Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2([O:53]C(C)=O)CO[C@@H:10]2C[C@@H]1O)=O.C[OH:64]>>[CH3:10][C:11]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:19][C:2]([OH:64])=[CH:3][CH:15]=1)=[O:53]
Reactant: CO
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Product: CC(=O)CCc1ccc(O)cc1

Procedure:
Taxus wallichiana known as the Himalayan yew is available in India. The applicants have investigating the different parts of this plant from different Himalayan regions of India for isolation of naturally occurring analogues of taxol, its important precursors and other biologically active compounds. During the course of investigation the applicants have isolated 2 compounds of 4-aryl-2-butanol namely betuligenol having formula C10H14O2, mp 69-70° C., [α]n+20 (C1, MeOH) and betuliloside having formula C16H24O7 mp 187-188°, [α]n+22° (C1, MeOH) from the leaves of T. wallichiana.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:48])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:49][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:48])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2C)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2C)CCCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A mixture of 2-({2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (87 mg, 0.127 mmol) and a 1M aqueous KOH solution (1.270 mL, 1.270 mmol) in dioxane (50 mL) was heated at 80° C. for 10 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (100 mL) and a saturated NaHCO3 solution. The organic layer was washed with a saturated NaCl solution (100 mL), concentrated onto Celite and purified by silica gel chromatography (ISCO 12 g) using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2. The product was taken up into a mixture of CH2Cl2 and Et2O and concentrated again to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a pale yellow solid (41 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.96 (m, 2H), 2.12 (s, 6H), 2.16 (s, 3H), 2.69 (t, J=6.41 Hz, 2H), 2.81 (d, J=4.58 Hz, 3H), 3.18 (br s, 2H), 3.71 (t, J=5.86 Hz, 2H), 6.23 (d, J=1.47 Hz, 1H), 6.82-6.96 (m, 2H), 7.00 (s, 1H), 7.16-7.34 (m, 1H), 7.79 (br s, 1H), 8.04 (s, 1H), 8.34 (d, J=8.42 Hz, 1H), 8.44-8.61 Hz, 1H), 10.16 (s, 1H), 11.22 (br s, 1H); ESIMS (M+H)+=531.17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][N:3]=[C:2]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)C#Cc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CC(C)O
Product: C[Si](C)(C)C#Cc1cnc(N2CCCCC2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine (200 mg, 0.6 mmol, 1.0 eq), piperidine (102.7 mg, 1.2 mmol, 2.0 eq) in iPrOH (4 ml) was stirred at room temperature for 2 h. Then the mixture was washed with water, extracted with EtOAc, dried (Na2SO4). EtOAc was removed by evaporation and the residue was recrystalized by PE to give compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(piperidin-1-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (101 mg, 44.3%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[N:12]=[CH:11][N:10]2[N:13]=[CH:14][N:15]=[C:9]2[C:8]=1[CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3].[F:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:5]([CH2:6][C:7]1[N:12]=[CH:11][N:10]2[N:13]=[CH:14][N:15]=[C:9]2[C:8]=1[CH2:16][CH2:17][CH3:18])[C:26]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[N:25]=1)=[O:27])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CCCc1c(CNCC(C)C)ncn2ncnc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(CN(CC(C)C)C(=O)c2cccc(F)n2)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of isobutyl-(8-propyl-[1,2,4]triazolo[1,5-c]pyrimidin-7-ylmethyl)-amine (2.8 mmol) and 6-fluoro-pyridine-2-carboxylic acid (0.47g, 3.34 mmol) in DCM (10 ml) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (Na2SO4) and solvent evaporated. Preparative TLC purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. H1 NMR δ (CDCl3) (mixture of rotamers) 9.25 (s, 0.51), 9.18 (s, 0.5H), 8.39 (s, 0.5H), 8.36 (s, 0.5H), 7.78-7.93 (m, 1H), 7.68 (d, 0.5H), 7.57 (d, 0.5H), 6.99 (d, 0.5H), 6.92 (d, 0.5H), 5.03 (s, 1H), 4.89 (s, 1H), 3.52 (d, 1H), 3.35 (d, 1H), 3.12 (t, 1H), 2.83 (t, 1H), 1.95-2.20 (m, 1H), 1.59-1.85 (m, 2H), 0.88-1.10 (m, 6H), 0.82 (t, 3H).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([NH:39]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:40]=[CH:41][CH:42]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-tert.butoxycarbonylaminomethyl-aniline in triethylamine.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.O=[C:7]1[CH2:10][CH:9]([S:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])=[O:12])[CH2:8]1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].N1C=CC=CC=1>C1COCC1.CCCCCC.Cl[Ti](Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:15]([O:14][S:11]([CH:9]1[CH2:10][C:7](=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8]1)(=[O:13])=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOS(=O)(=O)C1CC(=O)C1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCOS(=O)(=O)C1CC(=C(C(=O)OCC)C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
TiCl4 (0.5 mL, 4.854 mmol) was added to a solution of THF (25 mL) and CCl4 (5 mL) at 0° C. This was followed by the addition of butyl 3-oxocyclobutane-1-sulfonate (0.5 g, 2.42 mmol) at 0° C. and diethyl malonate (0.38 mL, 2.42 mmol). The resulting mixture was stirred at 0° C. for 5 minutes. Then pyridine (0.78 mL, 9.68 mmol) in THF (10 mL) was added and stirred at room temperature for 96 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate solution, brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography on silica gel (13% ethyl acetate in hexane) afforded 200 mg of the product (25% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH2:29][CH2:30][CH3:31])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 10.96 g (50 mmole) of 5-oxo1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated invacuo to give 12.0 g of 5-oxo-1-(phenyl-methyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(N(CC)CC)C.Br.[Br:23][C:24]1[CH:25]=[C:26]([CH2:31]Br)[C:27]([NH2:30])=[N:28][CH:29]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][N:5]([CH2:31][C:26]1[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([Br:23])[CH:25]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COC(=O)CNCCN1CCOCC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN(CCN1CCOCC1)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.4 %

