Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1Cc1cc2ccccc2nc1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(2-Aminoquinolin-3-yl)methyl]-3-methoxyphenol (40 mg, 0.14 mmol), triphenylphosphine (56 mg, 0.21 mmol) and methanol (7 μL, 0.22 mmol) were placed in THF (2 mL) at 10° C. and then mixed slowly with azodicarboxylate diisopropyl ester (44 mg, 0.22 mmol) in THF (1 mL). Then the mixture was stirred for 12 hours at room temperature. The batch was mixed with water and extracted with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulfate) and concentrated. The crude product was purified chromatographically (silica gel, dichloromethane, methanol). To remove traces of triphenylphosphine oxide, the slightly contaminated product was dissolved in diethyl ether and extracted with 2N aqueous hydrochloric acid. The aqueous phase was alkalized with dilute sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane extracts were washed with water until neutral, dried (sodium sulfate) and concentrated (yield: 5 mg, 9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cccc([C@H]2C[C@H]2C(=O)O)c1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Cis-2-(3-nitrophenyl)cyclopropanecarboxylic acid (355 mg, 1.7 mmole), described in Example 21, was dissolved in 50 ml ethanol and 20 mg of PtO2 was added. Hydrogenation at atmospheric pressure for 1 hr. followed by filtration and evaporation of the solvent afforded 288 mg of cis-2-(3-aminophenyl)cyclopropanecarboxylic acid. 177 mg (1 mmole) of cis-2-(3-aminophenyl)cyclopropanecarboxylic acid was dissolved in water (1 mL), t-BuOH (1 mL) and 2M NaOH (0.5 mL, 1 mmole). 250 μL (1.1 mmole) of di-tert-butyl dicarbonate was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and water and acidified with dilute H2SO4 and extracted with dichloromethane affording 264 mg of pure BOC protected cis-2-(3-aminophenyl)-cyclopropanecarboxylic acid. This acid was transformed to BOC protected title compound according to the procedure in Example 7. Finally, deprotection with THF 1 and 6M HCl 1 gave the title product. Analysis: Calculated: C 59.5, H 5.0, N 18.5. Found: C 59.5, H 4.9, N 17.2. Mp: 177.5°-178.2° C. 1H-NMR (250 MHz, CDCl3) δ 1.00-1.07 (m, 1H), 1.23-1.37 (m, 1H), 2.24-2.33 (m, 1H), 3.15-3.25 (m, 1H), 3.65 (broad s, 2H), 6.59-6.70 (m, 4H), 6.77 (broad s, 1H), 7.11 (t, 1H), 7.45 (dd, 1H), 7.72 (s, 1H), 8.81 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>C(OCC)C.C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: BrC1CCCC1
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=C1C2=CCCCN2C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 87.2 %

Procedure:
An acetonitrile (20 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.46 g, 1.54 mmol), potassium carbonate (0.16 g, 1.16 mmol) and cyclopentylbromide (0.18 mL, 1.69 mmol) was stirred for 2 hours under reflux. A saturated ammonium chloride solution (20 mL) and diethyl ether (20 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (20 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (25 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a pale yellow oil of 2-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.49 g, yield:87.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[I:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([I:28])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(I)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 mL of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The mixture was stirred at −78° C. for 30 min and N-iodosuccinimide (2.2 eq.) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hour. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1 N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 2-(4-fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-α]pyridine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 2H, J=5.8 Hz), 7.50–7.57 (m, 3H), 7.37 (d, 1H, J=7.1 Hz), 7.20 (d, 2H, J=5.8 Hz), 7.00 (t, 2H, J=8.6 Hz), 6.90 (t, 1H, J=7.8 Hz); MS m/z 416 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17]([CH2:20][CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:22][CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Amine preparation: Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester was prepared from 3-(methylthio)-1-propanol using standard conditions. Treatment with mCPBA in DCM yielded toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester. A mixture of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester and toluene-4-sulfonic acid 3-methanesulfonyl-propyl ester was heated in MeCN in the prescence of potassium carbonate to yield 4-[(3-methanesulfonyl-propyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1O.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[O:15][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 48 h

