Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C(N(CCCC)CCCC)CCC.[CH3:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[CH2:27]=[O:28].Cl>C1(C)C=CC=CC=1.O>[OH:26][C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][C:23]=1[CH:27]=[O:28]
Reactant: C=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
109 μl (0.93 mmol) of tin-tetrachloride and 882 μl (3.70 mmol) of tri-n-butylamine were added to a solution of 1.0 g (9.25 mmol) of 3-methyl-phenol in toluene (12 ml) and the mixture was stirred for 30 min at RT. Then 611 g of paraformaldehyde were added and the resulting mixture was heated to 100° C. for 16 hours. After cooling to RT water (40 ml) was added and the pH was adjusted to 2 by addition of 1N HCl. This mixture was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (silica gel; ether/cyclohexane 1:15) to yield 131 mg (10%) of 2-hydroxy-4-methyl-benzaldehyde as colorless crystals. 1HNMR (CDCl3, 300 MHz): δ 2.38 (s, 3H), 6.80 (s, 1H), 6.82 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 9.83 (s, 1H), 11.04 (s, 1H).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N1([C:29](=O)[C:28]2N(C)C=N[C:23]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O>[CH:28]([O:15][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[NH2:2])([CH3:29])[CH3:23]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Br
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
HBr (120 g) and tryptophan (5 g) were dissolved in water (1 L). Caffeine (100 g) and menthol (10 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[N:21]2[N:22]=[N:23][N:24]=[C:20]2[C:19]2[N:25]=[C:26]([CH2:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH2:30][OH:31])[C:18]=2[C:17]=1[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:56]1[C:60](=[O:61])[C:59]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:58]2[C:57]1=[O:66]>CN(C=O)C>[CH3:15][C:16]1[N:21]2[N:22]=[N:23][N:24]=[C:20]2[C:19]2[N:25]=[C:26]([CH2:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH2:30][O:31][N:56]3[C:60](=[O:61])[C:59]4[C:58](=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:57]3=[O:66])[C:18]=2[C:17]=1[CH3:35]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Diisopropyl azodicarboxylate (372 μL, 1.89 mmol) was added to a stirred solution of 3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)propan-1-ol (500 mg, 1.72 mmol), triphenylphosphine (496 mg, 1.89 mmol), and N-hydroxyphthalimide (308 mg, 1.89 mmol) in DMF (17 mL) at room temperature. After 4 hours, the solvent was removed under reduced pressure to afford an oil that was triturated with ethyl acetate to generate a pink solid. The solid was isolated by filtration and washed with ethyl acetate to yield 630 mg of 2-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a pink powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[O:34][N:33]=[C:32]([CH:35]([CH3:36])[CH3:37])[N:31]=3)[CH2:28][CH2:29]2)[CH3:23])=[CH:12][N:11]=1
Reactant: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cnc(OC(C)C3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.40 g, 1.69 mmol), crude (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.75 g, 2.29 mmol) and K2CO3 (0.48 g, 3.39 mmol) in DMF (16 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was purified by chromatography on an ISCO silica gel column using 0 to 30% EtOAc/hexanes to give 0.335 g (43%) of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.23 (d, 1H, J=1.0 Hz), 7.85 (t, 1H, J=8.2 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.6 Hz), 5.20-5.05 (m, 1H), 4.25-4.15 (m, 2H), 3.10-2.95 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.50 (s, 3H), 2.00-1.75 (m, 3H), 1.55-1.40 (m, 2H), 1.33 (d, 3H, J=6.4 Hz), 1.26 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(NN(C)C(=O)OC(C)(C)C)c2ccccc12
Temperature: 50 °C
Yield: 9.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 450 mg, 3.1 mmol), (4-methyl-1-naphthalene)boronic acid (Aldrich; 561 mg, 3.0 mmol), copper(II) acetate (559 mg, 3.1 mmol) and triethylamine (430 μL, 3.1 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N-methyl-N′-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester (79 mg, 9%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CCO
Product: CNCC(O)COc1ccccc1

