Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=CC=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:25][CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G49) can be prepared by the nucleophilic displacement of commercially available 1-(bromomethyl)-4-nitrobenzene (G47) with tert-butyl piperazine-1-carboxylate (G7) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (G48). Subsequent reduction with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal, gives tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G49).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([CH:16]([OH:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1>CS(C)=O>[NH2:8][C:9]1[N:10]=[C:11]([Cl:26])[C:12]([C:16](=[O:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:13]([Cl:15])[N:14]=1
Reactant: CC1(C)OCC(CC(O)c2c(Cl)nc(N)nc2Cl)O1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Triethylamine (5.25 mL) and a sulfur trioxide-pyridine complex (2.45 g) were added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-ol (2.32 g) and dimethyl sulfoxide (30 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for two hours. The reaction mixture was added dropwise to a 0.5 N hydrochloric acid solution (300 mL), followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (2.08 g, 90%) as a solid. The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:27])[CH:33]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: OB(O)c1cccc(O)c1
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
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(O)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2087 μmol) and 3-hydroxyphenylboronic acid (1.55 eq) in a mixture of DME/EtOH:1/1 (8 ml) were added Na2CO3 (4 eq) and Pd tetrakis (0.05 eq.). The reaction mixture was flushed with Ar and was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was cooled to RT, diluted with 1N NaHCO3 and extracted with EtOAc. The organic layer was extracted with 1N NaHCO3 and the combined aqueous layers were acidified with citric acid and 1N HCl. The aqueous layer was extracted with EtOAc, the organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by recrystallization from EtOAc.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].Br[CH2:27][CH2:28][CH2:29][CH3:30]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: CCCCBr
Product: CCCCOc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC(N(CCC)CCC)C2

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 0.38 g, 1 mmol) was treated with bromobutane (0.27 g, 2 mmol). Chromatographic purification yielded pure product 71 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 148-149° C.).
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH3:3].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Solvent: O
Solvent: CCO
Product: CCCN(CCC(=O)OCC)[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.3 %

Procedure:
Ethyl 8-(propylamino)-trans-1,4-dioxaspiro[4.5]-decane-7-carboxylate (129.6 g, 0.48 mole) was dissolved in ethanol (1500 ml), then ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed overnight, then additional ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed for 24 hours, at which time a third addition of ethyl acrylate (479 g, 0.48 mole) was made, followed by 60 hours of reflux. The mixture was then cooled to room temperature, poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 177.4 g of crude product. This was purified by HPLC to give 102.1 g of the title product (59.8%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-5-fluoropyrimidine. ESI-MS (m/z): 420 [M+1]+.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[N:20][C:21]=1[C:22]1[O:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnccc2C#N)nc1-c1nnc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccncc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(4-cyano-3-pyridyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate (140 mg, 0.2585 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL, 25.96 mmol) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, re-disolved in MeOH/DCM and concentrated (2×), dissolved MeOH/DCM and passed through bicarbonate cartridge, concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetonitrile and filtered to give yellow solid (83 mg, 94%); 1H NMR (400.0 MHz, DMSO) d 7.69-7.77 (m, 3H), 8.07 (d, 1H), 8.24-8.26 (m, 2H), 7.80-8.40 (br s, 2H), 8.90 (d, 1H), 9.09 (s, 1H) and 9.47 (s, 1H) ppm; MS (ES+) 342.16
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[C:24]([NH2:25])=[N:26][C:27]([NH2:29])=[N:28]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(C)(C)c1ccc(NC(=N)NC(=N)N)cc1
Reactant: CCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1ccc(C(C)(C)C)cc1

Procedure:
100 ml of ethanol, 4.8 ml (27.9 mmol) of 1-nonanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.5 mmol) of N1-(4-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 70% aqueous acetonitrile to obtain 16 g of colorless crystals having a melting point of 231 to 234° C.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:32]#[N:33])([NH:18][C:19]([C:21]2[C:29]3[O:28][C:27]([F:31])([F:30])[O:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CCO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2([N:18]=[C:19]([C:21]3[C:29]4[O:28][C:27]([F:31])([F:30])[O:26][C:25]=4[CH:24]=[CH:23][CH:22]=3)[NH:33][C:32]2=[O:1])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc3c2OC(F)(F)O3)CC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc3c1OC(F)(F)O3)NC2=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 91.3 %

Procedure:
A 1 N aqueous NaOH solution (0.274 ml, 0.274 mmol) and a 35% aqueous H2O2 solution (0.051 ml, 0.52 mmol) were added to a solution of 4-cyano-4-[(2,2-difluoro-benzo[1,3]dioxole-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (56.0 mg, 0.137 mmol) in THF (0.23 ml) at room temperature. The reaction mixture was stirred at room temperature for 43 hours, and a 35% aqueous H2O2 solution (0.030 ml, 0.31 mmol) was then further added at room temperature. After stirring at room temperature for 48 hours, the mixture was quenched with a 1 N aqueous HCl solution (0.2 ml) and concentrated under reduced pressure. A 6 N aqueous NaOH solution (0.33 ml, 2.0 mmol) was added to a suspension of the resulting residue in EtOH (1.2 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (0.4 ml) and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (51.2 mg, 91%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=2)[C:30](=[O:38])[NH:29]1)=O)(C)(C)C.O>CN1C(=O)CCC1>[CH:18]([C:16]1[CH:17]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:37][C:34]3[CH:35]=[C:36]4[C:31]([C:30](=[O:38])[NH:29][NH:28]4)=[CH:32][CH:33]=3)[N:11]=2)[NH:14][N:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(Nc2nc(Nc3ccc4c(=O)[nH][nH]c4c3)nc3ccccc23)[nH]n1
Temperature: 130 °C

