Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][C:10]2[CH:15]=[C:14](Br)[CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Li][CH2:21]CCC.C[Si](C)(C)[O:27][C@@H:28]1[C@@H:33]([O:34][Si](C)(C)C)[C@H:32]([O:39][Si](C)(C)C)[C@@H:31]([CH2:44][O:45][Si](C)(C)C)[O:30][C:29]1=[O:50].CS(O)(=O)=O>C1COCC1.CO.C(OC(=O)C)C>[CH2:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][C:10]2[CH:15]=[C:14]([C@@:29]3([O:50][CH3:21])[C@H:28]([OH:27])[C@@H:33]([OH:34])[C@H:32]([OH:39])[C@@H:31]([CH2:44][OH:45])[O:30]3)[CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: C=CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]CCCC
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 2-(4-(allyloxy)benzyl)-4-bromo-1-chlorobenzene (2.0 g, 5.92 mmol, prepared as described in Intermediate 1) in dry THF (50 mL), under nitrogen atmosphere, was added nBuLi (4.8 mL, 7.7 mmol, 1.6 M solution in hexanes) at −78° C. The reaction mixture was stirred at the same temperature for 30 min. A solution of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (3.6 g, 7.7 mol, prepared following the procedure given in US20070049537) in dry THF (40 mL) was added dropwise at the same temperature and stirred for another 3 h. After the completion of the reaction as confirmed by TLC, a solution of methanesulfonic acid (0.76 mL, 11.8 mmol) in methanol (30 mL) was added and the temperature was gradually raised to r.t. and stirred for 16 h. The reaction was quenched by the addition of triethylamine (3.3 mL) and volatiles were evaporated in vacuo. The residue obtained was dissolved in ethylacetate (300 mL) and washed with water (3×20 mL). The organic layers were dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.4:9.6 MeOH:DCM) to provide title compound (1.2 g, 45%).
Reaction SMILES: S(O)(=O)(=O)C.O[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH2:29][CH2:28]1
Reactant: Fc1ccc(C(F)(F)F)cc1N1CCNCC1
Reactant: O=C1CCC(CCO)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(CCN2CCN(c3cc(C(F)(F)F)ccc3F)CC2)CC1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 11.6 g (52.66 mmol) of 4-(2-hydroxyethyl)cyclohexanone mesylate, of 13.72 g (55.27 mmol) of 1-(2-fluoro-5-trifluoromethylphenyl)piperazine and 8.37 g (60.65 mmol) of potassium carbonate in 220 mL of acetonitrile is refluxed overnight, then cooled back to room temperature. Water (80 mL) is added. Organics are extracted with ethyl acetate (100 mL). The organic phase is washed with water (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a crude product. Purification by column chromatography over 320 g of silica gel (eluant dichloromethane/methanol 98/2 to 96/4) yields 15.86 g of 4-(2-fluoro-5-trifluoromethylphenyl)-1-[2-(4-oxocyclohexyl)ethyl]piperazine melting at 75-76° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1O)[C:11]([O:13][CH3:14])=[O:12]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[Cl:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
(I4B): Anhydrous DMF (242 ml) was cooled to −20° C. in a dry ice/acetone bath and the internal temperature was monitored carefully and maintained at or below this temperature. Neat oxalyl chloride (9.51 ml, 109 mmol) was then slowly added dropwise via addition funnel and the vessel was properly vented to allow the escape of gases generated. Following the addition, the cloudy-white suspension was stirred at −20° C. for 30 min. A solution containing methyl 3-bromo-4-hydroxy-5-nitrobenzoate (10 g, 36.2 mmol) in DMF (121 ml) was then added slowly, not allowing the internal temp to exceed −10° C. Following the addition, the suspension was warmed to room temperature and then heated to 100° C. for 2 h. The reaction was cooled to room temperature and stirred over weekend. The dark brown solution was poured into ice water and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with water and brine, and then dried over anhydrous sodium sulfate. Filtration and concentration afforded methyl 3-bromo-4-chloro-5-nitrobenzoate (10 g) as a yellow solid that was dried in vacuo overnight.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:18][C:17]1[C:2]2=[CH:3][C:4]3[CH2:5][CH2:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[N:1]2[CH2:14][CH2:15][N:16]=1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1c2-c2ccccc2CC1
Yield: 67 %

