Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[N:2]1.N(C1C=C(C=CC=1)C(OC)=O)=[N+]=[N-].[OH-].[Na+].ClC(OCC)=O.CCN(CC)CC.[K+].[C:44]([O:50][CH2:51][CH3:52])(=[O:49])[CH2:45]C([O-])=O.[Mg+2].[Cl-].[Cl-]>C[Si](C#C)(C)C.CC#N.CCN(CC)CC.CCO>[CH2:51]([O:50][C:44](=[O:49])[CH2:45][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:7]=1)[CH3:52]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(-n2ccnn2)c1
Agent: C#C[Si](C)(C)C
Agent: CCOC(=O)Cl
Agent: COC(=O)c1cccc(N=[N+]=[N-])c1
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from 3-[1,2,3]triazol-1-yl-benzoic acid, prepared by refluxing of methyl 3-azidobenzoate [CAS-No. 93066-93-41] in trimethylsilyl-acetylene, followed by saponification with aqueous NaOH in refluxing EtOH] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure K (method a). Obtained as a light yellow solid (2.22 g).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:17][C@@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C[O-]
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
8-bromo-2-{[(1R)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.23 g, 13.61 mmol) was heated to reflux with 25% sodium methoxide in methanol (8.8 ml, 13.61 mmol) and methanol (40 ml) for 4 hours. The reaction mixture was concentrated under reduced pressure and partitioned between saturated ammonium chloride (100 ml) and dichloromethane (100 ml). The aqueous was washed with further dichloromethane (100 ml) and the combined organics passed through a hydrophobic frit and concentrated to give the title compound as a pale yellow foam (4.80 g).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([C:5]1[O:9][C:8]([CH2:10][Br:15])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(C)(C)C)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)oc1CBr
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of methyl 5-tert-butyl-2-methylfuran-3-carboxylate (10.4 g, 53 mmol), N-bromosuccinimide(9.9 g, 55 mmol), and azobisisobutyronitrile (0.1 g, 0.6 mmol) in carbon tetrachloride (100 mL) was heated to reflux for 1.5 h. The suspension was cooled to room temperature, and succinimide was removed by filtration and rinsed with carbon tetrachloride. The combined filtrates were evaporated to dryness. The residue was subjected to Kugelrohr distillation (<1 mbar, 110-120° C.) to yield methyl 5-tert-butyl-2-(bromomethyl)furan-3-carboxylate (14.3 g, 98% yield) as a light-yellow oil. 1H-NMR (300 MHz, CDCl3): δ 6.28 (s, 1H), 4.80 (s, 2H), 3.85 (s, 3H), 1.28 (s, 9H) ppm.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.C.C(=O)([O-])[O-].[K+].[K+]>[Pt](=O)=O.C(O)(=O)C>[OH:10][CH2:9][CH:4]1[CH:3]([OH:2])[CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: OCc1ncccc1O
Agent: O=[Pt]=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: OCC1NCCCC1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 114 %

Procedure:
A mixture of 20.0 g (105 mmol) 3-hydroxy-2-(hydroxymethyl)-pyridine hydrochloride, 4.0 g (18 mmol) platinum(IV) oxide, 4 g charcoal (Norit SX1) and 300 ml acetic acid was stirred at room temperature for 20 h under a hydrogen pressure of 10 bar in an autoclave. The catalyst was filtered off and washed with acetic acid. The filtrate was concentrated in vacuo, redissolved in isopropanol and treated with 29.0 g (210 mmol) potassium carbonate. After stirring for 30 min. the mixture was filtered, and the solvent was evaporated in vacuo to give 15.7 g of crude (2RS,3RS)-2-hydroxymethyl-piperidin-3-ol. A portion of 2.0 g of the crude intermediate was dissolved in 50 ml dichloromethane and treated with 5.2 ml (30 mmol) N,N-diisopropylethylamine and 2.4 ml (16 mmol) benzyl chloroformate at 0° C. After 45 min. water and saturated ammonium chloride solution were added. The mixture was extracted with four portions of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.82 g (23% based on 3-hydroxy-2-(hydroxymethyl)-pyridine hydrochloride) of the title compound as an off-white oil.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[C:7]([CH3:9])[O:6][N:5]=1)=[N+:2]=[N-:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:3]=[N:2][N:1]([C:4]3[CH:8]=[C:7]([CH3:9])[O:6][N:5]=3)[C:19]=2[NH2:20])=[CH:14][CH:13]=1
Reactant: Cc1cc(N=[N+]=[N-])no1
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnn(-c3cc(C)on3)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To an ice-cooled and stirred mixture of 3-azido-5-methyl-isoxazole (0.5 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.712 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.327 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.900 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.120 g, 11% yield). M.p. 136.3-141.2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[F:15])[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccccc3F)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.2 %

