Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18]([O:20]CC)=[O:19].[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1oc2ccc(F)cc2c1-c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1oc2ccc(F)cc2c1-c1ccccc1Cl
Temperature: 0 °C
Yield: 93.3 %

Procedure:
A mixture of 3.69 g of compound D and 1.95 g of powdered potassium hydroxide in 30 cc of ethanol and 4 cc of water was heated under reflux for 6 hours. After cooling, ice water was added and the resulting mixture was washed with hexane. The aqueous layer was acidified with 1N HCl, and extracted with chloroform, which was then dried over magnesium sulfate. The solvent was distilled off to obtain 3.14 g of 3-(2-chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid. Yield: 93.3%.
Reaction SMILES: [ClH:1].Cl.C([O:6][CH:7]([CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[C:29]4[O:28][CH:27]=[C:26]([Cl:30])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:31][CH3:32])(=O)C.N.Cl.C(OCC)C>C(Cl)Cl.C(O)(C)C>[ClH:30].[ClH:1].[Cl:30][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([O:9][CH2:8][CH:7]([OH:6])[CH2:33][N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)=[C:11]([O:31][CH3:32])[CH:12]=4)[N:17]=[CH:16][N:15]=3)[C:29]=2[O:28][CH:27]=1
Reactant: COc1cc2c(Nc3cccc4c(Cl)coc34)ncnc2cc1OCC(CN1CCOCC1)OC(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4c(Cl)coc34)ncnc2cc1OCC(O)CN1CCOCC1
Yield: 157.7 %

Procedure:
A mixture of 7-(2-acetoxy-3-morpholinopropoxy)-4-(3-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline dihydrochloride (0.15 g) and a saturated methanolic ammonia solution (3 ml) was stirred at ambient temperature overnight. The solvent was evaporated and the residue was dissolved in methylene chloride (3 ml) and adsorbed to the top of a pre-packed silica column (NH2-silica; Isolute sorbent from International Sorbent Technology Ltd, ref. no. 9470-0100) and eluted with a 19:1 mixture of methylene chloride and methanol. The material so obtained was dissolved in methylene chloride (3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml) was added. Diethyl ether (10 ml) was added and the resultant precipitate was collected by filtration, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.11 g); Mass Spectrum: M+H+ 486.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([O:9][CH:10]2[CH2:13][N:12]([CH:14](C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)=[O:30].O.[NH2:34][CH2:35][C@H:36]([OH:38])[CH3:37]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]2[CH2:11][N:12]([C:14]([NH:34][CH2:35][C@H:36]([OH:38])[CH3:37])=[O:30])[CH2:13]2)=[CH:27][CH:28]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: C[C@@H](O)CN
Reactant: CC(C)(C)c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O)CNC(=O)N1CC(Oc2ccc(C(C)(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of compound (1) (2.30 g, 6.19 mmol) in dichloromethane (25 mL) was treated with phosgene solution (ca. 20 wt. % in toluene; 3.28 mL, 6.2 mmol) with water cooling. The solution was stirred for 1 h, cooled to 0° C., and (R)-1-amino-2-propanol (1.08 mL, 1.03 g, 13.7 mmol) added dropwise. The solution was stirred for 18 h. Dichloromethane (25 mL) was added, and the solution was washed with 1-M HCl (25 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by chromatography [SiO2; MeOH-ethyl acetate-hexane (0:2:3→0:1:0→1:9:0)] and triturated with ether to give the title compound (1.15 g, 61%) as a white solid, m.p. 98-99° C. Found: C, 66.5; H, 8.8; N, 9.1. C17H26N2O3 requires C, 66.6; H, 8.55; N, 9.1%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]4[NH:30][N:29]=[N:28][N:18]=4)=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])=[C:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12
Yield: 75.9 %

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dimethyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.355 g, 1.007 mmol) was reacted with NaN3 (0.327 g, 5.036 mmol) and NH4Cl (0.269 g, 5.036 mmol) in DMF (5 ml) to give the desired product (0.302 g, 0.764 mmol, 76%) as a white solid, dec. 261-262° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.61 (s, 3H), 5.52 (s, 2H), 7.14 (d, J=8.6 Hz, 2H), 7.45-7.51 (m, 5H), 7.55 (t, J=7.6 Hz, 2H), 7.67 (d, J=8.6 Hz, 2H), 7.75 (s, 1H), 16.80 (broad s, 1H); IR (solid) 3040, 2860, 2620, 1580, 1520, 1480, and 1230 cm−1; [ESI(+)], m/z 396 (M+H)+; Anal. Calcd. for C24H21N5O: C, 72.89; H, 5.35; N, 17.71; Found: C, 72.84; H, 5.33; N, 17.80.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][C:20](C)([O-])[CH3:21].[K+].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1.C(Br)C=C>CCOCC.O>[CH2:21]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH:20]=[CH2:19]
