Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1>O1CCCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4F)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 7.1 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (71 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.65 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (7.1 mg, 7.1%) as white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[N:29][CH:30]=2)[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:18][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:5][C:6]2[C:11]([C:2]=1[NH:31][C:27]1[CH:28]=[N:29][CH:30]=[C:25]([N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:26]=1)=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1Nc1cncc(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (70 mg, 0.27 mmol), 5-morpholinopyridin-3-amine (49 mg, 0.27 mmol) and XPhos precatalyst (20 mg, 0.027 mmol) in toluene (4 mL) was added sodium tert-butoxide (52 mg, 0.55 mmol) and the reaction was heated at reflux for 2 h. After this time the reaction was allowed to cool to rt and partitioned between EtOAc (60 mL) and water (20 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC gave 3-methyl-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-1,8-naphthyridin-4-amine. H NMR (400 MHz, CDCl3) δ ppm 9.03 (1H, dd, J=4.1, 2.0 Hz), 8.69 (1H, ddd, J=4.8, 1.7, 1.1 Hz), 8.20 (1H, dd, J=8.3, 1.9 Hz), 8.08 (1H, dt, J=7.9, 1.1 Hz), 7.84-7.93 (2H, m), 7.78 (1H, d, J=2.3 Hz), 7.31-7.42 (2H, m), 6.51-6.61 (1H, m), 6.37 (1H, t, J=2.4 Hz), 3.74-3.87 (4H, m), 3.00-3.10 (4H, m), 2.47 (3H, s). Mass Spectrum (ESI) m/e=399.2 (M+1).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([CH2:7][N:8](CC2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:6])[CH2:4][CH2:3]1.Cl.[H][H]>CO.[C].[Pd]>[ClH:1].[CH:2]1([C:5]([CH2:7][NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: O=C(CN(Cc1ccccc1)Cc1ccccc1)C1CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(CNCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
A total of 63.2 g of N, N-dibenzyl-aminomethyl cyclopropyl ketone hydrochloride was dissolved in 316 g of methanol, followed by dropwise addition of 11 g of 33% by weight hydrochloric acid. The inner atmosphere of the reaction system was replaced with nitrogen gas three times, 6.3 g of 5% by weight palladium-carbon was then added to the mixture, and the inner atmosphere of the reaction system was replaced with hydrogen gas three times, followed by stirring at room temperature for 2.5 hours. After the completion of the reaction, the resulting reaction mixture was filtrated using a filter aid (available from Kohjin Co., Ltd. under the trade name of “Cerafloc”), the filtrate was concentrated and thereby yielded 38.3 g of N-benzyl-aminomethyl cyclopropyl ketone hydrochloride as a colorless crystal.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ncccc2[N+](=O)[O-])CC1
Reaction time: 1.5 h

Procedure:
1-(3--Nitro-2-pyridinyl)piperazine is dissolved in 175 ml of methylene chloride and cooled to 0°. Then pyridine is added followed by benzylchloroformate (16.5 ml). The reaction is stirred 1.5 hr, then poured into saturated aqueous sodium bicarbonate and extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound, NMR (300 MHz, CDCl3) 8.34, 8.15, 7.38-7.32, 6.81, 5.17, 3.65 and 3.45 δ.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH2:15]([NH:17][C:18](=[O:20])[O-:19])[CH3:16].[CH3:21][O:22][C:23]1[C:24](Br)=[CH:25][C:26]2[CH:27]([CH3:35])[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([NH:17][C:18](=[O:19])[O-:20])[CH3:16].[CH3:21][O:22][C:23]1[C:24]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:25][C:26]2[CH:27]([CH3:35])[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1
Reactant: OB(O)c1cccs1
Reactant: COc1cc2c(cc1Br)C(C)C1CNCC21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1-c1cccs1)C(C)C1CNCC21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Thiophene-2-boronic acid (44 mg, 0.34 mmol), Pd(PPh3)4 (19 mg, 0.02 mmol), K2CO3 (71 mg, 0.51 mmol), and H2O (0.17 mL) were added to a solution of N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (60 mg, 0.17 mmol) in dioxane (3 mL) and stirred overnight at 100° C. The reaction mixture was diluted with EtOAC and H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MS calculated for C20H25NO3S+H: 358, observed: 358.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:18][O:17][C:11]1[CH:16]=[CH:15][C:14]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
To a solution of 4-methylbenzoyl chloride, 32-a, (10 g, 65 mmol) and anisole (8.8 g, 81 mmol) in DCM anhydrous was added aluminum(III) chloride (10.8 g, 81 mmol), the reaction mixture was then stirred for 10 h at ambient temperature. The resulting mixture was concentrated under reduce pressure, 100 ml of water was added, filtered, the residue was dried in vacuo. The product was obtained as a white solid, 32-b, (14 g, 95% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.71 (s, 3H), 6.85-6.89 (m, 2H), 7.11-7.19 (m, 6H). LC-MS 227 [MH]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[C:12]([O:19][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:11]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCBr
Reactant: CC(C)(C)c1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(=O)cc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc2c1
Reaction time: 2 h