Procedure:
A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 2-fluorophenylacetic acid (18 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N,N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate-toluene, 1:1), giving the title compound (15 mg, 32%). Rf 0.52 (ethyl acetate-toluene, 1:1).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13]O>>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(CN)cc1

Procedure:
Hydrogen chloride gas was blown into methanol (250 ml) on ice with stirring to prepare a methanol solution of hydrogen chloride (44.4 g). To the solution, 4-aminomethylbenzoic acid (25.70 g) was added at room temperature and the mixture was heated under reflux with stirring for 28 hours to obtain an almost homogeneous solution. The solvent was evaporated under reduced pressure from the solution to obtain methyl 4-aminomethylbenzoate hydrochloride (33.11 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[Na+].[I-].ClC([SiH3])(Cl)Cl.[OH-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][C:48]1=[O:53]>C(#N)CC.[Cu]I.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][C:48]2=[O:53])[N:7]=1)[CH3:10]
Reactant: O=C1COCCN1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: CCSc1nc(N2CCOCC2=O)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 5.1 %

Procedure:
A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33 g (8.87 mmol) NaI and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110° C. for 16 h. The mixture was then partitionated between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2CO3 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) CuI and 470 mg (4.65 mmol) 3-morpholinone. The reaction solution was then heated to 100° C. for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312). [M+H]+ 404.1.
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCCCS(C)(=O)=O)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OCCCS(C)(=O)=O)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfonyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.48 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (0.35 g, 78%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.C1C=CC=CC=1.S(Cl)([Cl:30])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([Cl:30])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(N=C(Cl)c2ccc([N+](=O)[O-])c(C)c2)cc1

Procedure:
14 g of N-(4-methoxyphenyl)-4-nitro-3-methyl benzamide in suspension in 70 ml of thionyl chloride were heated for 20 hours at reflux. The solvent was eliminated by entrainment with benzene, and after drying under reduced pressure at ambient temperature, 15 g of N-(4-methoxyphenyl)-4-nitro-3-methylbenzene carboximidoyl chloride melting towards 80° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Solvent: O
Product: O=C1CCCc2ccc(F)cc21
Temperature: 60 °C

Procedure:
0.055 mol of the compound obtained in Step D is introduced into a 500 ml round-bottomed flask together with 100 g of polyphosphoric acid. The reaction mixture is heated at 60° C. for 4 hours. The mixture is then cooled and poured into water; the precipitate formed is then dried and recrystallised.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Li].C([Li])CCC.N1C=CC=C(S[S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)C=1.[NH4+].[Cl-]>CO.C(Cl)Cl.C1COCC1>[O:9]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ncc(Br)cc1Oc1ccccc1
Reactant: c1ccc(SSc2cccnc2)nc1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 249.7 %

Procedure:
A nitrogen purged flask was charged with 5-bromo-3-phenoxypyridin-2-amine (5.00 g, 18.9 mmol) and THF (80 mL) and cooled to −78° C. Methyllithium (14.1 mL, 22.6 mmol) was added and stirred for 5 minutes. Butyllithium (9.05 mL, 22.6 mmol) was added and the reaction was stirred for 10 minutes at −78° C. (solids precipitated). 2-(2-(Pyridin-3-yl)disulfanyl)pyridine (10.4 g, 47.2 mmol) was added and the reaction was warmed to ambient temperature and stirred for 18 hours. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in methanol and NaBH4 (excess) was added and stirred for 10 minutes. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc (2×75 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (100% EtOAc to 1% methanol in EtOAc) to afford crude product. The material was dissolved in 2% MeOH in CH2Cl2 and washed with 1N NaOH. The organic layer was separated, dried, filtered, and concentrated to give 3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine (10.4 g, 47.2 mmol).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([C:20]1[N:21]=[C:22]([CH3:32])[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:19].[Cu][C:34]#[N:35].O.C(OCC)(=O)C>CN1CCCC1=O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[S:23][C:22]([CH3:32])=[N:21][C:20]=2[C:18]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH2:11][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[C:34]#[N:35])=[O:19])=[CH:26][CH:27]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2Br)c(-c2ccc(F)cc2)s1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2C#N)c(-c2ccc(F)cc2)s1

