Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1
Reactant: Clc1nc2ncnn2c(Cl)c1-c1ccsc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc2ncnn2c(NC2CCCC2)c1-c1ccsc1
Yield: 70.4 %

Procedure:
5,7-Dichloro-6-thien-3-yl-1,2,4-triazolo[1,5-a]pyrimidine (0.54 g, 0.002 mol) was dissolved in tetrahydrofuran (20 ml). A mixture of cyclopentylamine (0.2 g, 0.002 mol), tetrahydrofuran (2 ml) and triethylamine (0.25 g, 0.002 mol) was then added with stirring and the stirring continued for a further hour after the addition was complete. The solvent was then distilled off in vacuo and the residue treated with ethyl acetate and water (50 ml each). The organic phase was separated, dried with sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel using 8:2 ethyl acetate: petroleum ether (300 ml) as eluant to give 0.45 g 5-chloro-6-thien-3yl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]-pyrimidine as colourless crystals, m.pt. 78° C. Yield: 71% of theoretical.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NCCO
Product: C1CCC2(CC1)NCCO2

Procedure:
2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-1-oxaspiro[4.5]decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>C(Cl)Cl>[Cl:14][C:4]1[N:3]=[C:2]([NH:17][CH2:15][CH3:16])[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: CCN
Solvent: ClCCl
Product: CCNc1nc(Cl)cc2ncn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.5 g, 6.5 mmol) in DCM (10 mL) was added an aqueous ethylamine solution (70%, 8 mL, 6.368 g, 141.3 mmol). After stirring for 8 hours at room temperature, the reaction mixture was evaporated under reduced pressure to afford the title compound. ESI-MS m/z 239.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][C:23]1(C)[C:27](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:15]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:23]([CH3:27])=[CH2:22])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)c(Oc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)cc1Oc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of tert-butyl 4-bromo-3-phenoxybenzoate (400 mg, 1.15 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (193 mg, 1.15 mmol) and sodium carbonate (366 mg, 3.45 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction was concentrated. The residue was purified by pre-HPLC to get tert-butyl 3-phenoxy-4-(prop-1-en-2-yl)benzoate (309 mg, 87%) as a yellow solid LRMS (M+H+) m/z: calcd 311.16. found 311.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: Fc1ccc(CBr)cc1
Product: CC1(C)OC(=O)c2c(OCc3ccc(F)cc3)cccc2O1

Procedure:
5-(4-Fluoro-benzyloxy)-2,2-dimethyl-benzo[1,3]dioxin-4-one was prepared from 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one and 4-fluorobenzyl bromide under conditions analogous to example 46-a. Crude product was purified by silica gel chromatography (eluting with 40%-100% CH2Cl2 in hexanes) to provide the title compound. MS ESI(+) m/e: 303.06 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]([CH2:29]C5C=CC(OC)=CC=5)[C:27](C)=[N:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:39])[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]([CH3:29])[CH:27]=[N:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:39])[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nncn4C)ccc3C)csc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 4-chloro-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (85 mg; 0.151 mmol) (from Example 58 supra) with trifluoroacetic acid (1.0 mL; 13 mmol), anisole (100 μL; 0.92 mmol) (Aldrich) and sulfuric acid (50 μL; 0.94 mmol) was stirred at room temperature for 42 hours. The mixture was concentrated. The residue was diluted with dichloromethane and concentrated again. The residue was then diluted with dichloromethane and methanol and washed with saturated aqueous sodium bicarbonate solution and water. The aqueous phases were backwashed with a mixture of dichloromethane and methanol. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by flash chromatography (12 g column; EtOAc followed by a gradient to 60:40 EtOAc: methanol) to give 4-chloro-3-[2-methyl-5-(methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 56.3 mg, 84.20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Yield: 61 %

