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. After the residue was suspended in ethanol (10 ml), 1N-aqueous sodium hydroxide solution (2.9 ml) was added and the mixture was stirred at room temperature for 2 hours. This reaction mixture was concentrated and the residue was suspended in water (20 ml) and neutralized with 1N-hydrochloric acid (2.9 ml). The precipitate was collected by filtration, washed with water, and dried to provide 538 mg of white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:6][CH2:5]1
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: OCCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: OCCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
4-(2-Hydroxyethyl)-piperazine (7.2 ml; 58.7 mmol) was added to a suspension of 5-chloromethyl-8-hydroxyquinoline (5.413 g; 23.5 mmol) in CHCl3 (80 ml) at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was subsequently washed with a saturated NaHCO3 solution and brine, then dried with Na2SO4 and evaporated to dryness. Crystallization of the residue from a mixture of CHCl3-Hex gave 4.05 g (60%) of title product. M.p. 123-4° C. The mother liquor was evaporated and the residue was crystallized to yield 1.5 g of title product. Overall yield: 5.55 g (82%). A highly pure product was obtained by soxleth extraction using hexane as the extractant. TLC (CHCl3 MeOH NH3=8:2:0.5). Rf=0.4.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:27][C:28]1[CH:29]=[C:30]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:39]2[CH2:38][CH2:37][N:36]([C:30]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([OH:27])[CH:29]=3)[CH2:41][CH2:40]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1O
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: C=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.31 g=0.28 ml) of 4-chlorostyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetatein-hexane gives the product 1-(4-fluorophenyl)-4-[2-(4-chlorophenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14]Cl)[CH2:9][C@@H:8]1[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[SH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>C(#N)C.CO>[O:3]=[C:4]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:9][C@@H:8]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@H]1CN(CCCl)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: Sc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSc2ccccn2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 56.8 %

Procedure:
A mixture of 1.35 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(2-chloroethyl)piperidine-3-carboxylate dihydrochloride in 20 cm3 of acetonitrile was stirred at a temperature in the region of 20° C. under an inert atmosphere. 1.37 g of potassium carbonate and 0.456 g of potassium iodide were added, followed by 0.367 g of 2-mercaptopyridine and 1 cm3 of methanol. A red suspension was obtained, which suspension was heated at a temperature in the region of 80° C. for 1 hour 30 minutes. After cooling the reaction mass to a temperature in the region of 20° C., the insoluble material was filtered off and washed with acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; silica height 35 cm), elution was carried out with an ethyl acetate/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 19 to 40 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.77 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-ylthio)ethyl]piperidine-3-carboxylate was obtained in the form of a viscous oil with a red color.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCOCC1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 4-iodobenzoyl chloride (500 mg), morpholine (163 mg) and triethylamine (380 mg) in CH2Cl2 (20 ml) is stirred 2 h before washing with H2O (20 ml) and brine (20 ml). The organic layer is dried over MgSO4 and the solvent is evaporated to obtain 482 mg of (4-iodo-phenyl)-morpholin-4-yl-methanone, yellowish semisolid, MS (ESI) 318.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1C(=O)N([Br:22])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C/c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C/c1ccccc1CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a suspension of ethyl(E)-3-(2-methylphenyl)-2-propenoate (20.0 g; 105 mmol) and NBS (19.64 g; 110.3 mmol) in refluxing CCl4 was added benzoyl peroxide (1.27 g) and the mixture was stirred for 12 h. The solution was cooled to r.t., filtered and concentrated. Flash chromatography with EtOAc:hexane 5:95 yielded the title compound (14.18 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].CC(C)=O>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[C:4]([NH2:5])=[N:12][NH:13]2
Reactant: NN
Reactant: N#Cc1c(F)cccc1Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: Nc1n[nH]c2cccc(Cl)c12
Temperature: 90 °C
Reaction time: 19 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-6-fluorobenzonitrile (ABCR) (3 g, 19 mmol) in anhydrous ethanol (50 mL) was added hydrazine hydrate (3.74 mL, 77 mmol). The reaction was heated at 90° C. under a nitrogen for 3.5 hours. The reaction mixture was cooled to room temperature, treated with acetone (20 mL) and left to stand for 19 hours. The mixture was evaporated in-vacuo to yield an orange/brown solid, which was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid, which was absorbed onto Florisil (60-100 mesh), applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 24-29 were combined and the solvent was evaporated in-vacuo to yield the title compound as a yellow solid (2.14 g, 66%) LCMS (System B) RT=1.58 min, ES+ve m/z 168 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH3:2].Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:19][CH2:20]1)=[O:11])[CH3:2]
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: CCOC(=O)CCCCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of adipic acid mono ethyl ester (154 mg, 0.883 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate HCl salt (Example 9, step 2)(300 mg, 0.883 mmol) in DMF (2 mL) was added Huenig's base (0.771 mL, 4.42 mmol) and T3P® (50% in DMF) (1.031 mL, 1.767 mmol) and the mixture was stirred at RT for 4 hrs. The resulting mixture was diluted with EtOAc and washed with a saturated solution of sodium bicarbonate.