Procedure:
N-[2-(4,5-Dihydro-1H-benzo[g]indol-1-yl]ethyl]-acetamide (5.3 g) was stirred with 60 ml of phosphorus oxychloride at room temperature for 1 hour. The reaction mixture was hydrolyzed at 0° C. with 500 ml of 28% sodium hydroxide solution, diluted with 4000 ml of water and extracted three times with 300 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. 2.0 g of a total of 5.0 g of crude product were dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.3 g (67%) of 5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:3); m.pt.: 181° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH:12]=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:20]#[N:21].[K+]>O.O1CCCC1>[OH:13][CH:12]([CH:10]1[CH2:11][N:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)[C:20]#[N:21]
Reactant: [C-]#N
Reactant: O=CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1.13 g (4.49 mmoles) of crude 1-diphenylmethyl-3-formylazetidine in a mixture of 2 ml of water and 2 ml of tetrahydrofuran is added 878 mg (3 equivalents) of potassium cyanide, and the mixture is stirred at room temperature for 2 hours, mixed with water and extracted with methylene chloride. The extract is washed with water, dried, and evaporated to yield 1.046 g of crude 2-hydroxy-2-(1-diphenylmethylazetidin-3-yl)acetonitrile as hemi-solid product in 83% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)(=O)=O)=CC=1>[I-].C([N+](CC)(CC)CC)C.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](=[NH:11])[N:9]([CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: CC(C)(C)c1ccc(N)nc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(=N)n(C[C@H]2CCCO2)c1
Temperature: 25 °C

Procedure:
A mixture of Example 59B (0.5 g, 3.3 mmol), (R)-(tetrahydrofuran-2-yl)methyl 4-methyl-benzenesulfonate (0.9 g, 3.6 mmol), and tetraethylammonium iodide (0.4 g, 1.6 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 95° C. for 16 hours. After cooling to ambient temperature, the mixture was quenched with saturated NaHCO3 (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. LCMS (APCI+) m/z 235 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].[CH:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]=[C:18](Cl)[CH:17]=1.O>CC(N(C)C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:18]1[CH:17]=[CH:16][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: OCc1cccc(O)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(Oc2cccc(CO)c2)nc1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
Add 3-hydroxybenzyl alcohol (0.99 g, 7.94 mmol) and potassium carbonate (1.50 g, 10.83 mmol) to 6-chloronicotinitrile (1.00 g, 7.22 mmol) in dimethylacetamide (25 mL) and stir. Heat to 100° C. for 4 hrs. Let cool to ambient temperature and pour into water (100 mL). Extract with diethyl ether (3×100 mL). Combine the organic layers and wash with 1N NaOH (2×50 mL) and dry over magnesium sulfate. Filter and concentrate under reduced pressure to give the product (1.63 g, 99%): 1H NMR (CDCl3) 8.49 (d, J=2.2 Hz, 1H), 7.95 (dd, J=2.2 Hz, 8.7 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.77 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCCCC1CCOc1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a solution of 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (75 mg, 0.21 mmol) and 4-(dimethylamino)pyridine (13 mg, 0.10 mmol) in DMF (0.5 mL) was added acetic anhydride (20 μL, 0.23 mmol). The reaction mixture was stirred for 18 h before additional acetic anhydride (1 equiv.) and DMAP (3 equiv.) were added. After an additional 24 h, HPLC monitoring indicated reaction completion. The crude material was purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 39 mg (47%) of product. HPLC (Method C): Rt=4.70. MS (ESI+): mass calcd. for C23H26N4O3, 406.20; m/z found, 407.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.18 (s, 1H), 8.03-7.96 (m, 3H), 7.71 (d, J=8.6 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.41-4.26 (m, 1H), 4.15-3.94 (m, 1H), 4.04-3.98 (m, 1H), 3.69-3.64 (m, 1H), 2.67-2.60 (m, 1H), 2.41-2.21 (m, 1H), 1.97 (s, 3H), 1.98-1.85 (m, 1H), 1.72-1.52 (m, 5H), 1.48-1.23 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][N:25]([CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CN1CCC(O)CC1
Product: Cc1ccc(-c2nn(C3CCN(C)CC3)cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 55 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 1-methyl-piperidin-4-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH2:13][CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K2CO3 as base. MS (ISP): 209.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH:6]([CH2:8][C:9]([OH:11])=[O:10])[CH3:7].C(N(CC)CC)C>C1COCC1>[CH3:7][N:6]1[C:3](=[O:4])[CH2:2][O:10][C:9](=[O:11])[CH2:8]1
Reactant: CNCC(=O)O
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CC(=O)OCC1=O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Bromacetyl bromide (202 g, 1.0 moles) is dissolved in THF (400 ml) and rapidly added to a cooled (15° C.), vigorously stirred sarcosine (178.2, 2.0 moles)-THF (900 ml) mixture. After two hours of thorough mixing at room temperature the reaction mixture is filtered. Triethylamine (101 g, 1.0 moles) is added to the filtrate. This reaction mixture is stirred at 50° C. for 0.25 hours and then filtered. Evaporation of this filtrate's solvent produces roughly 80 g of crude, liquid N-methyl-2,5-morpholinedione. Vacuum distillation of this oil yields 60 g of N-methyl-2,5-morpholinedione (B.P. 114°-116° C. at 0.1 mm, ND23 =1.4967). Proton NMR analysis of the distillate shows chemical shifts at 2.952, 2.985, 3.94, 4.16, and 4.74 PPM. Elemental analysis of the compound is as follows--calculated for C5H7NO3 : C, 46.50; H, 5.48; N, 10.84; O, 37.17%. Found: C, 46.78; H, 5.80; N, 11.16; O, 36.47%.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:19](O)(=O)[CH3:20].[CH2:23](O)[CH3:24]>>[CH:2]1([N:7]2[C:11]3=[N:12][C:3]([CH2:2][N:7]4[CH2:20][CH2:19][C:23]5[C:24](=[CH:16][CH:9]=[CH:10][CH:13]=5)[CH2:11]4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCO
Reactant: CC(=O)O
Agent: [Na]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(CN3CCc4ccccc4C3)nc(=O)c1-2