Procedure:
Prepared in 61% yield from 2-bromo-4,5-difluorophenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.42-7.35 (m, 1H), 6.77 (dd, J=11.9, 7.2 Hz, 1H), 5.88 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.21-5.06 (m, 2H), 4.40-4.27 (m, 1H), 2.61-2.36 (m, 2H), 1.35 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N.C([O:17]CC)C>>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:17]
Reactant: CCOCC
Reactant: N#Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Product: O=Cc1cccc(OC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
103 g (0.544 mol) of stannous chloride and 400 ml of diethyl ether are introduced into a one liter three-necked flask equipped with a condenser, a mechanical stirrer and a gas bubbler tube. This mixture is cooled and saturated with hydrogen chloride gas until the stannous chloride is completely dissolved. A solution of 72.7 g (0.388 mol) of 3-trifluoromethoxy-benzonitrile in 75 ml of anhydrous diethyl ether is added dropwise but fastly via the dropping funnel, while the mixture is cooled with ice-water. The mixture is allowed overnight, then the aldehyde is steam distilled. The distillate is extracted several times with diethyl ether and the extracts are combined. 250 ml of a solution of sodium bisulphite (d=1.32-1.33) are added to the extracts and allowed overnight. The bisulfite compound is filtered off, washed with a small quantity of ice-water and then with diethyl ether. The compound is introduced into a one liter flask which contains solution of 60 g of potassium carbonate in 250 ml of water. The mixture is heated at 100° C. so as to decompose the bisulfite compound and to steam distil the aldehyde as it is formed. The distillate is extracted several times with diethyl ether. The combined ether phases are dried over sodium sulphate and filtered and the solvent is evaporated. 32 g (44% yield) of 3-trifluoromethoxy-benzaldehyde are obtained as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3([CH3:22])[O:21]CCO3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)O[CH:25](C)C.[Li+].CC([N-]C(C)C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:21])[CH3:22])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C3(C)OCCO3)ccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-indole-1-carboxylic acid tert-butyl ester [4.96 g, 16.35 mmol, Intermediate (19)] in anhydrous tetrahydrofuran (20 mL) is added triisopropyl borate (4.61 g, 24.51 mmol) and cooled to 0° C. under N2. To it is added LDA (1.8M in heptane/tetrahydrofuran/ethylbenzene, 14 mL) drop wise at 0° C. over 40 minutes periods. After another 35 minutes, the reaction is quenched by the addition of aqueous 2N hydrochloric acid at 0° C. The white solid precipitated is slowly acidified with 3N hydrochloric acid till pH=3. The mixture became solution which is extracted twice with ethyl acetate (100 mL). The combined ethyl acetate phases are dried over sodium sulfate and filtered. The solid crude is triturated with acetonitrile and water to obtain 5-acetyl-2-methyl-indole-1-carboxylic acid tert-butyl ester (4.76 g, 96%, Intermediate (20)] as light yellow solid; 1H NMR (CDCl3): δ 8.30 (2.67, 3H), 8.18 (1H, d), 7.90 (1H, d), 6.78 (1H, s), 2.61 (3H, s), 1.62 (9H, s); LC/MS: ESI+ 304 (M+H)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7]/[C:8](/[CH3:16])=[CH:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][OH:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7]/[C:8](/[CH3:16])=[CH:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: C/C(=C\C=C\CCCO)CCC1OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: C/C(=C\C=C\CCCOS(C)(=O)=O)CCC1OCCO1
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methanesulfonic acid (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dienyl ester was synthesized using the following procedure. To a cooled (0° C.) solution of (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dien-1-ol (1.60 g, 7.20 mmol), triethylamine (1.2 mL, 8.6 mmol), and 15 mL of CH2CI2 was added dropwise methanesulfonyl chloride (0.61 mL, 7.9 mmol). The reaction mixture was stirred at 0° C. to room temperature for 2.5 h, quenched with a saturated NaHCO3 solution, extracted with EtOAc, dried (Na2SO4), and concentrated to give 1.95 g (6.41 mmol, 89%) of methanesulfonic acid (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dienyl ester which was used without further purification: 1H NMR δ6.28 (dd, 1H, J-15.0, 10.9 Hz), 5.82 (d, 1H,J-10.7 Hz), 5.52 (dt, 1H,J-15.0, 7.0 Hz), 4.85 (t, 1H,J-4.8 Hz), 4.23 (t, 2H, J-6.4 Hz), 4.00-3.75 (m, 4H), 3.00 (s, 3H), 2.25-2.12 (m, 4H), 1.90-1.75 (m, 4H), 1.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1.NN>C(O)C.C(Cl)(Cl)Cl>[NH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cccc(C2CCCN2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl }-1H-isoindole-1,3(2H)dione (0.92 g) in ethanol (30 ml) and chloroform (5 ml) was added anhydrous hydrazine (98%, 0.42 ml) at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 1.5 hrs, cooled to ambient temperature, and filtered. The filter cake was washed with ethanol and the combined filtrates were concentrated. The residue was diluted with dichloromethane/ether. The organic solvents were decanted and concentrated to give N-(2-aminoethyl)-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 77.5 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.3 mmol) was added to a solution of 4-cyanophenol (5.0 g, 42.3 mmol), and K2CO3 (14.6 g, 0.10 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 hr. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine, and dried over sodium sulfate. The organic phase was filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with (hexanes/ethyl acetate 4:1) to give the product (9.0 g, 77.8%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M118) (0.39 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (237 mg, 78%).
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.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5[nH]ccc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:17]1([CH2:23][CH2:24][NH:25][CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2NCCc1ccccc1

