Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH:28]OS([O-])=O.[K+].C(=O)(O)[O-].[Na+].O>CO>[CH3:1][C:2]1([CH2:9][S:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[O:28])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: CC1(CSc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(CS(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Yield: 43.3 %

Procedure:
5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)methyl]imidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred at room temperature with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml) and Methanol (10 ml) for 18 hours. The solid was filtered off and crystallized from ethanol to give 20 mg of the title compound.
Reaction SMILES: BrCCC1C=CNN=1.C(N)CN.[NH:13]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][CH2:20][CH2:21][NH2:22])=[N:14]1.[C:23]([NH:25][C:26](=[N:29][CH3:30])SC)#[N:24]>>[C:23]([NH:25][C:26]([NH:29][CH3:30])=[N:22][CH2:21][CH2:20][NH:19][CH2:18][C:15]1[CH:16]=[CH:17][NH:13][N:14]=1)#[N:24]
Reactant: NCCNCc1cc[nH]n1
Reactant: CN=C(NC#N)SC
Agent: BrCCc1cc[nH]n1
Solvent: NCCN
Product: CNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
Reacting 3-bromethylpyrazole with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyrazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(d) gives N-cyano-N'-methyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=1.[Br:32]N1C(=O)CCC1=O>CN(C=O)C>[Br:32][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 50.4 %

Procedure:
Following General Procedure I, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (0.66 g, 1.5 mmol) was reacted with N-bromosuccinimide (0.30 g, 1.7 mmol) in DMF (10 mL) to afford the desired product (0.39 g, 51%) as a brown solid: ESI MS m/z 515 [C24H23BrN2O4S+H]+.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:5](=[N:3][OH:4])([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a stirred solution of sodium (0.48 g, 210 mmol) in methanol (210 ml) was added a solution of hydroxylamine hydrochloride (15.4 g, 221 mmol) in methanol (70 ml). The mixture was stirred at room temperature for 10 minutes before addition of benzonitrile (20.4 ml, 200 mmol) and the reaction stirred at room temperature overnight. The mixture was filtered through a pad of Celite and the flitrate concentrated in vacuo to approximately 100 ml. Diethyl ether (200 ml) was added and the precipitate filtered. The filtrate was evaporated in vacuo to dryness, and on drying the title compound was obtained as a waxy white solid (27.1 g, 100%). δH (DMSO-d6) 5.92 (2H, br s, NH2), 7.35-7.41 (3H, m, ArH), 7.65-7.91 (2H, m, ArH), 9.69 (1H, br s, OH).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][C:29]2=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>C1COCC1>[CH:21]1([CH2:27][C:28]2([CH2:37][O:36][CH2:34][CH3:35])[CH2:33][CH2:32][O:31][C:29]2=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOCCl
Reactant: O=C1OCCC1CC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOCC1(CC2CCCCC2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of lithium diisopropylamide prepared from diisopropylamine (6.50 mL) and butyllithium (29.0 mL of 1.6M solution in hexanes) in THF (105 mL) was treated dropwise with 2-(cyclohexyl-methyl)-γ-butyrolactone (6.96 g) at −78° C. The reaction mixture was stirred at the same temperature for additional 30 min and then treated dropwise with chloromethyl ethyl ether (5.05 g). Upon completion of the addition, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature overnight. After that, the mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with toluene. The combined organic phases were washed with water, dried over potassium sulfate, filtered, concentrated on a rotary evaporator and purified by column chromatography (silica gel, eluent-hexane) to give 5.90 g (64%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH3:13])[C:7]2=[O:12].[CH:14]1([CH2:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:14]1([CH2:21][C:22]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH3:13])[C:7]3=[O:12])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cn1ccc2c(N)cccc2c1=O
Reactant: O=C(O)CC1CCCCCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc2c(NC(=O)CC3CCCCCC3)cccc2c1=O

Procedure:
5-Amino-2-methyl-2H-isoquinolin-1-one (50 mg, 0.0003 mol), 2-cycloheptylacetic acid (90 mg, 0.0006 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (200 mg, 0.0006 mol), N,N-diisopropylethylamine (100 mg, 0.0009 mol) were stirred in methylene chloride (2 mL, 0.03 mol) at room temperature over 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) to give a yellow solid. 1H NMR δ (CDCl3) δ: 8.31 (d, J=7.9 Hz, 1H), 7.95-7.92 (m, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.20 (br, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.37 (d, J=7.3 Hz, 2H), 2.17 (br, 1H), 1.86-1.25 (12H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1)#[N:10]>N1C=CC=CC=1>[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:8][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=1)#[N:10]
Reactant: N#CCc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccnc1O
Solvent: c1ccncc1
Product: N#CCc1ccc(-c2nc3cccnc3o2)cc1
Reaction time: 8 h