Procedure:
Dissolve 2.5 g. of t-butoxycarbonyl-glycyl-glycine in dimethylformamide (20 ml.) containing 2,4,5-trichlorophenol (2.13 g.) and N-hydroxysuccinimide (1.4 g.) . Cool the solution in an ice bath and stir while adding dicyclohexylcarbodiimide (2.44 g.) in dimethylformamide (5 ml.). Allow the reaction mixture to stand at room temperature for 48 hours, filter the reaction mixture and evaporate the filtrate to dryness under reduced pressure. Chromatograh the residue on silica gel (150 g.). The desired product is eluted with 20% ethyl acetate/chloroform and crystallized from ether-hexane (m.p. 90°-91° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][C:15]=2[CH3:16])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[N:18][OH:19])[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccoc1C(=O)Cc1cccc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccoc1C(Cc1cccc(Cl)n1)=NO
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone (52.2 g, 221 mmol) in methanol (500 mL) was added hydroxylamine hydrochloride (76.96 g, 1.11 mol) followed by an aqueous solution of sodium hydroxide (44.3 g, 1.11 mol). The resultant suspension was heated at reflux for 2 hours and then cooled to room temperature. The mixture was concentrated and water was added to the residue while stirring. After stirring for 20 minutes, a white solid precipitated. This solid was collected by filtration and washed with water to give 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (29.0 g, 52%) as a white solid. 1H NMR (CDCl3): δ 7.54 (t, 1H), 7.31 (s, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.34 (s, 2H), 2.22 (S 3H). MS m/z 273 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](ON4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:45]1[C:53]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:54])[C:48]=2[CH:47]=[CH:46]1>CN(C)C=O>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([N:45]4[C:53]5[C:48](=[C:49]([OH:54])[CH:50]=[CH:51][CH:52]=5)[CH:47]=[CH:46]4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(-n2ccc3c(O)cccc32)cc1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.50 g, 0.95 mmol) in N,N-dimethylformamide (4 mL, 0.24M) was treated with cesium carbonate (0.62 g, 1.90 mmol) and 1H-indol-4-ol (0.15 g, 1.13 mmol). The resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), and acidified with a 1N aqueous hydrochloric acid solution. Ethyl acetate (75 mL) was added, and the mixture was filtered through filter paper, rinsing with water and ethyl acetate. The layers were separated, and the aqueous layer was back extracted with ethyl acetate (75 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 1-10% methanol/methylene chloride) followed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run) afforded impure 2-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (66 mg).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:14]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[C:20](=[O:31])[N:19]([CH2:32][CH2:33][CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:18](=[O:42])[N:17]([CH3:43])[C:16]=2[N:15]=1>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[C:20](=[O:31])[N:19]([CH2:32][CH2:33][CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:18](=[O:42])[N:17]([CH3:43])[C:16]=3[N:15]=[C:14]2[O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:29][CH:28]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OCCOC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOC1CCCCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 2-(cyclohexyloxy)ethanol (63.4 mg, 0.439 mmol, intermediate 38) in THF (5 mL) was added sodium hydride (23.4 mg, 0.586 mmol, 60% dispersion in mineral oil) at 0° C., and the mixture was stirred at room temperature for 30 min. Then a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.293 mmol, intermediate 14) in THF (1 mL) was added and the resulting mixture was stirred at reflux for 1 h. The reaction was cooled and quenched with ice-water. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give 7-(4-chlorobenzyl)-8-(2-(cyclohexyloxy)ethoxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (123 mg, 73% yield) as a yellow solid. LCMS retention time 2.064 min; LCMS MH+-THP 491.
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4].[ClH:25].O1CCOCC1>ClCCl.C(=O)(O)[O-].[Na+]>[ClH:25].[CH2:1]([N:5]1[CH2:22][CH:21]([CH2:23][F:24])[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#CCN1CC(CF)OC2(CCNCC2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
Tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 0.0676 mmol) was dissolved in dichloromethane (2 mL) and treated with HCl in dioxane (1.69 mL of 4 M, 6.76 mmol). The reaction mixture was stirred for 2 h, then diluted with dichloromethane (10 mL) and 1:1 saturated sodium bicarbonate/1 M NaOH (10 mL). The organic layer was separated, dried over Na2SO4, and concentrated to yield 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane hydrochloride (16.0 mg, 0.0666 mmol, 98%). ESI-MS m/z calc. 240.2. Found 241.5 (M+1)+; Retention time: 0.22 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)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: O
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
A solution of 3-bromoacetophenone (661 μL, 5.00 mmol) and 4-(triflouromethyl)benzeneboronic acid (950 mg, 5.00 mmol) in DME (50 mL) was added Na2CO3 (1.32 g, 12.50 mmol) and Pd(PPh3)4 (283 mg, 0.24 mmol) and water (25 mL). The mixture was then stirred at 100° C. for 20 hours, diluted with water and extracted with EtOAc. The organic layer was then washed with brine, dried (Na2SO4), filtered and reduced. Purification by flash chromatography (silica) eluting with petrol:EtOAc (gradient 19:1 to 9:1) afforded the title compound (1.01 g).
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH2:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=[CH2:13].C1(C=CC(O)=CC=1)O>>[CH:6]12[CH2:7][CH:8]([CH:4]=[CH:5]1)[CH2:9][CH2:10]2.[CH2:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=[CH2:13]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: C=CCCC(=O)[O-]
Agent: Oc1ccc(O)cc1
Product: C1=CC2CCC1C2
Temperature: 190 °C