Procedure:
A solution of (2-Morpholin-4-yl-ethylamino)acetic acid methyl ester (0.40 g, 2.0 mmol) and triethylamine (1.0 mL, 7.11 mmol) in DMF (20 mL) was treated with 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (0.70 g, 2.0 mmol). After stirring at room temperature under for 7 h, the cloudy mixture was diluted with H2O (50 mL) and then extracted with EtOAc (4×50 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) gave the title compound (0.46 g, 60%) as a colorless oil: MS (ESI) m/e 387 (M+H)+.
Reaction SMILES: C([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([Cl:18])=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:18][C:13]1[N:14]=[C:15]([Cl:17])[C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Clc1nc(Cl)c2[nH]ccc2n1
Temperature: 160 °C

Procedure:
To a suspension of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (177 mg, 0.64 mmol) in 1,2-dichlorobenzene (20 mL) was added AlCl3 (852 mg, 6.4 mmol). The reaction mixture was heated at 160° C. for 1.5 h, during which the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, added CHCl3 and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Added Hexanes and filtered off the product as purple solids (100 mg, 80%) and used for the next step without further purification.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[CH:29]6)=[CH:34][CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, white solid (90 mg, 72%), MS (ISP) m/z=500.4 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COCC(=O)O
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)COC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 2 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1 mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved in absolute CH2Cl2 (20 ml) and methoxy acetic acid (6.1 mmol) was added dropwise whilst cooling with ice and the resulting mixture was stirred for 2 hours at this temperature. The reaction mixture was poured onto water (50 ml), the organic phase was washed twice more with 30 ml of water and dried over MgSO4. The solvent was evaporated off and the residue separated by flash chromatography (CH2Cl2 /MeOH 9/1).
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16]C)=[O:14])[C:5]([O:7][CH2:8]C)=[O:6].[C:19]1([N:25]2[C:37]3[CH:36]=[CH:35][C:34](=[C:38]4[CH:50]=[C:49]5[C:41](=[N:42][C:43]6[C:48]5=[CH:47][CH:46]=[CH:45][CH:44]=6)[CH:40]=[CH:39]4)[CH2:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:37]3[CH:36]=[CH:35][C:34]([C:38]4[CH:39]=[CH:40][C:41]5[N:42]([C:3]6[CH:2]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]([N:42]7[C:41]8[CH:40]=[CH:39][C:38]([C:34]9[CH:35]=[CH:36][C:37]%10[N:25]([C:19]%11[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=%11)[C:26]%11[C:31]([C:32]=%10[CH:33]=9)=[CH:30][CH:29]=[CH:28][CH:27]=%11)=[CH:50][C:49]=8[C:48]8[C:43]7=[CH:44][CH:45]=[CH:46][CH:47]=8)=[CH:10][C:4]=6[C:5]([O:7][CH3:8])=[O:6])[C:43]6[C:48]([C:49]=5[CH:50]=4)=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1=Cc2c(c3ccccc3n2-c2ccccc2)CC1=c1ccc2c(c1)-c1ccccc1N=2
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Product: COC(=O)c1cc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc32)c(C(=O)OC)cc1-n1c2ccccc2c2cc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)ccc21

