Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[CH:7]2.[H-].[Na+].[CH3:19]I>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:19])[N:8]=[CH:7]2
Reactant: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ncc2cccc(Br)c2n1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
8-Bromo-N-(tert-butyl)quinazolin-2-amine (374a) (40 mg, 0.14 mmol) in THF (4 mL) at 0° C. was treated with NaH (60% dispersion in mineral oil, 8.6 mg, 0.21 mmol) and stirred at 0° C. for 30 min. MeI (10.71 μl, 0.17 mmol) was added and the solution was warmed to RT overnight (16 h). The reaction mixture was treated with brine and extracted with EtOAc (50 mL), dried over MgSO4, filtered and concentrated. Purification on a silica gel column (0-50% EtOAc in hexanes) afforded the title compound (34 mg, 0.12 mmol, 82% yield) as yellow viscous oil. m/z (ESI, +ve ion) 294.0/296.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-formylphenol (5.73 g., 0.03 mole), ethyl 4-bromobutyrate (11.7 g., 0.06 mole) and potassium carbonate (8.28 g., 0.06 mole) in dimethylformamide (25 ml.) is heated at 50°-60° C. for 11/2 hours. Water (50 ml.) is added and the mixture is extracted with ether. The ether extract is dried and evaporated. To the residue is added a solution composed of 48 ml. of 40% sodium bisulfite and 12 ml. of alcohol. The precipitated 4isulfite addition compound then is washed with alcohol and ether. The solid is suspended in water heated in a steam bath. An oily layer of the free aldehyde is formed. The hot water then is decanted and the oily layer is extracted with ether and the ether evaporated. The residue is heated to 80° C. in a mixture of potassium hydroxide (2.8 g.), methanol (30 ml.) and water (5 ml.), the resulting solution is evaporated to dryness and the residue dissolved in water. Upon acidification a solid separates. The solid is crystallized from benzene to obtain 2.9 g. of 4-(2,3-dichloro-4-formylphenoxy)butyric acid, M.P. 147°-148° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5]C[CH:3]=[CH:2]1.[C:8]([O:14]C)(=O)[CH2:9][C:10]([CH3:12])=[O:11].C[O-].[Na+].[OH-].[K+]>CO>[OH:11][C:10]12[CH2:12][CH:2]([CH2:1][CH2:6][CH2:5]1)[CH2:3][C:8](=[O:14])[CH2:9]2
Reactant: O=C1C=CCCC1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2CCCC(O)(C1)C2
Yield: 50.8 %

Procedure:
50.58 g of cyclohexenone and 72.95 g of methyl acetoacetate were measured and placed in a 1,000 ml flask. 300 ml of methanol was added to prepare the homogeneous solution. The solution was gradually mixed with 101.53 g of 28% sodium methoxide, and the mixture was refluxed in the flask equipped with a Dimroth condenser for 72 hours. The reaction solution was cooled, mixed with 100 ml of an aqueous solution containing 72.12 g of potassium hydroxide, and further refluxed for 13 hours. After the reaction was finished, the solvent was distilled away from the reaction solution under reduced pressure, and the residue was extracted with dichloromethane. The obtained organic layers were integrated, washed with a saturated aqueous solution of sodium chloride, and then dried over MgSO4. The solvent was distilled away under reduced pressure, and the residue was again dissolved in diethyl ether. The solution was reversibly extracted with water, and the obtained water layers were integrated and concentrated. The residue was recrystallized from diethyl ether to obtain the title compound as white crystals (41.19g, 50%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[N:6]1>CO.[Pd]>[NH2:10][C:8]1[CH:7]=[N:6][N:5]([CH2:4][C:3]([N:2]([CH3:14])[CH3:1])=[O:13])[CH:9]=1
Reactant: CN(C)C(=O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Cn1cc(N)cn1
Reaction time: 8 h