Procedure:
DCPD (dicyclopentadiene, Aldrich, 248 ml, 1.852 mol), ally-acetate (Aldrich, 500 mL., 4.63 mol) and hydroquinone (0.7 g, 0.006 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 190° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled twice under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 56° C. (yield: 30%, exo/endo=57/43).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[OH:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:19][CH2:20][C@H:21]3[CH2:24][C@H:23]([OH:25])[CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CC(O)C1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: O[C@H]1C[C@H](COc2ncc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 3-(hydroxymethyl)cyclobutanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C. and by separation of the received isomers-mixture using a chiral column (Lux2 Cellulose with heptane:isopropanol 85:15 as solvent).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C1C=CC(C[N:18]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[CH:19]2)=CC=1F)#N>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][N:18]1[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[CH:19]1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: Cc1ccc(F)c(C#N)c1
Product: N#Cc1cc(Cn2cncc2C=O)ccc1F

Procedure:
The titled product was prepared from 3-cyano-4-fluorotoluene using the same procedures as those described in Example 1, Steps D through G for the preparation of 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, except that 3-cyano-4-fluorotoluene was used in place of 4-cyano-3-fluorotoluene in Step D.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([OH:17])[CH:3]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([NH:26][CH3:27])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][S:23](=[O:25])(=[O:24])[NH:26][CH3:27])[CH:3]=1
Reactant: CNS(=O)(=O)CCCCI
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl 4-fluoro-2-hydroxybenzylcarbamate (Example 15; 12.2 mmol), 4-iodo-N-methylbutane-1-sulfonamide (Example 18; 18.3 mmol) and potassium carbonate (61 mmol) in DMF (60 ml) was stirred at 80° C. for 10 hours.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([Cl:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[ClH:40].[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) was suspended in DCM (6 ml) and treated with triethylamine (99 μl, 1.35 mmol). Then 4-methoxybenzene-1-sulfonyl chloride (112 mg, 0.54 mmol) was added, and the reaction was stirred at RT for 3 hours. Solvent was evaporated, and the crude was dissolved in EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenylsulfonamido)-2-phenylacetate hydrochloride (105 mg; 50% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]=[C:13]=[S:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)N=C=S
Reaction time: 1.5 h

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.017 mL, 0.126 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.014 g, 0.176 mmol, 3.5 eq) in ethyl acetate (1.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a 2-(4-fluorophenyl)ethanoyl isothiocyanate solution (0.126 M). 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.011 g, 0.050 mmol, 1.0 eq) was dissolved in CH2Cl2 (1.0 mL) and 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.126 M, 0.50 mL, 0.063 mmol, 1.3 eq) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-6% MeOH in CHCl3) to afford the title compound (0.008 g, 38%) as a solid. 1H NMR (CD3OD) δ 7.85-7.95 (m, 1H), 7.67-7.69 (m, 1H), 7.13-7.28 (m, 4H), 6.95-7.00 (m, 2H), 6.05-6.15 (m, 1H), 5.90-5.91 (m, 1H), 3.65 (s, 2H); MS(ESI+) m/z 415 (M+H)+; HRMS(ESI+) calculated: 415.1040, found: 415.1041.