Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: Cc1ccc(CC#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(CC#N)ccc1C
Yield: 61.2 %

Procedure:
To a solution of (3-hydroxy-4-methylphenyl)-acetonitrile (1.7 g, 11.5 mmol) in acetone (100 ml), K2CO3 (7.9 g, 57.5 mmol) and 1-bromo butane (6.1 ml, 57.5 mmol) were added. The suspension was refluxed for 24 h and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude was purified by flash chromatography (petroleum ether: EtOAc 9.5:0.5) affording the title compound (1.43 g, 61% yield) as colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[CH:26][CH:25]=1)[CH3:2].[CH3:33][Mg]Cl.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[N:10]3[C:12]([CH3:15])=[N:13][CH:14]=[C:9]3[CH:8]=[N:7][C:6]=2[N:5]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:32])([CH3:33])[CH3:31])=[CH:28][CH:29]=1)[CH3:2]
Reactant: C[Mg]Cl
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc(C(C)(C)O)cc2)n(COCC[Si](C)(C)C)c2ncc3cnc(C)n3c12
Temperature: 0 °C
Yield: 113.4 %

Procedure:
1-(4-(8-Ethyl-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-7-yl)phenyl)ethanone (0.092 g, 0.205 mmol, Preparation #W.1) in THF (5 mL) was cooled to about −20° C. and MeMgCl (3.0 M in THF, 0.1 mL, 0.3 mmol) was added. After about 5 min MeMgCl (3.0 M in THF, 0.1 mL, 0.3 mmol) was added then the mixture was warmed to about 0° C. MeMgCl (3.0 M in THF, 0.2 mL, 0.6 mmol) was added and the mixture was allowed to warm to about 15° C. over about 2 h. MeMgCl (3.0 M in THF, 0.2 mL, 0.600 mmol) was added to THF (3 mL) and the solution was added to the mixture portion-wise. An aqueous solution of NH4Cl (4 mL) was added slowly. The mixture was diluted with water (20 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-(4-(8-ethyl-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-7-yl)phenyl)propan-2-ol (0.108 g, 113%): LC/MS (Table 2, Method a) Rt=2.96 min.; MS m/z 465 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C=O)C>CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1sc2ccc(-c3ccccc3)nc2c1N
Temperature: 90 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol) and triethylamine (0.20 mL) were added to 3 mL of DMF containing [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (1:1 complex with CH2Cl2) under N2. The mixture was stirred at 90° C. for 4 h. The reaction was then cooled and diluted with Et2O. The organic layer was washed with H2O, brine, dried (MgSO4), concentrated and chromatographed (2:1 CH2Cl2 :hexane) to yield the title compound (140 mg, 50%): 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J=8 Hz, 1H), 8.07-8.13 (m, 3H); MS (DCI(NH3)) m/e 285 (M+H)+.
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].Cl>ClCCl.O1CCOCC1>[CH2:25]([N:27]1[C:4](=[O:17])[CH:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[NH:6][C:28]1=[O:29])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN1C(=O)NC(Cc2c[nH]c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.3 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.510 mg, 0.002 mol.) in dichloromethane (10 mL) was added triethyl amine (0.350 mL, 0.0025 mol.) followed by ethylisocyanate (0.198 mL, 0.0025 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was diluted with dioxane (10 mL) and then conc. HCl (5 mL) was added. The mixture was heated at reflux for 3-4 hr. The reaction mixture was extracted in ethyl acetate, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-04 (480 mg, 93%): mp 167-170° C. (lit. 163-164° C.), 1H NMR (400 MHz, CDCl3): 0.99 (t, J=6.8 Hz, 3H), 2.95-3.01 (dd, J=8.4 and 14.8 Hz, 1H), 3.34-3.46 (m, 3H), 4.19-4.22 (dd, J=3.6 and 8.8 Hz, 1H), 5.70 (s, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.06-7.10(dd, J=8.0 and 6.8 Hz, 1H), 7.16(dd, J=7.2 and 6.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 8,18 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][CH:8]3[C:7](=[O:14])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:22]=1[CH2:23]Cl>CN(C)C=O>[CH3:30][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[C:22]=1[CH2:23][N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][CH:8]2[C:7]1=[O:14]
Reactant: [H][H]
Reactant: COc1cccc(OC)c1CCl
Reactant: O=C1Nc2cccnc2N2CCCC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1CN1C(=O)C2CCCN2c2ncccc21
Temperature: 25 °C
Yield: 89 %