Procedure:
A solution of N,N-dimethyl-2-(4-nitro-1H-pyrazol-1-yl)acetamide (870 mg, 4.39 mmol) in methanol (22 ml) was evacuated/purged with nitrogen and treated with Pd on carbon (87 mg, 0.082 mmol). The resulting black suspension was evacuated/purged with a hydrogen balloon and stirred under the hydrogen overnight when the mixture was filtered through celite with methanol washes. The filtrate was concentrated to give the product.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])[CH:14]=[CH:15][CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](I)[CH:27]=[C:28]([CH3:30])[CH:29]=1.CNCCNC>[Cu]I.CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:17]2[CH2:21][CH2:20][N:19]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[C:18]2=[O:22])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: COc1cccc(N2CCNC2=O)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cccc(N2CCN(c3cc(C)cc(C)c3)C2=O)c1
Temperature: 160 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
A microwave test tube was charged with CuI (20 mg, 0.10 mmol, 0.20 equiv), K3PO4 (212 mg, 1.0 mmol, 2.0 equiv), N-(3-methoxyphenyl)-2-imidazolidone (96 mg, 0.5 mmol, 1.0 equiv), 3,5-dimethyliodobenzene (144 μL, 1.0 mmol, 2.0 equiv), N,N′-dimethylethylendiamine (22 μL, 0.20 mmol, 0.40 equiv) and dry DMF (2.0 mL), filled with argon. The test tube was sealed and the reaction mixture was stirred at 130° C. for 15 h and at 160° C. for further 15 h in the microwave. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with ethyl acetate. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane:ethyl acetate 4:1) provided 134 mg (91% yield) of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1>C(=S)=S>[ClH:31].[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:10]=[CH:9][C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:3]4[CH3:2])=[CH:13][CH:12]=3)=[CH:10][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCCC1c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CN1CCCC1c1ccc(-c2ccc(C(=O)c3ccc(Br)cc3)cc2)cc1
Yield: 30.8 %

Procedure:
350 mg of N-methyl-2-biphenylyl-pyrrolidine hydrochloride are suspended in 10 ml of carbon disulphide and treated with 341 mg of aluminium chloride. A solution of 842 mg of 4-bromo-benzoyl chloride in 3 ml of carbon disulphide is added dropwise to this viscous mass. The mixture is held at reflux for 2 hours and evaporated. The residue is triturated in toluene and then in ethyl acetate, with 90 mg of (±)(4-bromophenyl)-[4'-(1-methylpyrrolidin-2-yl)-biphenyl-4-yl]-methanone.hydrochloride, m.p. 225° C., being obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10](=[O:15])[NH:9][CH2:8][CH2:7]3)[CH2:3][CH2:2]1>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:11](=[C:12]([F:14])[CH:13]=2)[C:10](=[O:15])[NH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: O=C1NCCc2cc(C3CC3)cc(F)c21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]ccc2cc(C3CC3)cc(F)c12
Temperature: 100 °C
Yield: 33.6 %

Procedure:
To a solution of compound I (0.272 g, 1.32 mmol) in 8 ml dioxane placed in a pressure tube was added under argon DDQ (0.301 g, 1.32 mmol). The tube was sealed and the mixture heated at 100° C. for 18 hours with stirring. After cooling the reaction was diluted with ethyl acetate and the organic phase washed with 1N NaOH and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (75% ethyl actate/hexane to 100% ethyl acetate) to afford 90 mg (33% yield) of II.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:37])[F:38])[CH:29]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as off-white solid. MS: 477.2 (MH+).
Reaction SMILES: CN(OC)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:12][O:13][CH3:14].[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:14][O:13][CH2:12][C:11]#[C:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:15])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COCC#Cc1ccccc1C(=O)N(C)OC
Solvent: C1CCOC1
Product: COCC#Cc1ccccc1C(=O)Cc1ccccc1
Yield: 53 %

Procedure:
N-Methyl-N-(methyloxy)-2-[3-(methyloxy)-1-propyn-1-yl]benzamide (143) (0.35 g, 1.50 mmol) was treated with benzylmagnesium chloride in THF to give 0.21 g (53%) of the title compound (144) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.44 (s, 3H), 4.34 (s, 2H), 4.38 (s, 2H), 7.20-7.26 (m, 3H), 7.27-7.38 (m, 3H), 7.38-7.44 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H). LCMS (ESI): m/z 265 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]=[O:16])[CH3:5])[O:2]1.[I-].[CH3:32][S+](C)C.CC([O-])(C)C.[K+]>CN(C)C=O.ClCCl>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:29][CH2:28][C@H:27]4[C@@H:17]([CH2:18][CH2:19][C@@H:20]5[C@:25]4([CH3:26])[C:24](=[CH2:30])[CH2:23][CH2:22][CH2:21]5)[C@@H:6]2[C@H:7]3[CH:15]2[CH2:32][O:16]2)[CH3:5])[O:12]1
Reactant: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C=O)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C1CCC[C@@H]2CC[C@H]3[C@@H]4[C@@H](C5CO5)C56OCCOC5(OCCO6)[C@@]4(C)CC[C@@H]3[C@@]12C
Temperature: 0 °C

