Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][O:29][C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH2:28][CH:19]([N:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:16][CH2:17][CH3:18])[CH2:20]2)=[CH:25][CH:24]=1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
To a solution of 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 4.56 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (1.62 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OC(=O)C)(=[O:33])C>C(O)=O>[CH:31]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:33]
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1cccc2c1CCC2N(C=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.13 g) in formic acid (5 ml) was added acetic anhydride (1 ml) at 0° C. After being stirred for 5 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[N-formyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.12 g). MS (m/z): 425 (M+ +1) NMR (CDCl3, δ): 8.52 (0.25H, s), 8.43 (0.75H, s), 7.60-7.40 (4H, m), 7.38-7.24 (6H, m), 7.18-6.95 (1H, m), 6.78-6.55 (2H, m), 6.18 (0.25H, m), 5.28 (0.75H, m), 4.72 (0.75H, d, J=16.2 Hz), 4.51 (0.75H, d, J=16.2 Hz), 4.12 (0.5H, m), 3.79 (2.25H, s), 3.72 (0.75H, s), 3.20-2.94 (1H, m), 2.92-2.66 (1H, m), 2.62-2.38 (1H, m), 2.35-2.05 (1H, m)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
To a solution of 4-isopropylphenol (1.007 g, 7.39 mmol) in 15 mL dimethylformamide was added potassium carbonate (2.04 g, 14.79 mmol) and ethyl bromoacetate (1.23 mL, 11.09 mmol). The reaction was stirred for 48 h at ambient temperature. The mixture was diluted with 500 mL water and extracted with diethyl ether (2×200 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 1.61 g (98%) of ethyl-(4-isopropylphenoxy)acetate as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Cl:18]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: N#Cc1cc(F)c(N)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86° C. (reflux) for 5 h. LCMS showed ˜17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H2O and air dried to give the desired product as a beige solid. This product was used in the next step without any further purification. MS (m/z) 171.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CS[C:19](=[NH:21])[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:19]([NH2:21])[NH2:20]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc[nH]c1CSCCN=C(N)N
Yield: 52 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-].[K+].[CH2:11](Cl)[C:12]#[CH:13].O>CS(C)=O>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:13][C:12]#[CH:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: C#CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C#CCOc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To a solution of 25.0 g (0.229 mole) 3-hydroxy-6-methylpyridine in 200 ml DMSO there was added 12.8 g (0.22 mole) powdered potassium hydroxide and 20.0 g (0.266 mole) propargyl chloride. The mixture was stirred at room temperature for 6 hrs. and then poured into an equal volume of water. This mixture was extracted with ether. The ether extract was dried, filtered and concentrated to have 20.5 g crude product. Distillation gave 16.2 g 6-methyl-3-(2-propynyloxy)-pyridine. Yield 48% theory; b.p. 75° C. (1.0 mm); mp 32°-34° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7]
Reactant: NCCCCO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A solution of 22 ml (0.24 mol) of 4-amino-1-butanol in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 35.43 g (0.21 mol, 86% yield) of a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH3:3].[H-].[Na+].[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>O1CCCC1>[Br:16][CH2:17][C:18]1[CH:19]=[C:20]([CH2:24][N:7]([C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: BrCc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from step (i) (5 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (1.1 g) in tetrahydrofuran (40 ml) at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes then added dropwise to a solution of α,α′-dibromo-m-xylene (10.56 g) in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 2 hours, quenched with aqueous ammonium chloride and partitioned between ethyl and acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 2.8 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([O:16][C:14]([CH2:13][O:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(OCC(=O)OC(C)(C)C)c1
Yield: 101.4 %

Procedure:
A mixture of 3-methyl-6-nitrophenol (30.62 g, 200 mmol) and tert-butyl bromacetate (46.8 g, 240 mmol) in acetonitrile (700 mL) in the presence of potassium carbonate (69.1 g, 500 mmol) was refluxed for 2 h. Inorganic materials were removed by filtration and the filtrate was concentrated. The residue was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and extensively concentrated in vacuo to give 54.2 g of the title compound (quant): 1H NMR (CDCl3) δ7.82 (d, 1H, J=8.3 Hz), 6.87 (d, 1 H, J=8.3 Hz), 6.74 (s, 1H), 4.65 (s, 2H), 2.40 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([C:32]1[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:25][CH3:24])=[O:27])[CH:11]=[CH:10]3
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)c1

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (204 mg, 0.634 mmol, described in Intermediate 20), 3-methoxycarbonylphenylboronic acid (229 mg, 1.27 mmol), PdCl2(PPh3)2 (44 mg, 0.063 mmol), and potassium carbonate (290 mg, 2.10 mmol), in 1,2-dimethoxyethane (3 mL) and H2O (1 mL) was heated at 80° C. for 18 h. The cooled mixture was partitioned between H2O (40 mL) and EtOAc (40 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (40 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give the title compound. MS: m/z=422 (M+1). HRMS: m/z=422.1504; calculated m/z=422.1499 for C26H20N3O3.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17].[BrH:18]>>[BrH:18].[BrH:18].[BrH:18].[CH3:3][NH:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][S:17][CH2:16][CH2:15][NH2:14])[N:10]=1
Reactant: CNCc1nc(CO)cs1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: CNCc1nc(CSCCN)cs1

Procedure:
Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics:
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:43]2[N:42]=[C:41]([Cl:44])[N:40]=[C:23]([NH:24][C@H:25]([CH3:39])[CH2:26][S:27][C:28]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[NH:30][N:29]=3)[C:22]=2[N:21]=[CH:20]1)(=O)C.C[O-].[Na+]>CO>[C:16]([O:15][CH2:14][C@H:8]1[O:7][C@@H:6]([N:19]2[C:43]3[N:42]=[C:41]([Cl:44])[N:40]=[C:23]([NH:24][C@H:25]([CH3:39])[CH2:26][S:27][C:28]4[N:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][N:29]=4)[C:22]=3[N:21]=[CH:20]2)[C@H:5]([OH:4])[C@@H:9]1[OH:10])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4n[nH]c(-c5ccccc5)n4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4n[nH]c(-c5ccccc5)n4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 8 %