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(5-isopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.17 mmol) in NMP (1 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol). The mixture was heated at 130° C. for 3 hrs, cooled to room temperature, and then poured into water. The crude material was collected by filtration and treated with TFA in CH2Cl2 for 30 min.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[H][H]>C(O)(=O)C.[Pd]>[OH:1][NH:2][C:3]([C:5]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:6][CH2:7][N:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCC(C(=O)NO)(S(=O)(=O)c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)CC2)cc1

Procedure:
A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: Cn1c(=O)oc2ccccc21
Reactant: O=C(Cl)CCCl
Agent: Cl
Product: Cn1c(=O)oc2cc(C(=O)CCCl)ccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
The flask is equipped with a reflux condenser and taken to an oil bath at a temperature in the region of 40°-45° C. 0.04 mole of 3-methylbenzoxazolinone and 0.44 mole of 3-chloropropionic acid chloride are introduced. The mixture is heated to a temperature in the region of 75° C. for 2 hours 30 minutes. After cooling, the reaction mixture is poured into 300 g of ice, acidified with concentrated hydrochloric acid and stirred for 1 hour 30 minutes. The precipitate obtained is drained, washed with water and dried. The product is recrystallized in ethanol.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>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.CO>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: F[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3C[C@@H](F)[C@H](F)C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
A mixture of 152 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-iodopyridine, 60 mg of (3R)-3-ethynyl-3-quinuclidinol, 22 mg of tetrakis(triphenylphosphine)palladium(0), 7 mg of cuprous iodide, 106 μl of triethylamine and 1.5 ml of methanol was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography, eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1) and crystallized from hexane/ethyl acetate, to give 65 mg of the target compound.
Reaction SMILES: IC.[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[C:3]([O:7][C:8](=[O:19])[N:9]([C:10]1[CH:11]=[C:12]([CH3:18])[C:13]([Br:17])=[C:14]([CH3:16])[CH:15]=1)[CH3:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(C)c1Br
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1Br
Reaction time: 27 h
Yield: 18.8 %

Procedure:
Iodomethane (20.5 ml, 329 mmol) was added to a solution of (4-bromo-3,5-dimethyl-phenyl)-carbamic acid tert-butyl ester (47.5 g, 158 mmol) and cesium carbonate (80.6 g, 247 mmol) in DMF (165 ml) at room temperature, and the mixture was stirred for 27 hours. Further, cesium carbonate (26.9 g, 82.6 mmol) and iodomethane (20.5 ml, 329 mmol) were added at room temperature, and the mixture was further stirred for three days. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3,5-dimethyl-phenyl)-methyl-carbamic acid tert-butyl ester (9.34 g, 92%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1I.C(N(CC)CC)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:32])([F:31])[F:22])[CH:4]=2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#Cc1cccc(NC(=O)Cc2ccc(O)c(OC)c2)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3C(F)(F)F)c2)ccc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of N-(3-ethynylphenyl)-4-hydroxy-3-methoxypheny-acetamide (the compound of Example 19) (200 mg), 1-trifluoromethyl-2-iodobenzene (280 mg), copper (I) iodide (19 mg), bis(triphenylphosphine)palladium (II) dichloride (70 mg), triethylamine (1 g) and acetonitrile (3 ml) is heated with stirring at 50° C. under argon atmosphere for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H46N5O4Cl2 [(M+H)+] 694.2922, observed 694.2918.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](OC)=[O:9])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: COC(=O)c1cc(F)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)ccn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-fluoropicolinate (0.50 g, 3.20 mmol) in tetrahydrofuran (20 mL) at −78° C. was added slowly lithium aluminum hydride (0.15 g, 4.00 mmol). The solution was stirred at −78° C. for 2 h and water (1 mL) was added. The reaction mixture was allowed to warm to ambient temperature, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (4-fluoropyridin-2-yl)methanol as a pale yellow oil. To a solution of this oil in dichloromethane (10 mL) was added thionyl chloride (1.0 mL, 13 mmol) and the solution was stirred at ambient temperature for 16 h. The solution was concentrated in vacuo to afford 2-(chloromethyl)-4-fluoropyridine hydrochloride (0.42 g, 71%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.53-8.47 (m, 1H), 7.04-6.90 (m, 2H), 4.74 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([C:14]2[C:15]([Cl:25])=[N:16][N:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH3:13])=[O:11])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2>CS(C)=O.[NH4+].[Cl-]>[C:1]([NH:4][C@H:5]1[CH2:9][C:8]([C:10]([N:12]([C:14]2[C:15]([Cl:25])=[N:16][N:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH3:13])=[O:11])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C=C[C@H](C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N[C@@H]1CC=C(C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,4S)-4-acetamido-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-cyclopent-2-enecarboxamide (0.230 g, 0.639 mmol) dissolved in dimethylsulfoxide (DMSO, 10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.00 mL, 26.7 mmol). After stirring for 4 hours at a temperature of 100° C., the reaction was cooled and diluted with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with MeOH/CH2Cl2 to provide the title compound F41 as a yellow oil (0.120 g, 44%).