Procedure:
Ten grams of 4-(cyanomethyl)benzoic acid is refluxed in 70 mls. of thionyl chloride for four hours. The solvents are removed leaving a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.5 g. of 3-amino-2-hydroxy pyridine in cold pyridine there is added slowly, with cooling, 8 g. of 4-cyanomethyl benzoyl chloride. The mixture is allowed to come to room temperature and stirred overnight. The mixture is added to 300 ml. of ice and the solid amide separated by filtration and recrystallized from methanol. A mixture of 3 g. of the above amide in 50 mls. of phosphorus oxychloride is heated under reflux for 5 hours. The solvents are removed in vacuo and the residue is crystallized from ethyl acetate to give 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>CC(C)=O>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:1])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
Potassium carbonate (149 g, 1.08 mol) and iodomethane (252 mL, 4.05 mol) were added to a solution of 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) in dry acetone (700 mL) under argon. Overhead mechanical stirring was carried out for 16 hours. The reaction mixture was filtered, and acetone was removed under vacuum. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution, the aqueous layer was washed with ethyl acetate, the combined organic layers were washed with saturated potassium carbonate solution, brine, dried over sodium sulfate, and concentrated to yield the title compound as a light yellow solid; m.p. 58.5°-59.50° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1O)=[O:17].C(N(CC)C(C)C)(C)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:25]1[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=[CH:19][C:18]=1[CH:16]=[O:17])(=[O:5])=[O:4]
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.4 ml (14.27 mmol) of trifluoromethanesulfonic anhydride are added dropwise to a solution of 2 g (13.59 mmol) of 4-formyl-3-hydroxybenzonitrile and 2.5 ml (14.27 mmol) of N,N-diisopropylethylamine in 37 ml of anhydrous dichloromethane at 0° C. under an argon atmosphere. The reaction mixture is stirred at RT for 1 h, then diluted with 70 ml of dichloromethane and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.36 g (62% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[H-].[Na+].[C:33](Cl)(=[O:35])[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:33](=[O:35])[CH3:34])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(CNc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(4-methoxybenzylamino)imidazo[1,2-b]pyridazine-3-carboxamide 19A (80 mg, 0.187 mmol) in DMF (2 mL) was added 60% NaH (18.74 mg, 0.469 mmol). The mixture was stirred for 20 minutes and then a solution of acetyl chloride (0.038 mL, 0.540 mmol) in DMF (0.4 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was quenched with sat. NH4Cl. The light brown solid was collected by filtration, washed with water and dried under vacuum to give 19B (78 mg, 89%). {M+H]=469. HPLC Peak Rt=2.303 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([O:40][CH2:41][CH:42]3[CH2:46][O:45]C(C)(C)[O:43]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:38])([F:37])[F:39])[CH:27]=3)[C:22]([O:40][CH2:41][CH:42]([OH:43])[CH2:46][OH:45])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC3COC(C)(C)O3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(O)CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 8 h
Yield: 51.9 %