Procedure:
Sodium (0.24 g) was dissolved in ethanol (25 mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.09 g, 4.91 mmol) followed by ethyl 1,2,3,4-tetrahydro-2-isoquinolinyl acetate (2.15 g) were added. The reaction mixture was refluxed for about 2 days, the solvent was stripped and the residue was treated with water and acetic acid. A gum formed which was extracted with CHCl3 (3×100 mL) and the organic layers were combined, dried over MgSO4, filtered and stripped to afford a yellow solid which was washed with ether to afford (0.6 g) of crude product. The crude product was combined with the crude product from a similar experimental run and the mixture was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (1/1). Additional product was also obtained from concentration of the above ether filtrate and purification by column chromatography as described above. The product fractions were pooled and recrystallized from ether to afford 1-cyclopentyl-3-ethyl-6-(1,2,3,4-tetrahydro-2-isoquinolinylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 149-151° C.
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][F:13].[NH2:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[F:13][CH2:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=1[O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1
Reactant: CS(=O)(=O)c1cccc(CF)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(CF)cccc4S(C)(=O)=O)cc23)n1

Procedure:
The compound of Example 150 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-fluoro-1-(fluoromethyl)-3-(methylsulfonyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:14]1([C@H:10]2[C@H:11]([OH:13])[CH2:12][NH:8][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CNC[C@H]1N1CCCC1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
Dissolve 4′-hydroxy-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (751 mg, 2.93 mmol) in dichloromethane (13 mL) and cool the mixture to 0° C. Add trifluoroacetic acid (2.5 mL, 33.1 mmol) and warm the mixture to room temperature for one hour. Remove the volatiles via reduced pressure and then purify by applying to two 10 g SCX cartridges. Wash the material with methanol then elute the material with 2N ammonia in methanol to give 460 mg (99%) of the title compound as a clear oil. 1H NMR(DMSO-d6) δ 1.60 (m, 4H), 2.31 (s, 1H), 2.41 (m, 5H), 2.53 (m, 1H), 2.81 (m, 1H), 2.93 (m, 1H), 3.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: NCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Br)ccc1NCCN1CCOCC1
Yield: 49.7 %