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C=CCBr
Product: C=CCn1ccc2ccccc21
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 ml of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide. The mixture was stirred while 11.72 g (100 mmoles) indole was added. The stirring was continued for 3 hours. All of the solid did not dissolve. Then 14.1 g (116.5 mmoles) of allyl bromide in 100 ml of ether was added during 0.5 hour. The stirring was continued for 67.5 hours. Water (200 ml) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 ml). The combined ether phases were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 16.02 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 10% acetone-Skellysolve B and 2200 ml fractions were collected. The fractions were assayed by silica gel tlc (1×4") (10% acetone-Skellysolve B). Fractions 17-23 were combined giving 11.60 g (74%) of 1-allylindole as a yellow brown oil.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N:10]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: BrCc1ccc(I)cc1
Solvent: ClCCl
Solvent: CCO
Product: Ic1ccc(CN2CCC(N3CCCC3)CC2)cc1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-pyrrolidin-1-ylpiperidine. Yield: 0.57 g (51% of theory); C16H23IN2 (M=370.28); calc.: molecular ion peak (M+H)+: 371; found: molecular ion peak (M+H)+: 371; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](/[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)\[CH3:23])C.Cl>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24](/[C:22](/[CH3:23])=[CH:21]/[CH2:20][OH:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 1M solution of DIBAL-H in toluene (10 ml, 10 mmol) was added dropwise, at −70° C. over 10 min, to a stirred solution of (E)-ethyl-3-(4′-chloro-biphenyl-4-yl)-but-2-enoate (1.0 g, 3.32 mmol) in dry THF (25 ml), and the mixture warmed to room temperature over 4 h. Methanol (1 ml) was carefully added, followed by 1N HCl (50 ml) and the resulting mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the product, (E)-3-(4′-chloro-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid: 0.86 g (100%).
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[NH2:44][O:45][CH2:46][C:47]([OH:49])=[O:48].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:29][CH:30]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13](=[N:44][O:45][CH2:46][C:47]([OH:49])=[O:48])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: NOCC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=NOCC(=O)O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)acetic acid (0.045 g), pyridine (20 mL) was stirred at 80° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.05 g, 22%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH:14]=O)([CH3:13])[CH3:12].[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:16]1([CH:14]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]([CH3:12])([CH3:13])[CH3:10])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccccc1)n1nnc2ccccc21

Procedure:
A suspension of benzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10](=[O:17])[NH:11]3)=[CH:6][C:5]=2[O:4]1.I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10]([O:17][CH:25]([CH3:27])[CH3:26])=[N:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC(C)I
Reactant: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(-c2ccccc2)c2cc3c(cc2n1)OCCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion, 44 mg, 1.07 mmol) in 1 mL of DMF was added a suspension of 6,7-ethylenedioxy-4-phenylquinazolin-2(1H)-one (100 mg, 0.36 mmol) in 4 mL of DMF and stirred at rt for 15 min. 2-Iodopropane (150 μL, 1.45 mmol) was then added and the mixture was heated to 60-70° C. for 1.5 h. Excess sodium hydride Was quenched with water and the solution extracted with 25 mL of 9:1 EtOAc:hexane. The extract was washed with 2×25 mL water and brine, then dried with MgSO4 and concentrated in vacuo. The crude solid was subjected to flash column chromatography eluting with acetone:hexane to give the title compound 6,7-ethylenedioxy-2-isopropoxy-4-phenylquinazoline (95 mg, 83%). 1H NMR (CDCl3): 7.75 (d, 2H), 7.52 (m, 3H), 7.44 (s, 1H), 7.29 (s, 1H), 5.49 (m, 1H), 4.43-4.30 (m, 4H), 1.46 (d, 6H), followed by the title compound 6,7-ethylenedioxy-1-isopropyl-4-phenylquinazolin-2(1H)-one (9 mg, 8%). 1H NMR (CDCl3): 7.70 (d, 2H), 7.50 (m, 3H), 7.30 (s, 1H), 7.05 (s, 1H), 5.15 (m, 1H), 4.41-4.26 (m, 4H), 1.68 (d, 6H).