Procedure:
To (RS)-1-[2-(3-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E81 (270 mg, 0.53 mmol) in N-methyl-pyrrolidinone (8 ml) was added copper(I)cyanide (96 mg, 1.06 mmol) and the mixture stirred under argon at reflux for 6 h. The reaction mixture was cooled, poured into water (80 ml) and ethyl acetate (50 ml) and then filtered through kieselguhr. The filtrate was separated and the aqueous phase extracted with ethyl acetate (2×). The combined organics were washed with water (4×50 ml), dried and the solvent removed in vacuo. Chromatography (silica gel) afforded the title compound as a white amorphous solid (94 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:8]=1[F:9])N.N([O-])=O.[Na+].[I-:18].[K+]>Cl.O>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[C:4]([I:18])[CH:3]=1
Reactant: Nc1cc(Cl)c(F)c(C(F)(F)F)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Fc1c(Cl)cc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
In 300 mL of 6N hydrochloric acid, 4.00 g of 3-chloro-4-fluoro-5-trifluoromethylaniline was added, and stirred at room temperature for 30 minutes. In the mixture, a solution of 1.42 g of sodium nitrite in 5 mL of water was added dropwise at such a rate that internal temperature would not exceed 5° C. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. In the reaction mixture, a solution of 4.70 g of potassium iodide in 15 mL of water was added dropwise at the same temperature with stirring. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour and then at room temperature for 15 hours. After the completion of the reaction, the reaction mixture was extracted with 50 mL of diethyl ether twice. The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.70 g of the crude aimed product as yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:21]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:22]([C:30](O)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH2:36]([O:35][C:33]([NH:21][C@@H:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]([NH:12][C@@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:20])=[O:31])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A solution of L-PHENYLALANINE BENZYL ESTER HYDROCHLORIDE (2 g, 6.85 mmol), Z-Phe-OH (2.257 g, 7.54 mmol), DIPEA (2.99 mL, 17.14 mmol) and DCM (100 mL) was treated with 1-HYDROXY-7-AZABENZOTRIAZOLE (1.120 g, 8.23 mmol) and EDC (1.577 g, 8.23 mmol) and stirred at rt for 15 h. The mixture was washed with saturated NaHCO3 (2×100 mL), 1 M HCl (2×50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-benzyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-3-phenylpropanoate (3.2 g, 5.96 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.11 (m, 21H), 4.96 (d, J=2.0 Hz, 4H), 4.63-4.45 (m, 1H), 4.06-3.91 (m, 2H), 3.34-2.96 (m, 3H), 2.85 (br. s., 4H)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[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:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]#[N:43])[CH2:38][CH2:37]1>>[C:42]([CH:39]1[CH2:40][CH2:41][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[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:33])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37][CH2:38]1)#[N:43]
Reactant: N#CC1CCNCC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)N1CCC(C#N)CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and piperidine-4-carbonitrile hydrochloride (and Cat. No.). LCMS (M+H)+: m/z=566.2.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C([N:13]=[C:14]([NH2:28])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[N:17]=1)(C)(C)C.[OH-:29].[Na+]>S(=O)(=O)(O)O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[N:17]=1)[C:14]([NH2:28])=[NH:13]
Reactant: CC(C)(C)N=C(N)Nc1cccc(SCCCC#N)n1
Reactant: [OH-]
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N=C(N)Nc1cccc(SCCCC(N)=O)n1

Procedure:
A solution of 4-[2-(2-t-butylguanidino)pyrid-6-yl thio]butyronitrile hydrogen maleate (0.1 g.) in concentrated sulphuric acid (0.5 ml.) was kept at room temperature for 72 hours. The solution was added to crushed ice and then basified with 10N aqueous NaOH and the mixture extracted three times with EtOAc. The combined extracts were dried and evaporated to dryness. A solution of the residue in acetone was added to a solution of maleic acid in acetone, and the crystalline precipitate was collected to give 4-(2-guanidinopyrid-6-ylthio)butyramide hydrogen maleate (0.04 g.), m.p. 169°-170°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:12](O)[CH:13]=[CH2:14].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:14]([O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)[CH:13]=[CH2:12]
Reactant: C=CCO
Reactant: Cc1cc(O)cc2cc[nH]c12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCOc1cc(C)c2[nH]ccc2c1
Temperature: 100 °C

Procedure:
7-Methyl-1H-indol-5-ol (5.2 g, 35.3 mmol) was dissolved in toluene (221 mL) and prop-2-en-1-ol (2.42 mL, 35.3 mmol) was added followed by cyanomethylenetributylphosphorane (21.32 g, 88 mmol). The reaction was heated at 100° C. After 1 hour the reaction was cooled to room temperature, concentrated and purified by silica gel flash chromatography (0:100 EtOAc:heptanes) to provide the title compound. MS (ESI+) m/z 188.15 (M+H).