Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN2[C:4]3[C:5](CCC2)=[C:6]2[O:13][C:11](=[O:12])[C:10](C(O)=O)=[CH:9][C:7]2=[CH:8][C:3]=3C1.[N:22]([CH2:25][CH2:26][CH2:27]O)=[N+:23]=[N-:24].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:25]([N:22]=[N+:23]=[N-:24])[CH2:26][CH3:27].[O:13]1[C:6]2[C:7](=[CH:8][CH:3]=[CH:4][CH:5]=2)[CH:9]=[CH:10][C:11]1=[O:12]
Reactant: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Reactant: [N-]=[N+]=NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCN=[N+]=[N-]
Product: O=c1ccc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A solution of Coumarin 343 (0.285 g, 1.00 mmol) and 3-azido-1-propanol (0.505 g, 5.00 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and EDC.HCl (0.575 g, 3.00 mmol) and DMAP (0.006 g, 0.05 mmol) were sequentially added. The orange solution was stirred at 0° C. for 2 h, then at ambient temperature overnight. The reaction mixture was washed with water (2×50 mL) and dried over MgSO4. The volatiles were removed under reduced pressure and the crude product purified by flash chromatography (CC, SiO2, 1) 100% CH2Cl2; 2) CH2Cl2/Et2O 10:1). The isolated product still contained some 3-azido-1-propanol starting material, which was then removed by coevaporation with toluene under reduced pressure. Obtained 0.110 g (0.299 mmol, 30%) of (28) as an orange oil that partially solidified by standing at ambient temperature over several days.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CSc1ncc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ncc(N)cn1
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A solution of 5 g (29.2 mmol) of 2-methylsulfanyl-5-nitropyrimidine in 200 mL of absolute ethanol and 120 mL of glacial acetic acid was added 16.31 g (292 mmol) of iron powder and the mixture was heated in an oil bath maintained at 80° C. for 2 hours. The reaction was diluted with 250 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with two portions of 100 mL of water, and the pH of the organic layer was adjusted by adding saturated aqueous sodium carbonate solution until the pH was 8. The organic layer washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2.1 g (51%) of 2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1-c1ccc(CBr)cc1
Yield: 61.3 %

Procedure:
A mixture of 4′-methyl-2-chloro-biphenyl (1.08 g, 5.33 mmol), NBS (1.14 g, 6.40 mmol) and AIBN (175 mg, 1.06 mmol) in CCl4 (37 mL) was heated at reflux for 3 h. The reaction mixture was diluted with CH2Cl2 and the organic solution was washed sequentially with aqueous saturated NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 5% EtOAc/hexanes) to afford the title compound (920 mg). 1H NMR (CDCl3 400 MHz) δ7.63-7.25 (m, 8H), 4.56 (s, 2H).
Reaction SMILES: [C:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:19]1CCC[CH2:20]1.C([Li])CCC.CN(C)C=O>C(Cl)Cl>[F:18][C:13]1[C:12]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:20]=[O:19]
Reactant: C1CCOC1
Reactant: CCCCCCCCCC#Cc1ccccc1F
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a solution of 2-(1-undecynyl)fluorobenzene (7.00 g) and tetrahydrofuran (70 ml) was added slowly n-butyllithium (1.6M, 17.8 ml) at -78° C. The reaction mixture was stirred at -78° C. for 1.5 hrs. Dimethylformamide (2.28 ml) was added slowly, and the solution was allowed to warm to room temperature over 1 hr, with stirring. Methylene chloride (300 ml) was added, and the solution was washed with 50% hydrochloric acid. The aqueous phase was extracted with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (250 g), eluting with hexane followed by ethyl acetate/hexane (1:4). The appropriate fractions were collected and evaporated to provide 3.53 g (45.2%) of product as an oil.
Reaction SMILES: F[B-](F)(F)F.[FH:6].[FH:7].F.C(N(CC)CC)C.[C:16]([CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]>>[C:16]([CH:21]1[CH2:26][CH2:25][C:24]([F:7])([F:6])[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(F)(F)CC1
Reaction time: 23 h

Procedure:
Procedure for the fluorination of carbonyls in various solvents (examples 68-69): To a mixture of the diethylaminodifluorosulfinium tetrafluoroborate (458 mg, 2.0 mmol) and triethylamine trihydrofluoride (163 μL, 1.0 mmol) in the solvent (2.0 mL), at room temperature and under nitrogen, is added 4-carboethoxycyclohexanone (159 μl, 1.0 mmol). The reaction mixture is stirred for 23 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using pentane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide 4-carbethoxy-1,1-difluorocyclohexane admixed with 4-carbethoxy-1-fluorocyclohex-1-ene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:17])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:37]=[CH:36][C:22]([C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(Cl)Cl.[Cu]I>[O:17]=[C:9]1[N:8]([C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:35]=3[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:24])=[CH:21][CH:20]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10]1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: O=C1NC(c2ccccc2)C2(CCCCC2)O1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2cccnc12)c1ccc(N2C(=O)OC3(CCCCC3)C2c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 11 %