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][C:12](=[NH:16])OCC)=[N:3]1.[CH2:17](N)[CH2:18][NH2:19].Cl>C(O)C>[ClH:1].[NH:19]1[CH2:18][CH2:17][N:16]=[C:12]1[CH2:11][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:2][N:3]=1
Reactant: NCCN
Reactant: CCOC(=N)Cc1noc2ccccc12
Agent: Cl
Solvent: CCO
Product: c1ccc2c(CC3=NCCN3)noc2c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
In ethanol (10 ml) was dissolved ethyl 1,2-benzisoxazole-3-acetimidate hydrochloride (2.0 g) and thereto was added ethylenediamine (0.6 g) under ice-cooling and the mixture was allowed to stand at 5°C overnight. To the mixture was added ethanolic hydrochloric acid and the precipitated crystallines were separated by filtration and recrystallized from ethanol to give the desired compound (1.85 g). m.p. 223° to 228°C.
Reaction SMILES: [CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=32)[CH2:4][CH2:3]1.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CC(O)=O>[I-:15].[CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N+:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][C:13]=32)[CH2:4][CH2:3]1
Reactant: CN1CC[C@H]2CCc3ccncc3[C@H]21
Reactant: CCCCCCCCCI
Solvent: CC(=O)O
Product: CCCCCCCCC[n+]1ccc2c(c1)[C@@H]1[C@H](CC2)CCN1C
Product: [I-]
Yield: 78.4 %

Procedure:
To a stirred solution of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinoline (120 mg, 0.64 mmol) in AcOH (2 ml) was added 1-iodononane (488 mg, 1.92 mmol). The mixture was heated at reflux under nitrogen for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 222 mg (79%) of cis-1-methyl-8-nonyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACN) as a brown oil. 1H NMR (300 MHz, CDCl3) δ9.05 (1H, s, C9-H), 9.03 (1H, d, J6.0 Hz, C7-H), 7.81 (1H, d, J6.0 Hz, C6-H), 4.88 (2H, m. pyCH2), 3.47 (1H, d, J8.7 Hz, C9b-H), 2.36 (3H, s, NCH3), 1.60-3.10 (9H, m, CH2+CH), 2.00 (2H, m, pyCH2CH2), 1.10-1.50 (12H, m, 6×CH2), 0.83 (3H, t, J6.9 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ161.7, 143.4, 142.5, 139.2, 127.5, 63.5, 61.5, 55.9, 41.3, 35.9, 32.1, 32.0, 30.3, 29.5, 29.3, 29.2, 28.2, 27.6, 26.2, 22.8, 14.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:8][CH2:9][OH:10])[CH2:6][CH3:7])[CH3:4].Cl[C:12]1[C:25]2[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]3)[N:15]=[C:14]([CH3:26])[CH:13]=1>C1COCC1>[CH2:3]([N:5]([CH2:6][CH3:7])[CH2:8][CH2:9][O:10][C:12]1[C:25]2[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]3)[N:15]=[C:14]([CH3:26])[CH:13]=1)[CH3:4]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 5.25 g, 131.1 mmol) in anhydrous THF (90 mL) a solution of N,N-diethyl-2-hydroxyethylamine (15.30 g, 131.1 mmol) in anhydrous THF (60 mL) was slowly added. The mixture was stirred at room temperature for 20 minutes and a solution of 4-chloro-2-methyl-[1,10]phenanthroline(6.00 g, 26.2 mmol) in anhydrous THF (90 mL) was slowly added. The reaction mixture was refluxed for 18 hours and then allowed to cool down to room temperature, quenched with 1N HCl and evaporated. The residue was redissolved in 1N NaOH (150 mL) and extracted with methylene choride (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with hexane and purified by flash chromatography (SiO2, MeOH/DCM, 1:40) to yield the pure product as an orange oil (5.1 g, 63%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:52][CH3:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][O:52][CH3:53])[CH2:48][CH2:49]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: CO