Procedure:
To a stirred solution of 6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (2.7 g. 0.01 mole) in 30 ml. of dry dimethyl formamide was added sodium hydride (0.5 g., 0.02 mole of 50% dispersion in mineral oil). When the evolution of hydrogen subsides, 2.7 g. (0.01 mole) of 2,6-dimethoxybenzyl chloride was added. The reaction mixture was stirred at room temperature for eighteen hours, and the dimethyl formamide was removed under vacuo. The residue was triturated with cold water, filtered and recrystallized from ethanol to give white crystals of the title compound, 2.7 g. (89% yield) m.p. 200°-202° C.; hydrochloride salt, m.p. 220°-223° C.
Reaction SMILES: C[O:2][C:3](=O)[NH:4]S(C1C=CC=CC=1)(=O)=O.C1(S(N)(=O)=O)C=CC=CC=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1>[CH:25]1([NH:31][C:3](=[O:2])[NH2:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)NS(=O)(=O)c1ccccc1
Reactant: NC1CCCCC1
Agent: NS(=O)(=O)c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)NC1CCCCC1

Procedure:
2.0 g of 4-(β<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl carbamic acid methyl ester (melting point 160 - 161° C, prepared from 4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido]-ethyl)-benzenesulfonamide and chlorofomic acid methyl ester) in 30 ml of dioxane were gently boiled for 2 hours together with 0.5 g of cyclohexyl amine in a vessel with descending condenser. The solvent was then concentrated under reduced pressure, the residue was dissolved in dilute ammonia and precipitated with dilute hydrochloric acid, the reaction mixture was filtered with suction and the precipitate recrystallized from methanol. The N-[4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea obtained melted at 189 - 190° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CN(C)C=O>[C:15]([S:17][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[CH:5][CH:4]=1)(=[O:18])[CH3:16]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)c1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Allyl 4-(bromomethyl)benzoate (98 g, 0.4 moles) in dry dimethylformamide (100 ml) was added dropwise to a cooled suspension of potassium thioacetate (46 g, 0.4 moles) in dry dimethylformamide (200 ml). The cooling bath was removed and the mixture was stirred overnight. The reaction was poured into water and extracted with ethyl acetate (×3). The combined extracts were washed with water and brine. The mixture was dried and evaporated to give allyl 4-(acetylthiomethyl)benzoate as an orange oil (100 g, 100% yield). 1H NMR δ (CDCl3) 2.36 (3H, s, COCH3), 4.13 (2H, s, CH2), 4.82 (2H, m, CH2O), 5.32 (2H, m, CH2CH--), 6.05 (1H, m, CHCH2), 7.35 (2H, d, Ph-H), 7.98 (2H, d, Ph-H).
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([CH3:8])=O)C.[CH3:16][CH:17]([NH:26][NH2:27])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1>C(O)C>[CH3:8][C:6]1[NH:27][N:26]([CH:17]([CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:4](=[O:15])[C:5]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(NN)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Solvent: CCO
Product: Cc1[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c(=O)c1-c1ccccc1

Procedure:
20.6 g of α-phenylacetoacetic acid ethyl ester were added dropwise under nitrogen to a solution of 20.5 g (0.1 mol) of α-methyl-3,4-dichlorobenzylhydrazine in 20 ml of absolute ethanol, during which the temperature of the reaction mixture rose to 55°C. After heating the reaction solution for two hours under reflux, the reaction product crystallized out on cooling the reaction mixture. The crystals were filtered off, rinsed with ether and recrystallized from an ethanol/dimethylformamide mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH:22][C:8](=[O:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1cccc(-c2nnco2)c1
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: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Yield: 80.6 %