Procedure:
0.183 g (0.5 mmol) of the compound of Example 1 and 0.25 g (2.5 mmol) of potassium hydrogen carbonate are stirred for a few moments in 10 ml of dimethylformamide at 110° C. under nitrogen until they have completely dissolved. 0.7 ml (5 mmol) of [1-bromo-n-hexane] are then added and the reaction is continued under the same conditions for two hours.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH2:8][CH2:9][OH:10])=[CH:5][CH:4]=1)[CH3:2].CO[CH:13](OC)[CH2:14][NH2:15].C(S(O)(=O)=O)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][O:10][CH:13]([CH2:14][NH2:15])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CCO)s1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(s1)CCOC2CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-ethylthiophen-2-yl)ethanol (1 g, 6.4 mmol, 1.1 eq) and aminoacetaldehyde dimethylacetal (612 mg, 5.83 mmol, 1 eq) was added CF3SO3H (2.7 g, 17.5 mmol, 3 eq) dropwise at 0° C. After stirring at room temperature overnight, the reaction mixture was diluted with water, adjusted pH to ˜8 with Na2CO3, and extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The crude product was purified by column chromatography.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]3([CH2:18][CH2:17][CH2:16][C@@:15]([CH2:20][N:21]4[C:25]5[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=5[N:23]=[CH:22]4)([CH3:19])[CH2:14]3)[O:11][C:10]2=[O:32])=[C:5]([CH3:33])[CH:4]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C>[CH3:19][C@:15]1([CH2:20][N:21]2[C:25]3[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:16][CH2:17][CH2:18][C@:12]2([O:11][C:10](=[O:32])[N:9]([C:6]3[C:5]([CH3:33])=[CH:4][C:3](=[O:2])[NH:8][CH:7]=3)[CH2:13]2)[CH2:14]1
Reactant: COc1cc(C)c(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(=O)[nH]cc1N1C[C@@]2(CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-(((5S,7S)-3-(6-methoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (5000 mg, 11.22 mmol) and sodium iodide (5047 mg, 33.7 mmol) in Acetonitrile (42.900 mL) was added TMSCl (4.30 mL, 33.7 mmol). The reaction was stirred at room temperature overnight. More sodium iodide (5047 mg, 33.7 mmol) and TMSCl (4.30 mL, 33.7 mmol) were added and stirred overnight at room temperature. The reaction mixture was concentrated to remove MeCN, and the residue was partitioned between saturated aqueous sodium metabisulfite (30 mL) and 10% MeOH/DCM (50 mL). The layers were separated, and the aqueous layer was extracted with 2×DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The material was purified by ISCO Rf chromatography (220 g column, silica load): 0-20% MeOH/DCM (20 min), 20% MeOH/DCM (20 min). Obtained 1-(((5S,7S)-7-methyl-3-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white foam (3.35 g, 69%). MS (m/z) 432.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Si:29]([O:36][CH2:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:44]=O)[S:42][CH:43]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Si](OCCC1C=CSC=1C=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O.CC(O)=O>[Si:29]([O:36][CH2:37][CH2:38][C:39]1[CH:40]=[C:41]([CH2:44][N:26]2[CH2:25][CH2:24][C:22]3([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]4[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=4)=[O:17])[CH2:23]3)[CH2:28][CH2:27]2)[S:42][CH:43]=1)([C:32]([CH3:33])([CH3:35])[CH3:34])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(C=O)c1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)[Si](C)(C)OCCc1ccsc1C=O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
(2-Isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.50 g) was added to a stirred solution of a 4:1 mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde and 3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 27, step b) (0.40 g) and AcOH (0.085 mL) in N-methyl-2-pyrrolidinone (6 mL). After 5 min, sodium triacetoxyborohydride (0.48 g) was added. After 16 h water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed three times with water and evaporated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate:isohexane:triethylamine, 20:80:5 separated the two isomeric products and gave the subtitled compound as a gum. Yield 0.27 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[NH4+].[Cl-]>COCCOC.CO.[Pd]>[NH2:17][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COCCOc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CO
Product: COCCOc1cc(C(N)=O)c(N)cc1OC
Reaction time: 12 h

Procedure:
A mixture of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzamide (4.5 g, contains some NH4Cl) and 10% Pd/C (ca. 0.5 g) in DME (200 mL) and MeOH (200 mL) was hydrogenated under a balloon of H2 at RT for 12 h. The mixture was filtered through a pad of Celite® and concentrated in vacuo to give 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzamide as an off white solid (2.8 g, 11.6 mmol). HPLC retention time 2.80 mins.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30]Cl)[C:25]=1[CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO.C(OCC)(=O)C>[CH2:14]([O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:25]=1[CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 108.6 %