Product: COCCN1CCN(c2cc(OC)c(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (200 mg, 0.43 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 241, step B) (108 mg, 0.39 mmol) and p-toluenesulfonicacid (197 mg, 0.95 mmol) were weighed into a 20 mL vial. 2 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 24 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (125 mg, 0.18 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.40 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=5.13 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=8.07 Hz, 1H), 7.73 (d, J=9.16 Hz, 1H), 7.60 (t, J=7.70 Hz, 1H), 7.45-7.50 (m, 2H), 7.40 (tt, J=8.43, 6.23 Hz, 1H), 7.14-7.24 (m, 2H), 6.98 (t, J=6.97 Hz, 1H), 6.78 (s, 1H), 6.49 (d, J=5.13 Hz, 1H), 3.79 (s, 3H), 3.46 (t, J=5.87 Hz, 2H), 3.24 (s, 3H), 2.86 (t, J=4.58 Hz, 4H), 2.50-2.62 (m, 6H), 2.14 (s, 3H); MS (ESI): 705 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20]
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c2ccccc2c1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-methyl-4-(3-amino-4-chlorophenyl)-1-(2H)-phthalazinone (38.72 g, 0.136 mol), CH2Cl2 (380 mL) and pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (15.75 mL) in CH2Cl2 (75 mL). The reaction mixture was stirred overnight, poured into 1N HCl (400 mL) and stirred for 45 minutes. The mixture was filtered and the filtrate layers were separated. The solid thus obtained was treated with saturated NaHCO3, filtered, stirred with hexane, then filtered, stirred with hot methanol, then filtered and finally stirred with hot ethyl acetate and filtered to afford 38.8 g (78%) of 2-methyl-4-(3-methylsulfonylamino-4-chlorophenyl)-1-(2H)-phthalazinone, m.p. 234°-236° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C:25]([CH3:35])([CH3:34])[CH2:26][NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:26][C:25]([OH:24])([CH3:35])[CH3:34])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (25.2 g) and 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (7.00 g) in 2-propanol (200 mL) was added piperidinium acetate (10.8 g). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (11.5 g).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:43]([CH:49]=O)[O:42][C:41]1([CH3:52])[CH3:51])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1>[CH2:30]([O:37][C:38]([N:40]1[C@@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[C@H:43]([CH:49]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:42][C:41]1([CH3:51])[CH3:52])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Yield: 88.1 %

Procedure:
71.6 mg of lithium chloride was suspended in 5 ml of dry THF under an argon atmosphere, and 426 mg of ethyl 2-diethylphosphonobutanoate dissolved in 0.6 ml of dry THF was added thereto under stirring. The mixture was stirred at room temperature for 5 minutes, and then 323 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to simply as DBU) was added thereto in the form of a 50: dry THF solution, and the mixture was stirred at room temperature for 10 minutes. Then, 450 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine dissolved in 1.0 ml of dry THF was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the solution was extracted three times with ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 518 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate as colorless oily substance.