Procedure:
A solution of 4-bromopyridine-2-carboxylic acid (3.76 g, 18.6 mmol), 3-[1,3,4]oxadiazol-2-yl-phenylamine (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (7.1 g, 18.7 mmol), and diisopropylethylamine (15 mL) in N,N-dimethylformamide was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was stirred with acetonitrile (40 mL) and water (40 mL). The solid thus obtained was isolated by filtration, washed with water (20 mL), acetonitrile (20 mL) and diethyl ether (40 mL), and dried under reduced reassure to give N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide as a white powder (5.2 g, 15.0 mmol, 81% yield).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.C([O:8][C:9](=O)[C:10](Br)=[C:11](Br)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])C>CO.O.O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:11]1[O:1][N:4]=[C:9]([OH:8])[CH:10]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(F)cc1F
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Oc1cc(-c2ccc(F)cc2F)on1
Temperature: 5 °C
Yield: 78.5 %

Procedure:
Sodium hydroxide (10.9 g) was dissolved in methanol (110 ml), and a solution of hydroxylamine hydrochloride (4.2 g) in water (10 ml) was added dropwise thereto at 5° C. with stirring. A solution of α,β-dibromo-2,4-difluorocinnamic acid ethyl ester (19.6 g) in tetrahydrofuran (20 ml) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 2 hours, followed by reflux for 5 hours. The solvent was evaporated under reduced pressure and the residue was poured into ice-cold water. The pH of the reaction mixture was adjusted to a value of 2 with conc. hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous NaCl solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: cyclohexane/ethyl acetate=1/1) to obtain the title compound (8.2 g, 79%) as colorless crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:27][C:28](=[O:30])[CH3:29])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(=O)C.C(=O)([O-])[O-].Cl>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:27][C:28](=[O:30])[CH3:29])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(-c2ccc(COC(C)=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: CC(=O)Nc1nc(-c2ccc(CO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-(acetylamino)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl)benzyl acetate (1.218 g) in metanol (24 ml) was added pottasium carbonate (379 mg) at 20° C., and the mixture was stirred for 1 h. To the reaction mixture was added 0.1N-hydrochloric acid (27.4 ml), and the mixture was extracted with chloroform (500 ml), dried over magnesium sulfate and evaporated to give N-{4-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -1 °C
Reaction time: 0.5 h

Procedure:
solution of 110.6 g (0.475 mol, 95% assay) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 25.2 g (0.6 mol) of cyanamide in 600 mL of acetonitrile was cooled to −5° C. To this solution was added 750 g (0.575 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 45 min with the temperature kept below 0° C. The reaction mixture was allowed to stir at −1° C. for 30 min To the mixture was added 9.5 g (0.05 mol) of sodium metabisulfite in 25 mL of water and the two phase mixture was allowed to settle. The aqueous phase was re-extracted 2×'s with 50 mL of acetonitrile. The organics were combined and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 40:54 (area) ratio of two isomers.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][C:11]#[N:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:22][OH:23]>O.CCO>[OH:23][NH:22][C:11](=[NH:12])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(OCC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1

Procedure:
To a mixture of (4-methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5 mmol), K2CO3 (1.3 g, 9.5 mmol) in H2O (30 mL) and EtOH (15 mL) was added hydroxylamine hydrogenchloride (1.32 g, 19 mmol). The mixture was heated under reflux overnight, cooled and ethanol was removed in vacuo and the residue was extracted with EtOAc (150 mL). The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: FC1C(N2CCNCC2)=C[C:9]2[NH:8][CH:7]=[C:6]3[C:18](=O)N(C4C=CC=CC=4)N=[C:5]3[C:4]=2[CH:3]=1.F[C:29]1[C:30]([F:49])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:48])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CC1CC(C)CNC1>>[CH3:18][CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][N:8]([C:29]2[C:30]([F:49])=[CH:31][C:32]3[C:33]4[C:34]([C:39](=[O:48])[N:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)=[CH:35][NH:36][C:37]=3[CH:38]=2)[CH2:7]1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Agent: CC1CNCC(C)C1
Product: CC1CC(C)CN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)C1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 3,5-dimethylpiperidine. 1H-NMR (DMSO-d6) δ (ppm): 0.99 (6H, d, J=6.33 Hz), 1.80 (4H, br), 2.47 (2H, t, J=8.62 Hz), 3.46 (2H, brd, J=11.81 Hz), 7.13 (1H, m), 7.26 (1H, d, J=7.97 Hz), 7.40 (2H, t, J=7.69 Hz), 7.79 (1H, d, J=13.18 Hz), 8.19 (2H, d, J=7.69 Hz), 8.65 (1H, s). m/z 391.5 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:40])=[C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24](=[O:29])[CH2:25][N:26]([CH3:28])[CH3:27])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:41][Br:42]>CC#N>[Br-:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:40])=[C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([CH2:25][N+:26]([CH3:41])([CH3:28])[CH3:27])=[O:29])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CBr
Solvent: CC#N
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)C[N+](C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: [Br-]
Reaction time: 18 h

