Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7](I)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:32]=[CH:33][C:34]([C:7]3[C:6](=[O:19])[C:5]4[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=4)[O:9][C:8]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 48.8 %

Procedure:
7-Bromo-3-iodo-2-phenyl-chromen-4-one (320 mg, 0.75 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (295 mg, 0.8 mmol), tetrakis(triphenyphosphine)palladium (0) (87 mg, 0.075 mmol) and sodium carbonate (159 mg, 1.5 mmol) were suspended in DME (10 mL) and water (5 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated in a microwave at 125° C. for 15 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a pale yellow foam (200 mg, 49%). LCMS (Method A): RT=5.45 min, [M+H]+=546/548.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)C(C)C)(C)C.[Cl-].[Mg+2].[Cl-].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C(Cl)=O)=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a suspension of potassium ethyl malonate (17.12 g, 100.6 mmol) in acetonitrile (150 mL) were added N,N-diisopropylethylamine (28 mL, 160 mmol) and magnesium chloride (12.11 g, 127.2 mmol). The resulting mixture was stirred for 1 hour. A solution of 4-chlorophenylacetyl chloride (10.12 g, 53.53 mmol) in acetonitrile (100 mL) was then added and the mixture was heated to 60° C. and stirred for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in 1N aqueous HCl (250 mL) and was extracted with EtOAc (100 mL×2). The combined organic phases were dried Over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica, elution with a 0%-80% mixture of EtOAc in hexane (linear gradient, 45 min) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutanoate (5.0 g, 39%) as a yellow oil. LC/MS (FA) ES− 239. 1H NMR (d6-DMSO, 400 MHz): δ: 7.37 (2H, d, J=13.8 Hz), 7.20 (2H, d, J=13.8 Hz), 4.07 (2H, q, J=7.2 Hz), 3.89 (2H, s), 3.66 (2H, s), 1.17 (3H, t, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9]C.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([OH:9])[CH:4]=1
Reactant: COc1cc(N)ccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Nc1ccc(Br)c(O)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A suspension of 4-bromo-3-methoxy-phenylamine (37.6 g, 0.186 mol) and tetrabutylammonium iodide (96 g, 0.260 mol) in dichloromethane (1.2 L) was cooled down to −78° C. A 1M solution of boron trichloride in dichloromethane (520 mL, 0.521 mol) was added dropwise, within 20 min. The cooling bath was removed. After 3 hours, the reaction mixture was poured onto ice water (4.5 kg). The organic layer was extracted with water. The combined aqueous layers were washed with dichloromethane. The pH was adjusted to 9 using sodium hydrogencarbonate. Sodium chloride was added until saturation. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were evaporated. The solid was washed with dichloromethane and dried under vacuum. 35.2 g of the title compound were obtained. Brown solid, ISP-MS: m/e=189.1 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[C:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC(CC2N3C=CN=C3C(CC(OC)=O)=CN=2)=CC=1.[Cl:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][C:56]=1[Cl:57])[C:51](O)=[O:52].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CO.C(OCC)(=O)C.[Pd].ClCCl>[Cl:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][C:56]=1[Cl:57])[C:51]([NH:1][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C:9]2[N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[C:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[O:52]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)n2ccnc12
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)Cc1cnc(Cc2ccc(N)cc2)n2ccnc12
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)n2ccnc12
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A mixture of methyl [5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (28 mg, 0.09 mmol) and Pd/C (wet, 3 mg) in methanol (1 mL) was stirred under hydrogen atmosphere for 1 hour. After the removal of Pd/C by filtration through a Celite pad, the filtrate was concentrated in vacuo. The resulting crude methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (26 mg, 0.09 mmol) was dissolved with dichloromethane (1 mL). To this solution was added 3,4-dichloro-benzoic acid (20.1 mg, 0.11 mmol), 1-hydroxybenzotriazole (14.2 mg, 0.11 mmol), triethylamine (0.037 mL, 0.26 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.9 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The solution was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:methanol, 19:1) to give methyl (5-{4-[(3,4-dichloro-benzoyl)amino]benzyl}imidazo[1,2-c]pyrimidin-8-yl)acetate (29 mg, 70%) as slightly yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:36]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Na].CS.[Cl-].[NH4+]>CO.O>[C:15]([C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][CH:12]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(C)(SC)c1cccc(C(=O)c2ccccc2)c1
Agent: CS
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Yield: 67.7 %

Procedure:
Methyl α-methylthio-α-(m-benzoylphenyl)propionate (628 mg) was dissolved in 2 ml of anhydrous methanol, and 1.5 ml (2.34 M) of a methanol solution of sodium salt of methyl mercaptan was added. The mixture was heated under reflux for 1.5 hours. After cooling, an aqueous solution of ammonium chloride (2.0 g/10 ml) was added to stop the reaction. The reaction mixture was diluted with 10 ml of water, and then extracted with 30 ml of diethyl ether and then twice with 10 ml of diethyl ether. The extract was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and then with 5 ml of water, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure, and the residue (377 mg) was chromatographed on a silica gel column using methylene chloride as an eluent to afford 363 mg of methyl α-(m-benzoylphenyl)propionate as a colorless oil in a yield of 68%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21]CS([O-])(=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:32].[Li+]>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C@H:20]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:21][Cl:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H](CCS(=O)(=O)[O-])NS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H](CCl)NS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a 250 mL three neck flask fitted with a thermometer, condenser, stirbar, under argon was added the bis-methanesulfonyl derivative 6 (44 g, 0.091 mol) dissolved in DMF (200 mL). Lithium chloride (5.8 g, 0.136 mol) was added in one portion. The reaction mixture was heated to 80° C. with an oil bath. After 90 min the reaction was allowed to cool to room temperature and diluted with 50% ethyl acetate in hexanes (880 mL). The layers were separated and the organic layer was washed with water (2×550 mL) and brine (550 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to 35 g (90%) of the chlorosulfonamide 7 as a yellow viscous oil. HPLC analysis showed a purity of 95%. 1H NMR (300 MHz, CDCl3) δ 7.3-7.7 (m, 10H), 4.6-4.8 (m, 1H), 3.6-4.0 (m, 5H), 2.9 (s, 3H), 1.1 (s, 9H).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:3].[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[ClH:1].[CH2:24]([N:21]1[CH2:20][CH2:19][N:18]([C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[O:17])[CH2:23][CH2:22]1)[CH2:25][CH3:26]
Reactant: CCC=O
Reactant: N#Cc1ccc(N2CCC(C(=O)N3CCNCC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1CCN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[1-(4-cyanophenyl)-piperidine-4-carbonyl]-piperazine hydrochloride (D34) (0.3 g) in dry DCM (10 ml) was treated with triethylamine (0.25 ml) and propionaldehyde (0.25 ml). The reaction mixture was stirred at rt for 30 min. Sodium triacetoxyborohydride (3.7 g) was added and the reaction was stirred at rt overnight. The reaction mixture was treated with 1N NaOH (2 ml) and stirred at rt for 15 min followed by the addition of water (20 ml) and DCM (20 ml). The organic layer was dried (MgSO4) and filtered and the filtrate was absorbed onto silica gel (5 g) and purified by column chromatography (silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. The fractions containing the required product were evaporated and the free base was dissolved in MeOH (1 ml) and treated with ethereal HCl to give the title compound (E116) as a solid (50 mg). MS electrospray; (+ve ion) 341 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[N:9]=[C:10]([NH2:21])[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:13]=2[N:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:21][C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[C:13]2[N:14]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[S:7][C:8]=2[N:9]=1
Reactant: CCCCCc1nc2c(N3CCNCC3)nc(N)nc2s1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: CCCCCc1nc2c(N3CCN(C(=O)COc4ccc(OC)cc4)CC3)nc(N)nc2s1
Yield: 34 %

Procedure:
This compound was prepared from 2-pentyl-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 34%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[OH:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl>[Cl:23][C:6]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanol (C4) (60 g, 170 mmol) and chloroform (1.8 L) was added Dess-Martin periodinane (110 g, 258 mmol) in portions at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours, and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with aqueous sodium hydroxide solution (0.5 N, 2×800 mL), then with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. Recrystallization from methanol afforded the product as a light yellow solid. Yield: 31.3 g, 90.1 mmol, 53%. LCMS m/z 346.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.69 (s, 3H), 7.07-7.15 (br AB quartet, JAB=8 Hz, ΔνAB=8 Hz, 4H), 8.15 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:20]1([CH:19]2[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6](=[O:8])[O:7]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)c1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)c2sccc21