Procedure:
To a 50 mL dried round bottom flask containing a degassed solution of 4-phenyl-1-oxa-3-azaspiro[4.5]decan-2-one (1 eq., 1.73 mmol) and 4-iodo-N-(quinolin-8-yl)benzamide (1.2 eq.) in DMF (15 mL), potassium carbonate (2.5 eq.) and trans (N,N)-dimethyl cyclohexanediamine (0.5 eq.), was added CuI (0.1 eq). The resulting mixture was then stirred at 120° C. for 15 hours. Reaction progress was monitored by TLC (TLC eluent: 10% MeOH in DCM). The reaction mixture was cooled and poured into crushed ice (5 g). The solid thus obtained was filtered, washed with water (25 mL) and dissolved in DCM. The DCM solution was then washed with water (100 mL), brine (50 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography using silica gel and DCM as eluting solvent to yield (R+S) 4-(2-oxo-4-phenyl-1-oxa-3-azaspiro[4.5]decan-3-yl)-N-(quinolin-8-yl)benzamide (90 mg, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 10.46 (s, 1H), 8.95 (dd, J=4.4, 1.6 Hz, 1H), 8.66 (d, J=6.4 Hz, 1H), 8.44 (dd, J=8.4, 1.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.75-7.72 (m, 3H), 7.68-7.61 (m, 3H), 7.32-7.39 (m, 4H), 5.52 (s, 1H), 2.08-2.11 (m, 1H), 1.83-1.89 (m, 1H), 1.74-1.53 (m, 3H), 1.35-1.42 (m, 2H), 1.20-1.23 (m, 3H). m/z (ESI) 478.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[NH:12]1[C:16]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1>>[NH:14]1[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[C:4]3/[C:3](=[O:11])[N:2]([CH3:1])[C:10]4[C:5]/3=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:17][C:16]=2[N:12]=[N:13]1
Reactant: O=Cc1ccc2nn[nH]c2c1
Reactant: CN1C(=O)Cc2ccccc21
Product: CN1C(=O)/C(=C/c2ccc3[nH]nnc3c2)c2ccccc21

Procedure:
The title compound was synthesized according to the method described for Example A11B, except substituting 1-methylindolin-2-one (18 mg, 0.124 mmol) and 1H-benzo[d][1,2,3]triazole-6-carbaldehyde (20 mg, 0.136 mmol) and then purified by preparatory HPLC to obtain 3.4 mg, 10% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.23 (bs, 1H), 8.00 (bs, 1H), 7.95 (s, 1H), 7.84-7.75 (m, 1H), 7.59 (d, J=7.58 Hz, 1H), 7.34 (t, J=8.00 Hz, 1H), 7.04 (d, J=7.83 Hz, 1H), 6.92 (d, J=7.58 Hz, 1H), 3.35 (s, 3H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.11.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=2)[CH:3]=1.S([C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1)(C)(=O)=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl.CO.CN(C=O)C>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]3[CH:3]=[C:2]([NH:1][C:34]4[N:39]=[C:38]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)[CH:37]=[CH:36][N:35]=4)[C:7]([CH3:8])=[CH:6][N:5]=3)=[O:29])=[CH:12][C:13]=2[C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Reactant: Cc1cnc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flask was added N-(4-amino-5-methylpyridin-2-yl)-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide (7.1 g), 2-mesyl-4-(3-pyridyl)pyrimidine (5.0 g) and DMF (50 mL). After the solution was cooled to about 0° C., sodium hydride (60%, 1.5 g) was added in several portions and the reaction was stirred at the same temperature for 2 hours, then warmed up to room temperature for 1 hour. A mixture solvent of chloroform/methanol (30:1, 100 mL) was added and the PH value was adjusted to 7 using 10% citric acid. The aqueous phase was extracted, then the organic combined phase was washed with brine, dried, filtered, concentrated and Purified through column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
A mixture of 4-fluoro-aniline (1.12 g; 10 mmol), 2-bromopropane (1.13 ml) and K2CO3 (1.38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O (2×20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. 1H-NMR (CDCl3) 6.89-6.82 (m, 2H); 6.53-6.47 (m, 2H); 3.58-3.49 (m, 1H); 1.18 (d, 6H, J=6.25 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[F:11][CH:12]([C:17](OC)=[O:18])[C:13](OC)=[O:14].C[O-].[Na+]>CO>[F:11][C:12]1[C:13](=[O:14])[N:10]=[C:8]([S:7][CH3:6])[NH:9][C:17]=1[OH:18]
Reactant: CSC(=N)N
Reactant: COC(=O)C(F)C(=O)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CSc1nc(=O)c(F)c(O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.1 %