Procedure:
To a solution of 1,2-epoxy-3-phenoxypropane (15 g), in ethanol (50 ml) was added 25-30% methylamine in water (50 ml) and the mixture heated under reflux for 1 h. The ethanol was removed in vacuo and the residue acidified with 2 N hydrochloric acid. The aqueous solution was extracted with ether acetate then made alkaline with 2 N sodium hydroxide and extracted into ether. The combined ethereal extracts were dried (Na2SO4), filtered and evaporated to give a semi-solid (14.8 g). The product was distilled in vacuo to give the title compound as white crystals b.p. 110°/0.07 mm, m.p. 74°-77° (9 g).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.I[CH2:38][C:39]#[N:40]>O1CCCC1.O>[C:39]([CH2:38][N:13]1[C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[C:4]1=[O:3])#[N:40]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.28 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min 2-Iodoacetonitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoaceto-nitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoacetonitrile (14 μL, 0.20 mmol) is added, and the mixture is stirred for 2 h, diluted with water and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=529; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:19])[CH3:18])[C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:6].O>O1CCOCC1.O>[C:17]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:16][CH:15]=2)[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[CH2:11][C:12]1([CH3:21])[CH3:20])(=[O:19])[CH3:18]
Reactant: COC(=O)c1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A 2 M NaOH solution was added dropwise to a stirred solution of 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (1.2 g) in dioxane/water 4:1 (v/v) (50 ml) until pH 12. After stirring for 18 h, the reaction mixture was poured into water and extracted with ethyl acetate at pH 2. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCC/C=C\CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCC/C=C\CCCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Alcohol 7 (115 mg, 0.541 mmol) in dichloromethane (100 ml) at 0° C. was treated successively with carbon tetrabromide (395 mg, 1.20 mmol) and triphenylphosphine (312 mg, 1.20 mmol), and allowed to warm to room temperature with stirring over 2 h. The reaction mixture was triturated with water and extracted with methylene chloride, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography using hexanes as an eluent, thus affording pure 8 as a light oil (105 mg, 0.381 mmol, 70%); δH(270 MHz, CDCl3); 0.87 (3H, t, J=6.1 Hz), 1.1-1.65 (14H, m), 1.85 (2H, quin, J 7.0), 2.03 (4H, m), 3.4 (2H, t, J 6.8) and 5.35 (4H, m); δC(67.5 MHz, CDCl3) 27.06, 27.32 27.72, 27.91, 28.04, 28.96, 29.32, 29.37, 29.71, 29.83, 31.96, 32.82, 34.01, 129.31, 130.47.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:17]C(=O)C)([CH3:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=O)C.[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[ClH:30].NC(CCC1C=CC=CC=1OCCCCCCC)(CCC)CO>>[ClH:30].[NH2:17][C:6]([CH3:16])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:10]=1)[CH2:5][OH:4]
Reactant: CCCCCCCCBr
Reactant: CC(=O)NC(C)(CCc1cccc(O)c1)COC(C)=O
Agent: CCCCCCCOc1ccccc1CCC(N)(CO)CCC
Agent: Cl
Product: CCCCCCCCOc1cccc(CCC(C)(N)CO)c1

Procedure:
2-Acetamido-4-(3-hydroxyphenyl)-2-methylbutyl acetate and octyl bromide were used in the same manner as working example 52 (9) and (10) to give the subject compound as white crystals, melting at 130-132° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22](N(OC)C)=[O:23])([CH3:17])([CH3:16])[CH3:15].C([Mg]Cl)(C)C>C1COCC1.ClCCl>[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22]([C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cn1c(=O)c(Br)cc2ccccc21
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)CNC(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.3 M solution of 3-bromo-1-methylquinolin-2(1 H)-one (1 equiv; prepared as described in Tetrahedron, 64 (26), 6030-6037; 2008) and tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1.2 eq) in dry THF, isopropylmagnesium chloride (3 eq) was added dropwise at room temperature. The mixture was stirred for 30 min at room temperature, diluted with dichloromethane, washed with sat. aq. NH4Cl dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, Pethroleum ether/EtOAc, from 7% to 60% EtOAc). The pooled fractions were concentraded under vacuum to the title compound. MS (ES) C17H20N2O4 requires: 316.35, found: 317. 1H-NMR (400 MHz, DMSO-d6) δ: 8.53 (1 H, s), 7.99 (1 H, d, J=7.2 Hz), 7.78 (1 H, t, J=6.8 Hz), 7.61 (1 H, d, J=8.4 Hz), 7.35 (1 H, t, J=7.2 Hz), 6.97 (1 H, bt, J=5.6 Hz), 4.45 (1 H, d, J=5.6 Hz), 3.70 (3 H, s), 1.39 (9 H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][C:24](=O)[CH3:25].C1C[O:30]CC1>>[F:15][C:13]1[CH:12]=[C:11]([C:23]([OH:30])([C:19]2[S:18][CH:22]=[CH:21][N:20]=2)[CH2:24][CH3:25])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: C1CCOC1
Reactant: CC(=O)Cc1nccs1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Mg]
Product: CCC(O)(c1cc(F)cc(OCc2ccccc2)c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 3-benzyloxy-1-bromo-5-fluorobenzene (EP: 0385662, ICI, Pharma) (5.4 g, 19.4 mmol) in dry THF (30 mL) containing magnesium (941 mg, 38.7 mmol) was heated until the Grignard reagent was formed then the reaction mixture was stirred at r.t. for 30 min. and transferred to a solution of 1-(thiazol-2-yl)propanone in dry THF at 0° C. The reaction mixture was stirred for 30 min. then an aqueous solution of NH4OAc (25%) was added and the THF evaporated. The residue was diluted with EtOAc and washed successively with H2O, brine, dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane:EtOAc 9:1 to give 2.2 g, (50%) of the title product.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)ccc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.011 g of product in 46% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:30]([OH:31])=[C:28]([OH:29])[CH:27]=1)=[O:22])[CH2:13][C:14](=[O:20])[O:15]C(C)(C)C)=[O:10])C1C=CC=CC=1.C(O)(=O)/[CH:35]=[CH:36]/[C:37]1[CH:44]=[CH:43][C:41]([OH:42])=[C:39]([OH:40])[CH:38]=1>>[C:9]([NH:11][C@H:12]([C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:30]([OH:31])=[C:28]([OH:29])[CH:27]=1)=[O:22])[CH2:13][C:14](=[O:20])[OH:15])(=[O:10])/[CH:35]=[CH:36]/[C:37]1[CH:44]=[CH:43][C:41]([OH:42])=[C:39]([OH:40])[CH:38]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(O)C[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1
Yield: 52.4 %