Temperature: -50 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A solution of thiophene-3-carboxylic acid (2.00 g, 15.6 mmol) in THF (20 mL) is added dropwise to a cold (−80° C.) solution of lithium bistrimethylsilylamide (17.2 mL of a 2M solution 34 mmol) in THF (30 mL). The resulting pale yellow solution is warmed to −50° C. and is stirred at −50° C. for 1 hr during which time a white precipitate is formed. The reaction mixture is cooled to −80° C. and treated dropwise with benzaldehyde (3.0 mL). The white precipitate gradually disappeared during the addition. The reaction mixture is warmed to −20° C. and stirred for 30 min. The reaction mixture is then poured into aqueous 2M HCl solution (120 mL). The resulting mixture is stirred at room temperature while a stream of air is blown into the reaction vessel to assist in the evaporation of THF. The white precipitate which forms is collected by filtration and dissolved in Dichloromethane (20 mL) and Et3N (12 mL). The reaction mixture is treated with TsCl (3.42 g, 17.2 mmol) and stirred overnight. The reaction mixture is treated with NaHCO3 solution and the organic phase is collected, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography (silica gel, 10% ethylacetate/hexane) to give the title compound (0.39 g, 12%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+].Cl[CH:20]([F:22])[F:21]>C(O)(C)C>[F:21][CH:20]([F:22])[O:15][C:11]1[C:10]([F:16])=[C:9]([CH:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)Cl
Reactant: CCN1CCC(c2cccc(O)c2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCN1CCC(c2cccc(OC(F)F)c2F)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1-ethylpiperidin-4-yl)-2-fluorophenol (0.43 g, 1.9 mmol) ) in isopropanol (5 ml) and aqueous sodium hydroxide (30%, 5 ml) was added chlorodifluoromethane gas through a liner for 1 min. The mixture was heated to 65° C. and bubbling of chlorodifluoromethane was continued for an additional 30 min. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. MS m/z (rel. intensity, 70 eV) 273 (M+, 14), 272 (13), 259 (12), 258 (bp), 84 (13).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:5]=1[C:6]#[N:7])([O-])=O.N1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N+:16]([C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:4]([N:1]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]=1[C:6]#[N:7])([O-:18])=[O:17]
Reactant: C1COCCN1
Reactant: N#Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Product: N#Cc1c(N2CCOCC2)cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
2-nitro-4-trifluoromethyl-6-morpholinylbenzonitrile is prepared from 2,6-dinitro-4-trifluoromethylbenzonitrile and morpholine as in example 10, m.p. 174°-178° C.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:13])[CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[NH:12][C:10](=[O:11])[CH2:9][C@@H:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](CC(N)=O)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccccc1
Temperature: -10 °C
Yield: 82 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (S)-3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 mL) and the mixture was cooled to −10° C. Benzyl chloroformate (3.12 mL, 0.022 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (18 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction (starting material gone by TLC) was quenched by adding EtOAc (65 mL) and 1.0 M hydrochloric acid (10 mL). The aqueous phase was then basified with 1N NaOH. The aqueous phase was extracted 3×EtOAc. The organics were collected together and with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography using a Biotage system (10% EtOAc/90% hexane to 20% EtOAc/80% Hexane) afforded the title compound in 82% yield.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:28]([F:29])=[CH:27][N:26]=[C:25]([O:30]C)[CH:24]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[C:28]([F:29])=[CH:27][NH:26][C:25](=[O:30])[CH:24]=5)[N:22]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(F)cn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′-fluoro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (19 mg, 0.04 mmol) in chloroform (0.5 mL) was added iodotrimethylsilane (32 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for three hours. At this point the reaction mixture was purified directly by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (5.1 mg, 47%). ESI-MS m/z calc. 443.38. found 444.3 (M+1)+. Retention time 1.63 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:22][N:30]=[C:28]([C:27]5[CH:32]=[CH:33][C:24]([NH2:23])=[N:25][CH:26]=5)[N:29]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (114 mg, 52%). MS (ISP) 440.2 [(M+H)+]; mp 254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH:16]1OCCC[O:17]1.Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C1OCCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
To a stirred solution of Compound 39 (1.0 g) in acetone (30 ml) was added conc. HCl (4 ml) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and the residue was extracted with ether. The combined solution was washed with sat. NaHCO3 aq., and brine, dried(MgSO4) and concentrated in vacuo to give crude product (790 mg) as a yellow solid. The crude product was purified by column chromatography on silica gel with hexane-isopropyl ether(10:1-3:1) to give Compound 40 (275 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34]COCC[Si](C)(C)C)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCOc1ccccc1COc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: Oc1ccccc1COc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
Cleavage of the SEM group from (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine using a 2N solution of hydrogen chloride in methanol analogously to the procedure described in Example 5 (g) yielded (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-hydroxy-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine as a colourless resin; MS: 458 (M+H)+.