Procedure:
5-Bromo-2-fluorobenzonitrile (1.0 g) and 4-(2-aminoethyl)morpholine (0.65 g) were mixed together in acetonitrile (5 ml) at 70° C. for 4 hours, cooled and poured into a solution of aqueous sodium hydrogen carbonate and was extracted into ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with 2.5% methanol in dichloromethane containing 1% triethylamine to afford the sub-titled compound as an oil (0.77 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[NH:7][CH2:6][C@H:5]1[CH3:11])[CH:2]=[CH2:3].N1C2C=CC=CC=2N=N1.[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O.[Si:33]([O:40][C:41]1[CH:42]=[C:43]([Mg]Br)[CH:44]=[CH:45][CH:46]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1(C)C=CC=CC=1.O1CCCC1.O>[CH2:1]([N:4]1[C@H:5]([CH3:11])[CH2:6][N:7]([C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([O:40][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH:42]=2)[C@@H:8]([CH3:10])[CH2:9]1)[CH:2]=[CH2:3]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc([Mg]Br)c1
Reactant: C=CCN1C[C@H](C)NC[C@H]1C
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)OC)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@H]1C
Temperature: -17.5 °C
Reaction time: 1.5 h

Procedure:
A solution of (−)-(2R,5S)-1-allyl-2,5-dimethylpiperazine (22.26 g), benzotriazole (17.18 g) and methyl 4-formylbenzoate (23.7 g) in toluene (400 ml) was heated under reflux with azeotropic removal of water for 3 hours. The solution was cooled and added to a cold solution (−20° C.) of 3-tert-butyldimethylsilyloxyphenylmagnesium bromide (prepared from 82.9 g of corresponding bromide and 7.29 g of magnesium turnings) in tetrahydrofuran (300 ml) at such a rate as to maintain the internal temperature in the range −20 to −15° C. The resulting solution was stirred at −20° C. for 1.5 hours and then warmed to room temperature, quenched with saturated aqueous ammonium chloride solution (200 ml). The layers were separated and the aqueous solution extracted with ethyl acetate (2×200 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel (85/15/2 hexane/ethyl acetate/diethyl amine) to afford the title compound, 54.45 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:24]([C:25]([CH3:28])([CH3:27])[CH:26]=1)=[C:7]1[CH:8]=[C:9]3[C:22](=[CH:23][C:6]1=[CH:5]2)[C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]1[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:29][C:30]1([CH3:64])[C:54]2[C:34]([CH:35]=[C:36]3[CH:53]=[C:52]4[C:39]([C:40]5[C:45]([C:46]6[C:51]4=[CH:50][CH:49]=[CH:48][CH:47]=6)=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:38][C:37]3=2)=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[CH3:27][C:25]1([CH3:28])[C:24]2[C:4]([CH:5]=[C:6]3[CH:23]=[C:22]4[C:9]([C:10]5[C:15]([C:16]6[C:21]4=[CH:20][CH:19]=[CH:18][CH:17]=6)=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:8][C:7]3=2)=[CH:3][C:2]([C:32]2[CH:33]=[C:34]3[C:54]([C:30]([CH3:64])([CH3:29])[CH:31]=2)=[C:37]2[CH:38]=[C:39]4[C:52](=[CH:53][C:36]2=[CH:35]3)[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]4=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:26]1
Reactant: CC1(C)C=C(Br)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
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: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(C2=CC(C)(C)C3=c4cc5c6ccccc6c6ccccc6c5cc4=CC3=C2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 48 %

Procedure:
A mixture of 4.2 g (10 mmol) of 12-bromo-10,10-dimethyl-10H-indeno[1,2-b]triphenylene, 5.2 g (11 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.12 g (0.1 mmol) of Tetrakis(triphenylphosphine)Palladium, 15 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After finishing the reaction, The mixture was allowed to cool to room temperature. Than 100 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 3.3 g (yield 49%) of yellow product which was recrystallized from chloroform. MS (m/z, EI): 686.7. 1H NMR (CDCl3, 400 MHz): δ 9.05 (s, 2H), 8.86 (d, J=7.88 Hz, 2H), 8.79 (d, J=7.76 Hz, 2H), 8.74 (s, 2H), 8.71 (d, J=7.84 Hz, 4H), 8.10 (d, J=7.64 Hz, 2H), 7.84 (s, 2H), 7.81 (d, J=7.80 Hz, 2H), 7.76˜7.67 (m, 8H), 1.77 (s, 12H).