Procedure:
To a liquid prepared by dissolving with stirring 5.7 g (0.038 mol, 0.9 eq.) of 2-mercaptobenzimidazole and 9.7 g (0.0504 mol, 1.2 eq.) of a 28% sodium methoxide solution in 120 mL of methanol, a liquid containing 12.0 g of 4-nonyloxy-2-chloromethyl-3-methylpyridine dissolved in 60 mL of methanol was added at 29° C. Subsequently, the mixture was heated to reflux for 0.5 hours and cooled, and then methanol was solid dried under reduced pressure. A brown oily residue resulting therefrom was dissolved in 240 mL of ethyl acetate, and then the organic layer was washed with 120 mL of water. 36 g of silica gel was added with stirring to the organic layer, subsequently the silica gel was removed by filtration, and then the filtrate was concentrated to dryness under reduced pressure, to obtain 16.4 g of pale green brown crystals. The pale green brown crystals were recrystallized from ethyl acetate (10 vol.), to obtain 5.5 g of pale brown crystals (HPLC: 98.8 Area %, yield 32.9%).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=3)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[Na]>O>[CH3:36][C:33]1[CH:32]=[CH:31][C:30]([N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)=[CH:18][CH:19]=2)=[CH:35][CH:34]=1
Reactant: COc1cccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)c1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3cccc(O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 ml of N,N-dimethylformamide were added to a mixture of 4.06 g (10.0 mmol) of N,N-bis(4-methylphenyl)-4-amino-3'-methoxystilbene and 1.68 g (20.0 mmol) of sodium thioethylate. The thus prepared mixture was refluxed with stirring for 4 hours. The mixture was then cooled to room temperature, and poured into water. The ether component was extracted from the reaction mixture by a separating funnel. The thus obtained organic layer was washed with water, and dried over magnesium sulfate and further dried under reduced pressure, thereby producing a dark green oily material.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)=[O:3].[O:16]1CCOC[CH2:17]1.Cl>[Cl-].[Na+].O>[OH:16][CH2:17][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1
Reactant: O=C(Cl)CCCCCCC1=CCCC1=O
Reactant: C1COCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCCCC1=CCCC1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6.3 g of 2-[6-(chloroformyl)hexyl]cyclopent-2-en-1-one (Example 268) and 16 g of tris-trimethylsilyloxyethylene (Example 267) are stirred at 90° to 100° C. under argon for one hour. To this mixture is added 25 ml of dioxane and 10 ml of 0.6N hydrochloric acid. The mixture is heated at 80° C. for 30 minutes. The mixture is poured into brine and extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether containing 2% acetic acid to give 1.7 g of the title compound (Rf =0.45).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:20][C:10]=1[CH3:11]
Reactant: CCOC(=O)C(=O)NC(Cc1cccc(Br)c1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)o1
Yield: 53.2 %

Procedure:
The solution of ethyl 2-(1-(3-bromophenyl)-3-oxobutan-2-ylamino)-2-oxoacetate (1.0 g, 2.9 mmol) in POCl3 (10 mL) was refluxed overnight. The mixture was concentrated, treated with H2O (40 mL), neutralized with aqueous NaHCO3 and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (EtOAc:Petroleum ether=1:5) to afford ethyl 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylate as a yellow oil (0.5 g, 51%). MS (ES+) C14H14BrNO3 requires: 323, 325 found: 324 [M+H]+, 326 [M+2+H]+(1:1).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:27][CH:26]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 67.8 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 3.21 g of p-chlorophenol to give a gel which crystallized on trituration with 50 ml of petroleum ether (6.45 g). Recrystallization from 50 ml of hexane yielded a 5.8 g of a white solid, mp 79°-82° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH2:15](Br)[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[O:20]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:15][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3CCCO3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), tetrahydrofurfuryl bromide (51 mg, 0.31 mmol, Alfa Aesar, Cat. No. A15192), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate. The organic solution was washed with water and brine, and dried over Na2SO4. After filtration the filtrate was concentrated to yield 51 mg of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:11]=1
Reactant: BrCc1cccc2ccccc12
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6-bromo-2-methyl-4-nitro-1H-benzo[d]imidazole (prepared following the same procedure as Example 1) (3 g), 1-(bromomethyl)naphthalene (2.85 g) and K2CO3 (3.23 g) in DMF (100 mL) was stirred at 80° C. overnight. It was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (4.63 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 6.16 (s, 2H), 6.32 (d, 1H, J=7.5 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.61-7.72 (m, 2H), 7.87 (d, 1H, J=7.5 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.14 (d, 1H, J=1.8 Hz), 8.19 (d, 1H, J=7.5 Hz), 8.28 (d, 1H, J=1.8 Hz); LC-MS: m/e=296 [M+1]+.