Procedure:
N-[6-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-dimethylamino-acetamide (Ex. 14, 10 mg, 0.018 mmol) was stirred in MeCN (0.5 mL) and a solution of MeBr (ca. 30% in MeCN, 0.01 mL) added, followed after 15 mins by a further MeBr solution (0.05 mL). The reaction mixture was stirred for 18 hrs before being concentrated in vacuo to give title compound as an off-white solid (11 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: OB(O)c1ccc(Br)cc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-bromophenylboronic acid according to Method C (Example 178).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with tert-butyl N-(4-formylphenyl)carbamate was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give tert-butyl N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]carbamate.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[C:24]3([CH2:32][CH2:31][C:30]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([NH:33]CC4C=CC(OC)=CC=4)[CH2:29][CH2:28]3)[O:25][CH2:26][CH2:27][C:18]2=1>O1CCCC1.CO.[Pd]>[CH2:43]([C:30]1([NH2:33])[CH2:31][CH2:32][C:24]2([C:19]3[NH:20][C:21]4[C:17]([C:18]=3[CH2:27][CH2:26][O:25]2)=[CH:16][C:15]([F:14])=[CH:23][CH:22]=4)[CH2:28][CH2:29]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCc2c3[nH]c3ccc(F)cc23)cc1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: NC1(Cc2ccccc2)CCC2(CC1)OCCc1c2[nH]c2ccc(F)cc12

Procedure:
A solution of the free base of 6′-fluoro-4′,9′-dihydro-N-(4-methoxybenzyl)-4-benzyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine citrate (200 mg, 0.4 mmol) in tetrahydrofuran (20 ml) and methanol (20 ml) was mixed with 10% palladium on activated carbon (40 mg) and hydrogenated for 7 h under 3 bar and at 40° C. Then the reaction mixture was filtered through a pleated filter, the filter residue was washed with methanol and the filtrate was concentrated to small volume under vacuum. The crude product (186 mg) was purified by flash chromatography (20 g, 21×2 cm) with methanol. Yield: 136 mg (64%), beige-coloured solid. Melting point 198-205° C. (decomposition).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:9][CH:10]=1)([F:4])[CH3:3].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:20].[F:4][C:2]([C:5]1[CH:6]=[C:7]([C:21]2[CH:22]=[C:23]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[N:24]=[N:25][CH:26]=2)[CH:8]=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cccc(C(C)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=315.4 (M+H+), was prepared from 2-[3-(1,1-difluoro-ethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12]C(OC(C)(C)C)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH2:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)NCCc1ccccc1
Reaction time: 6 h

Procedure:
N-(tertiarybutoxycarbonyl)-L-leucine N-phenethylamide (6.17 g, mole) was dissolved in a 1:1 TFA/CH2Cl2 mixture (60 ml). After stirring for 6 h at 20° the reaction mixture was concentrated in vacuo and the residue in CH2Cl2 (50 ml) washed with saturated aq. NaHCO3 (100 ml). The aqueous extract was back extracted with CH2Cl2 (50 ml×3) and the combined organic extracts concentrated to an oil in vacuo. The crude L-leucine N-phenethylamide so obtained was used as such in the next step.