Procedure:
The compound is synthesised by the same procedure as for the corresponding step of Example 5 by reaction of 13.6 g (43 mmol) of diethyl dibromoterephthalate and 39 g (95.9 mmol) of 9-phenyl-3,3′-bicarbazole. The pure product is obtained by recrystallisation. The yield is 31 g (31 mmol), corresponding to 80% of theory.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1>B(Br)(Br)Br.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
A solution of 3-chloro-6-(4-methoxy-phenyl)-pyridazine (Step 1, 2.5 g, 0.0113 mol) in 1 M BBr3/CH2Cl2 (34 mL) was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was re-dissolved in 100 mL of EtOAc. The organic phase was washed with 40 mL of water followed by 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid was washed with 50% EtOAc/hexane mixture to give the title compound as a yellow solid MS (ESI pos. ion) m/z: 207.2(M+H). Calc'd Exact Mass for C10H7ClN2O: 206.63.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[N:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1[CH3:7].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[CH3:16][C:4]1[N:5]([C:8]2[N:13]=[CH:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[N:3]=1
Reactant: Cc1nc(I)c(C)n1-c1cc(=O)n(C)cn1
Reactant: C#Cc1cccc(C)c1
Product: Cc1cccc(C#Cc2nc(C)n(-c3cc(=O)n(C)cn3)c2C)c1

Procedure:
The title compound, yellow solid, MS: m/e=319.2 (M+H+), was prepared in accordance with the general method of example 1c from 6-(4-iodo-2,5-dimethyl-imidazol-1-yl)-3-methyl-3H-pyrimidin-4-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[N:8][CH:9]=1.Br[CH2:14][CH2:15]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)[CH:7]=[N:8][CH:9]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2cncc(Br)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
A suspension of 7 mL NaOH (50/50 w/w in H2O) was charged with 2-(5-bromopyridin-3-yl)acetonitrile (from example 199: 0.36 g, 1.9 mmol). 1-Bromo-2-chloroethane (0.29 g, 2.01 mmol) was added followed by a catalytic amount of benzyl triethylammonium chloride (5 mg). The reaction mixture was stirred for 20 h at 60° C. and then poured into water. The resulting solution was extracted into ethyl acetate. The combined organic extracts were washed successively with water and brine, dried over Na2SO4 filtered and then concentrated to yield 1-(5-bromopyridin-3-yl)cyclopropanecarbonitrile (0.25 g, 41%), which was used without further purification. 1H NMR (400 MHz, CDCL3) δ (ppm): 8.49 (d, 1H, J=2 Hz); 7.78 (d, 1H, J=4 Hz); 3.94 (q, 2H, J=7.6 Hz); 1.69 (d, 3H, J=7.6 Hz). LCMS Method Y: retention time 1.54 min; [M+1]=212.6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc2ncc(C#N)c(O)c2n1
Product: CCOc1ccc2ncc(C#N)c(Cl)c2n1
Yield: 100 %

Procedure:
A solution of 6-ethoxy-4-hydroxyl-[1,5]naphthyridine-3-carbonitrile (500 mg, mmol) in POCl3 was heated at reflux for 2 hrs under nitrogen. The temperature was reduced to 45-50° C. (bath) and heated at this temperature for an additional 2 hrs. After cooling, the solvent was removed by rotary evaporation. The residue was treated with a mixture of ice and water, made basic by using NH4OH, and extracted with CH2Cl2. The combined extracts were washed (brine), dried (Na2SO4), and concentrated to give the title compound as a white solid (522 mg, 100%). H-NMR δ (DMSO-d6): 1.437 (3H, t, CH3), 4.572 (2H, q, CH2), 7.495 (1H, d, C8-H), 8.407 (1H, d, C7-H), 9.108 (1H, s, C2-H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].C(N(CC)CC)C>O1CCCC1>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 25 g of 4-trifluoromethylbenzoyl chloride in tetrahydrofuran was added to 14.5 g of 2,6-dimethylaniline and 16.7 ml of triethylamine in tetrahydrofuran. The reaction was stirred at ambient temperature overnight, chilled, and filtered. The filtrate was evaporated in vacuo and the residue therefrom was dissolved in chloroform, washed sequentially with 1M hydrochloric acid, 1M sodium hydroxide, water, and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. Crystallization from methanol provided the desired title product in 85% yield, m.p. 206°-207° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH2:32][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 420.2 [M+1]+. (0.035 μM)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:14]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:17]=1[CH:18]=O)[CH3:15].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([CH2:14][CH3:15])[C:17]=1[CH2:18][NH:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH3:25]
Reactant: Cc1cc(N)c2nc(C)c(C)n2c1
Reactant: CCc1cccc(CC)c1C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCc1cccc(CC)c1CNc1cc(C)cn2c(C)c(C)nc12
Yield: 46.7 %

Procedure:
A stirred mixture of 8-amino-2,3,6-trimethylimidazo[1,2-a]pyridine (0.5 g, 2.8 mmol), 2,6-diethylbenzaldehyde (0.7 g, 4.3 mmol) and zinc(II)chloride (0.44 g, 3 mmol) in 50 ml methanol was treated with sodium cyanoborohydride (0.19 g, 3 mmol) and then refluxed for 20 h. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethylene and water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel with dichloromethylene first and then dichloromethylene:ethylacetate (1:1) which yielded 0.42 g of the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH:28]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][OH:34])[C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: OCCNCCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(CCO)CCO)cn2)CC1
Yield: 77 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using diethanolamine. And then, the product was recrystallized with isopropanol and ether to give a desired compound.