Procedure:
Partial deacylation of the purified 2',3',5'-Tri-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine (described in Example 27) using sodium methoxide in methanol to provide the title 5'-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3yl) ]thio-2-propyl}-adenosine (0.035 g, 8%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ 1.34 (3H, d, --CHCH3), 2.02 (3H, s, --COCH3), 4.53-4.68 (2H, q, H-2' and --CHCH3), 5.40, 5.61 (2H, 2d, 2'- and 3'-OH), 5.86 (1H, d, H-1'), 7.38-8.01 (5H, 3m, Ar-H), 8.37 (1H, s, H-2). HPLC retention time 16.9 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: C[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC)=[CH:3][CH2:4][OH:5].[C:15](OCC)(=O)C>[Pd]>[CH3:15][C:4](=[O:5])[CH2:3][CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(C)=CCO
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCCCCCCCCC(C)=O

Procedure:
Pd-C (1.0 g) was added to an ethyl acetate solution (300 ml) of 3-methyl-2-dodecen-1-ol (3″) (30 g, 0.15 mol) obtained from 2-undecanone (1″) in the same manner as in Example 2, and the mixture was stirred for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate obtained was concentrated and then distilled under reduced pressure to obtain 3-methyldodecan-1-ol (4″) (20 g, 67%). b.p. 122-123° C./4 torrs. 1H-NMR (90 MHz, CDCl3) 0.8-1.0 (6H,m,Me), 1.0-1.7 (20H,m,2˜11-H and OH), 3.66 (2H,q,J=7,1-H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)#[N:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:33]#[N:34])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (39%).
Reaction SMILES: C1(C2C(C(F)(F)F)=C([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)ON=2)C=CC=CC=1.[C:31]1([C:37]2[O:41][N:40]=[C:39](C3OC4C5C(=CC(C=C)=CC=5)CCC=4N=3)[C:38]=2[C:57]([F:60])([F:59])[F:58])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[C:38]=2[C:57]([F:60])([F:59])[F:58])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)oc1-2
Reactant: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Product: O=Cc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)oc1-2

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 48C employing 2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (Preparation 48E). LC/MS M+1=411.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C(O)(C)C>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[C:37]([C:36]([F:35])([F:44])[F:45])[CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[CH:19]=1)=[O:34]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12
Solvent: CC(C)O
Product: Cc1cccc2c(-c3ccnc(Nc4cccc(C(F)(F)F)c4)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12

Procedure:
The title compound was prepared through standard displacement conditions by microwaving N-{3-[3-(2-chloropyrimidin-4-yl)-7-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-trifluoromethylaniline in isopropanol at 150° C. for 15 min. 1H NMR (400 MHz, DMSO d-6) 2.73 (s, 3H), 3.76 (s, 3H), 6.50 (s, 1H), 7.02 (m, 2H), 7.22 (m, 2H), 7.33 (m, 2H), 7.43 (m, 2H), 7.57 (m, 1H), 7.70 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 9.52 (s, 1H), 10.9 (s, 1H); LCMS (ESI): [M+H]+=581.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:37]1[CH2:40][CH:39]([OH:41])[CH2:38]1>>[OH:41][CH:39]1[CH2:40][N:37]([C:30](=[O:32])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:38]1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: OC1CNC1
Agent: Cl
Product: CC(C(=O)N1CC(O)C1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood, Cat. No. 013898). LCMS (M+H)+: m/z=539.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[N:10][C:11]=1Cl.[K+].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[N:25][CH:26]=1>>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:11]2[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:7]([Cl:14])[N:8]=[C:9]([CH3:13])[N:10]=2)(=[O:29])=[O:28])=[N:25][CH:26]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Reactant: Cc1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1

Procedure:
According to the procedure described in Example 1g) 1.00 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-methyl-pyrimidine was reacted with 5-methyl-2-pyridine sulfonamide potassium salt to give 1.5 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.57 min, [M+1]+=421.42, [M−1]−=419.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][C:20]#[N:21])[CH2:13][CH2:12][CH2:11][C:10](=[CH:14]N(C)C)[C:9]2=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][C:20]#[N:21])[C:9]3[N:47]=[C:45]([NH:44][C:34]4[CH:35]=[CH:36][C:37]([N:38]5[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]5)=[C:32]([O:31][CH3:30])[CH:33]=4)[N:46]=[CH:14][C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=C1CCCC(CC#N)(c2ccc(Cl)cc2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(CC#N)(c2ccc(Cl)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from [1-(4-chloro-phenyl)-3-[1-dimethylamino-methylidene]-2-oxo-cyclohexyl]-acetonitrile (118 mg, 0.39 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (124 mg, 0.33 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (114 mg, 71%). MS ISP (m/e): 485.5 [(M+H)+]. mp 156-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH2:12][CH2:13]O)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][C:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[NH:11][CH:10]=1
Reactant: COc1ccc2[nH]cc(CCO)c2n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCBr)c2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanol (353 mg, 1.84 mmol) in DCM (5.0 mL), CBr4 (700 mg, 2.11 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (554 mg, 2.11 mmol) was added. After stirring at rt for 2 h the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hex 1:9 to 3:7) to yield the title compound as a brown oil, which was stored in the freezer. LC-MS conditions B: tR=0.45 min, [M+H]+=255.03.