Procedure:
3.8 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-5α-androstane-15α-carbaldehyde in 46 ml of dimethylformamide is stirred under argon with 3.0 g of trimethylsulfonium iodide and 2.3 g of potassium tert-butylate at room temperature. After 30 minutes the reaction mixture is added to ice/water. The precipitated product is suctioned off, dissolved in dichloromethane, washed neutral with water. 3.5 g of 3,3;17,17-bis(ethylenedioxy)-1-methylene-15α-(2-oxiranyl)5α-androstane is obtained as foam.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.O>C1(C)C=CC=CC=1>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c(Cl)ncnc2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7-methyl-3H-quinazolin-4-one (10.6 g, 69 mmol) in toluene (350 mL) is added triethylamine (17.5 g, 173 mmol) followed by phosphorous oxychloride (12.3 g, 80 mmol). The resulting solution is heated to 80° C. After 4 hours, the solution is cooled to ambient temperature. The reaction mixture is poured into 500 mL of water. The layers are separated and the organic layer is washed with H2O, saturated NaHCO3, and saturated NaCl, dried over MgSO4, filtered and concentrated. The resulting crude product is purified by recrystallization from EtOAc. The title compound is obtained as a white solid (10 g, 56 mmol). 1H NMR (CDCl3, 300 MHz) δ9.02 (s, 1H), 8.16 (d, 1H), 7.87 (s, 1H), 7.55 (d, 1H), 2.62 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:13][N:12]([CH3:19])[C:11](=[O:20])[C:10]=12.ClC1C=C(C=CC=1)C(OO)=[O:37].C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[N:7]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:13][N:12]([CH3:19])[C:11](=[O:20])[C:10]=12)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)cc12
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn(C)c(=O)c2c(S(=O)CCCO)n(Cc3cccc4ccccc34)cc12
Yield: 13.6 %

Procedure:
2,6-Dihydro-7-[(3-hydroxypropyl)thio]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (0.34 g) prepared as described in Example 3 above was dissolved in dichloromethane (7 ml) and 3-chloroperoxybenzoic acid (229 mg) was added. After 4 hours sodium bicarbonate (aqueous) and sodium metabisulfite (aqueous) were added and the mixture was extracted thrice with dichloromethane. The combined organic extracts were washed with brine, dried, filtered and evaporated. The residue was chromatographed eluting with ethyl acetate and then ethyl acetate:ethanol (19:1-9:1) to give 2 products. The more polar product was triturated with ether to give 2,6-Dihydro-7-[(3-hydroxypropyl)sulfinyl]-2-methyl-4(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (A) (48 mg) whilst the less polar product was recrystallised from isohexane-ethyl acetate to give 2,6-dihydro-7-[(3-hydroxypropyl)sulfonyl]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (B) (94 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: Brc1ccc(Br)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(Br)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 55.4 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (2.60 g, 10.0 mmol) synthesized in Reference example 56 and 1,4-dibromobenzene (7.08 g, 30 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 2.3 g (yield 55%). Melting point was 202 to 204° C. (hexane-ethyl acetate).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CCCCCC.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:28]=[CH:29][C:30]2[S:34][CH:33]=[CH:32][C:31]=2[CH:35]=1.[C:36]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.COCCOC>[S:34]1[C:30]2[CH:29]=[CH:28][C:27]([CH:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:36]([O:44][CH2:45][CH3:46])=[O:43])=[CH:35][C:31]=2[CH:32]=[CH:33]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccc2sccc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2sccc2c1
Yield: 100.6 %