Procedure:
N-(N′-benzyloxycarbonyl-Oγ-tert-butyl-L-aspartyl)dopamine (1.0 g, 2.3 mmol) was deprotected by hydrogenolysis as described in example 5. The product thus obtained was then coupled with caffeic acid (621 mg, 3.5 mmol) according to the indications of example 4. Purification by flash chromatography using 30-50% AcOEt/CH2Cl2 containing 1% AcOH yielded 519 mg (47%) of the title compound as yellow crystals.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([B:12](O)O)[CH2:9][CH2:10][CH3:11]>C(Cl)Cl.CCOCC>[CH2:8]([B:12]1[O:7][CH2:6][CH2:5][NH:1][CH2:2][CH2:3][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2′-azanediyldiethanol (26.12 g, 246 mmol) in DCM (250 ml) and ether (500 mL) was added n-butylboronic acid (25.4 g, 242 mmol) and molecular sieves (3A, 4-6 mesh, 65 g). It was stirred at ambient temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting white solid was recrystallized with DCM/ether to provide white crystals as the title product. NMR (300 MHz, CDCl3): δ 0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H), 1.20-1.37 (m, 4H), 2.82 (br, 2H), 3.24 (br, 2H), 3.95 (br, 4H), 4.27 (br, 1H). MS (DCl—NH3) m/z 172 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.COC(C1N=NC(NCC2C(C3C=CC=CC=3)=NOC=2C)=CC=1)=O.[CH:51]1([NH2:54])[CH2:53][CH2:52]1>>[CH:51]1([NH:54][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:53][CH2:52]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Agent: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC2CC2)nn1
Yield: 75 %

Procedure:
As described for example 67e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (106 mg, 0.3 mmol) was converted, instead of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (83 mg, 75%) which was obtained as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:18]([CH3:25])([CH3:26])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Yield: 84.4 %

Procedure:
A mixture of 1-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (690 mg, 1.83 mmol), ammonium formate (461 mg, 7.31 mmol), 10% Pd/C (100 mg) in methanol (10 ml) and water (1 ml) was refluxed overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with brine and dried over MgSO4. Evaporation of solvent provided the title compound as oil (444 mg, 84%).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CCOC(C)=O.O=[Si]=O>C(NC(C)C)(C)C.C1COCC1.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.[Cu]I>[CH3:11][C:8]1([CH3:12])[CH2:7][O:6][C:5]2[CH:13]=[CH:14][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)COc2ccc(I)cc2OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=[Si]=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC1(C)COc2ccc(C#C[Si](C)(C)C)cc2OC1
Temperature: 57 °C

Procedure:
To a mixture of [PdCl2(PPh3)2] (1.73 g) and copper(I) iodide (845 mg) under Ar is added a degassed solution of 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (7) (15.0 g) in diisopropylamine (225 ml) and THF (225 ml). Trimetylsilylacetylene (7.27 g) is added and the mixture is stirred over night at 57° C. After addition of AcOEt (1 L) and filtration over dicalite, the solution is washed with 1 N aq. HCl sol. (3×1 L) and brine (2×1 L). The organic layer is dried over Na2SO4 and the solvent is evaporated to yield (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-trimethyl-silane (6b) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])=[O:14]
Reactant: CO
Reactant: O=C(O)c1ccc2ccccc2c1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2ccccc2c1Br

Procedure:
To 2.00 g 1-bromo-naphthalene-2-carboxylic acid in 20 ml of dry methanol 5 ml of sulfuric acid were added. After 5 h at reflux, the reaction was poured onto ice-water, and the precipitated product was collected by filtration and washed until neutral. After recrystallization from heptane 1.90 g 1-bromo-naphthalene-2-carboxylic acid methyl ester were obtained.