Procedure:
A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g), phenylethylamine (15.6 ml) and p-toluensulfonic acid (8.7 g) in 250 ml of toluene was refluxed with removal of water for twenty hours. The mixture was then treated with a dilute NaOH solution, and extracted with ethyl acetate (3x). The combined organics were washed with water and dried (saturated NaCl solution, MgSO4).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[O:35]C)[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[O:10].ClCCl>O>[F:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][C:34]=1[OH:35])[C:9]([NH:11][NH:12][C:13]([C:15]1[O:16][CH:17]=[C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:14])=[O:10]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Boron tribromide (1 M dichloromethane solution: 6.00 ml) was added dropwise to a mixture of the compound of Example 31 (0.86 g) and dichloromethane (20 ml) at 0° C., and the mixture was stirred at 25° C. overnight. Water was added to the reaction solution. The thus-precipitated crystals were collected by filtration, purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), and recrystallized from ethanol, thereby giving 0.64 g of the desired compound. Melting point: 243-245° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C:33]1[CH2:34][C@@H:35]2[C@H:38]([CH:39]=1)[C:37](=[CH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)(C(C)(C)C)(C)C>O>[OH:31][CH2:32][C:33]1[CH2:34][C@@H:35]2[C@H:38]([CH:39]=1)[C:37](=[CH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(CO[Si](C)(C)C(C)(C)C)=C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(CO)=C[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutyl ammonium fluoride (1.0 M tetrahydrofuran solution, 8.69 mL, 8.69 mmol) was added to a tetrahydrofuran solution (15 mL) of tert-butyl(±)-[(1R,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)bicyclo[3.2.0]hept-3-en-6-ylidene]acetate (2.03 g, 5.79 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (1.29 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.[N:32]1([CH2:38][C:39]([NH2:41])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:35]3[CH2:36][CH2:37][N:32]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:33][CH2:34]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with 2-piperazin-1-yl-acetamide hydrochloride (Matrix) to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide in an analogous manner as described in example 1. LR-MS: 586.2 [(M+H)+]
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][N:11]3[CH2:10]2)=[CH:5][C:4]=1[O:26][CH3:27])#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH3:27][O:26][C:4]1[CH:5]=[C:6]([C@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][NH:16][CH2:17][CH2:18][N:11]3[CH2:10]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@@H]2CN3CCNC[C@@H]3CO2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3R,9aR)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (120 mg, 0.321 mmol) was dissolved in 10 mL of 4 M HCl in dioxane and stirred at room temperature for 8 h. The mixture was concentrated to ¼ the original volume and diluted with 10 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to afford the title compound: NMR (DMSO-d6, Z (cis) isomer, 500 MHz) δ 7.77 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 4.95 (bs, 1H), 4.08 (bs, 2H), 3.96 (s, 3H), 3.85-3.60 (bs, 3H), 3.58-3.34 (m, 6H); LC/MS: (IE, m/z) [M+1]+=274.