Procedure:
To a stirred solution of 2-methyl-2-thiopseudourea sulfate (41.7 g, 0.15 mol) and dimethyl fluoromalonate (45 g, 0.30 mol) in MeOH (600 mL) at 0° C. (ice bath) was added NaOMe (48.6 g, 0.90 mol) in portions. After the addition was complete, the ice bath was withdrawn and the reaction mixture was stirred at room temperature overnight. LCMS showed the formation of the desired pyrimidinone product. The reaction mixture was concentrated to near dryness under vacuum, diluted with water (50 mL), and acidified with 6N HCl (˜150 mL) to ˜pH 2 to precipitate the product. After filtration, the solid was washed with 1N HCl (2×10 mL) and dried under vacuum to afford 5-fluoro-6-hydroxy-2-methylthio-4(1H)-pyrimidinone (35.7 g, 68%) as a white solid. LCMS: (M+H)+: 177.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2nn(-c3ccnc(N4CCOCC4)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.120 g, 0.00023 mol) and morpholine (10 mL) was heated at 100° C. for 6 days. The solvent was removed in vacuo and the residue was slurried in water (25 mL) for 4 hours. The mixture was filtered and the crude solid was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 35%-80% acetonitrile-0.050 M ammonium acetate over 20 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(2-morpholino-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.048 g, 0.00008 mol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:29][CH:28]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (504 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h. The reaction mixture was then treated with 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (151.9 mg, 19.7%) as a colorless oil: EI-HRMS m/e calcd for C21H23ClN2O3 (M+) 386.1397, found 386.1398.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH:11](=O)[CH2:12][CH2:13][CH3:14].[BH4-].[Na+]>>[CH2:11]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: CCCC=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCNc1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (399 mg; 3 mmol; 1 eq.), n-butanal (238 mg; 0.291 ml; 3.3 mmol; 1.1 eq.) and NaBH4 (228 mg; 6 mmol; 2 eq.) as described in method 3; Yield: 0.311 (54.9%); MS m/z: 190.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.91 (t, 3H, 3J=7.5 Hz); 1.35-1.44 (m, 2H); 1.52-1.59 (m, 2H); 2.99 (t, 2H, 3J=7.1 Hz); 5.27 (br s, 1H); 6.53-6.55 (m, 2H); 7.25-7.27 (m, 1H); 7.84 (s, 1H); 11.83 (br s, 1H); HPLC (METHOD [A]): rt 7.51 min (95.9%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
The reaction conditions for N-alkylation taught by G. D. Maynard et al., Bioorganic & Medicinal Chemistry Letters, 3(4), pp. 753-756, 1993, were used in the following preparation. A stirred mixture of 5.0 grams (0.032 mole) of ethyl piperidin-4-ylcarboxylate, 5.4 grams (0.032 mole) of 1-(2-chloroethyl)-4-methoxybenzene and 4.4 grams (0.032 mole) of potassium carbonate in 50 mL of dried N,N-dimethylformamide was heated at 70° C. for about 16 hours. After this time the reaction mixture was cooled and partitioned between diethyl ether and water. The organic layer was separated and washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with diethyl ether/hexane mixtures as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.4 grams of ethyl N-[2-(4-methoxyphenyl)ethyl]piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]12[CH2:15][C@@:12]([NH:16][C:17]([C:19]3[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10][CH2:9]2)(C)(C)C.[CH3:27][C:28]1[N:29]=[C:30]([C:33]([OH:35])=O)[S:31][CH:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.Cl.O1CCOCC1>[CH3:27][C:28]1[N:29]=[C:30]([C:33]([NH:7][C@@:8]23[CH2:15][C@@:12]([NH:16][C:17]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)=[O:18])([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[O:35])[S:31][CH:32]=1
Reactant: Cc1cncc(C(=O)N[C@@]23CCC[C@@](NC(=O)OC(C)(C)C)(CC2)C3)n1
Reactant: Cc1csc(C(=O)O)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cncc(C(=O)N[C@@]23CCC[C@@](NC(=O)c4nc(C)cs4)(CC2)C3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of {(1R,5S)-5-[(6-methyl-pyrazine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-carbamic acid tert-butyl ester (intermediate 13, 0.050 g, 0.14 mmol) in 1 mL of methylene chloride, 4 M of hydrogen chloride in 1,4-dioxane (0.5 mL) was added. After stirring at rt overnight, the reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was dissolved in methylene chloride (1.0 mL), 4-methyl-1,3-thiazole-2-carboxylic acid (19.8 mg, 0.14 mmol), triethylamine (7.73 μL, 0.56 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (61.4 mg, 0.14 mmol) were added. After stirring at rt for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on the CombiFlash® system (hexane/ethyl acetate: 100/0 to 10/90 in 10 mins, then hexane/ethyl acetate: 10/90) to afford 31 mg (58%) of 6-methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide. Analytical data are listed in Table 3.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:27][N:26]=2)(=[O:30])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[Cl:17]
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
306 mg of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine, 320 mg of 5-isopropyl-2-pyridine-sulphonamide and 180 mg of K tert.butylate dissolved in 2 ml of DMSO were reacted at 90° C. for 3 hours. After cooling to room temperature the reaction medium was acidified with aqueous citric acid; the compound was extracted with ethyl acetate and, after distillation of the solvent, crystallized from ethanol. 250 mg of N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-sulphonamide were obtained as white crystals with m.p. 174°-175° C.
Reaction SMILES: [OH:1][CH:2]([C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1.[H-].[Na+].I[CH3:38]>>[CH3:38][O:1][CH:2]([C:20]1[S:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH3:19])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(4-(3-Methoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid is prepared from 2-(4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.