Procedure:
To 1,2-dimethoxyethane (10 mL) suspension of 0.02 g of tris(dibenzylideneacetone)dipalladium(0) were added 0.11 g of 10% (w/w) tri(tert-butyl)phosphine/hexane, 1.76 g of cesium carbonate, 0.50 g of 5-bromobenzothiophene and 0.45 g of diethyl malonate, which was then refluxed for 2 hours. To the reaction mixture were added water and ethyl acetate, followed by adjustment to pH2 using 2 mol/L hydrochloric acid. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to provide 0.69 g of diethyl 2-(1-benzothiophen-5-yl)malonate as white solid form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[O:23]=[C:22]1[N:8]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccncc2n1C1CCNCC1
Yield: 129.6 %

Procedure:
A solution of 4-amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g, 9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran (100 mL) was refluxed overnight. The reaction was cooled, concentrated and partitioned between chloroform (500 mL) and saturated sodium carbonate (100 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 209 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:8]=1[CH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16](O)[CH3:17])[C:11]=12.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([CH:16]([CH3:17])[CH2:15][N:12]1[CH:13]=[CH:14][C:10]2[CH2:9][C:8]3[C:19]([C:11]1=2)=[CH:20][CH:21]=[CH:22][C:7]=3[Cl:6])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1cccc(Cl)c1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(Cn1ccc2c1-c1cccc(Cl)c1C2)N=[N+]=[N-]
Yield: 61.8 %

Procedure:
0.92 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.47 g of (RS)-1-(5-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.3 ml of triethyl-amine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 50 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.77 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 80 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). 1.0 g (62%) of (RS)-1-(2-azido-propyl)-5-chloro-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a light yellow oil.
Reaction SMILES: ClC1C=C(C=C(C(F)(F)F)C=1)C=O.Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([Cl:31])[CH:22]=2)=[CH:19][CH:20]=1.[CH:32]([NH:34][NH2:35])=O>C(O)CCC>[Cl:31][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:32]=[N:34][N:35]=3)[N:17]=2)[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(Cl)cc(-c2ccc(Cl)nn2)c1
Reactant: NNC=O
Agent: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Solvent: CCCCO
Product: FC(F)(F)c1cc(Cl)cc(-c2ccc3nncn3n2)c1

Procedure:
As described in Example 35, 3-chloro-5-(trifluoromethyl)benzaldehyde is converted to 3-chloro-6-[3-chloro-5-(trifluoromethyl)phenyl]pyridazine. This compound is reacted with formylhydrazine in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[F:5][C:6]([F:21])([F:20])[C:7]1[CH:19]=[C:10]2[C:11]([CH:17]=[O:18])=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[N:9]2[N:8]=1.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([C:6]([F:21])([F:5])[F:20])[CH:19]=[C:10]2[C:11]([C:17](=[O:18])[CH2:1][CH3:2])=[CH:12][CH:13]=1
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reactant: C=C[Mg]Cl
Agent: [Mn+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(OC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Vinyl magnesium chloride (1.32 mol/L tetrahydrofuran solution, 22.7 mL) was added dropwise to a solution of the compound of Example 115 (6.09 g) in tetrahydrofuran (250 mL) at −78° C. in a stream of argon gas. The mixture was allowed to gradually warm to room temperature. A saturated aqueous ammonium chloride solution was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale yellow oil. This product was dissolved in chloroform (500 mL). To the solution, activated manganese dioxide (75%, 100 g) was added and the mixture was stirred at room temperature for 8 hours. Subsequently, additional activated manganese dioxide (75%, 50 g) was added and the mixture was stirred at room temperature overnight. Manganese dioxide was removed by filtration through Celite (thoroughly washed with ethyl acetate) and the solvent was evaporated to afford the title compound as a yellow powder (5.39 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-4-trifluoromethyl-pyrimidine (0.1 g, 0.55 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 150° C. in a microwave for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate and hexane to provide (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 395 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.48(d, 1H), 7.37-7.32 (m, 5H), 6.72 (d, 1H), 5.08 (s, 2H), 4.67 (bs, 1H), 4.22 (m, 2H), 3.49 (m, 2H), 2.08 (m, 2H), 1.68-1.60 (m, 2H), 1.35 (s, 3H).