Procedure:
(2R,4S)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (147 mg) is dissolved in tetrahydrofuran (2 ml), then thereto is added 1N-hydrochloric acid (2 ml), and the mixture is stirred overnight. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=3:2→3:7) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2,3-dihydroxypropoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (72 mg). MS (m/z): 674 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1Br
Temperature: 60 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
A round-bottom flask was charged with 1-bromo-2-iodo-4-(trifluoromethyl)benzene (5.00 g, 14.25 mmol; Combi-blocks, San Diego, Calif.), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (3.41 g, 16.39 mmol), potassium phosphate (6.05 g, 28.5 mmol) and Pd(dppf)Cl2CH2Cl2 (1.164 g, 1.425 mmol). The flask was flushed with Ar, and DMF (47.5 mL) was then added. The flask was sealed, heated to 60° C. for 12 h, and then stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EtOAc (three times). The combined organics were washed with brine, dried and concentrated under a vacuum. The product was purified by chromatography using silica gel (0 to 100% EtOAc/Heptane) to yield 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (2.956 g, 9.69 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.06 (td, J=0.7, 8.1 Hz, 1H), 7.86-7.73 (m, 2H), 7.53 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.0 Hz, 1H), 3.64 (s, 3H); m/z (ESI) 305.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>O1CCCC1.CCCCCC>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)#[N:30]
Reactant: Cc1cccc2cncn12
Reactant: N#CCCCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 26.5 ml of 1.6 N n-butyllithium in hexane is added dropwise maintaining the temperature below 2°. After 30 minutes this solution is transferred under nitrogen over 45 minutes to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is reextracted with 2 N hydrochloric acid (3×15 ml). Basification of the aqueous phase to pH=10 with 50% sodium hydroxide, extraction with ethyl acetate (2×75 ml), drying over magnesium sulfate, evaporation and chromatography (SiO2, ethyl acetate) yields 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.Br[CH2:42][CH2:43][O:44][CH3:45].[N-]=C=O>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:45][O:44][CH2:43][CH2:42][N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12]1
Reactant: COCCBr
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Agent: [N-]=C=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 1; 100 mg) and diisopropylethylamine (78 μl) in acetonitrile (3 ml) was added 2-bromoethylmethylether (31 μl). The resulting solution was stirred at room temperature for 16 hrs, followed by heating at 45° C. for 24 hrs. Polymer bound isocyanate (1 mmol/g, 300 mg) was then added and the mixture was shaken at room temperature for 72 hrs before filtering and concentrating in vacuo. Residue was dissolved in dimethylsulphoxide and purified using the prep-HPLC to give 4-[4-(2-methoxyethyl)piperazin-1-yl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (8 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CC(C)([O-])C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][N:25]=1)=[O:22]
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1
Reactant: FC(F)(F)Oc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(OC(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Temperature: 120 °C

Procedure:
A solution of N-[(1S,2S)-2-aminocyclopentyl]-5-chloro-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 31; 120 mg, 0.35 mmol), 2-bromo-5-(trifluoromethoxy)pyridine (CAS number 888327-36-4; 127 mg, 0.53 mmol) and potassium tert-butoxide (118 mg, 1.05 mmol) in toluene (10 ml) was degassed under a nitrogen atmosphere for 15 minutes. To this was then added BINAP (22 mg, 0.035 mmol) and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) and the reaction mixture was again degassed for 15 minutes. The reaction mixture was heated at 120° C. for 15 hours and then was diluted with water, filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and extracted with ethyl acetate. The organics were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-2.5% methanol/DCM) to afford the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][C:10]=1[CH3:30])(=O)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:10]([CH3:30])[CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: C1CCNC1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
A solution of 110 mg (0.25 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate in 2.11 mL (25 mmol) pyrrolidine is heated to 70° C. for 3 h. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated and after recrystallisation from EtOH the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCCC)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:15][C:13](=[O:14])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-heptadecadienoic acid (7.5 g) and 4-nitrophenol (3.77 g) in 30 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (4.2 g). The mixture was stirred at room temperature for 3 days to give, after the usual work up, 8.5 crude ester. The material was purified by HPLC (ether-hexane; 1:7), then was crystallized from 2-propanol to furnish 5.88 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 46°-47° C.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([F:35])[C:16]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=[C:17]([C:19]2[CH:20]=[C:21]([F:28])[C:22]([C@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=2)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([F:35])[C:16]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=[C:17]([C:19]2[CH:20]=[C:21]([F:28])[C:22]([C@H:25]([NH:27][C:8]([C:5]3[CH2:6][CH2:7][C:2]([F:1])([F:11])[CH2:3][CH:4]=3)=[O:10])[CH3:26])=[N:23][CH:24]=2)[CH:18]=1
Reactant: C[C@@H](N)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reactant: O=C(O)C1=CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1=CCC(F)(F)CC1)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reaction time: 20 h

Procedure:
The above carboxylic acid (223 mg, 1.37 mmol) and the compound of Reference Example 4 (482 mg, 1.37 mmol) were dissolved in 2.3 mL of degassed DMF. HOBT (21 mg, 0.14 mmol) and EDCI (303 mg, 1.58 mmol) were added, and the mixture was made basic with triethylamine (139 mg. 1.37 mmol). After 20 hours at ambient temperature, 10 mL of water and 1 mL of 10% sodium bicarbonate were added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, and then dried over sodium sulfate. Filtration and removal of solvent provided the crude product which was subjected to chromatography on silica gel eluting with 5 to 50% EtOAc in hexanes to give N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4,4-difluorocyclohex-1-ene-1-carboxamide