Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10][P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(CO)CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CBr)COP(=O)(Cl)Cl
Reaction time: 8 h

Procedure:
To a solution of 18.35 g of phosphorous oxychloride in 55 ml of carbon tetrachloride was added dropwise a solution of 3-bromo-2,2-dimethyl-1-propanol in 20 ml of carbon tetrachloride. This mixture was stirred overnight, evaporated in vacuo, then evaporated twice from toluene at 35° C. and dried. The residue was distilled on a Kugelrohr 100° C., 0.3 mm giving the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[N:38][C:37]([O:36][CH3:35])=[CH:42][CH:41]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OC)nc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxy-5-pyridineboronic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: O=c1[nH]c2nccc(Nc3cccc(OCc4ccccc4)c3)c2c2ccccc12
Yield: 71.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using 83 (100 mg, 0.43 mmol) and 3-benzyloxy-phenylamine (130 mg, 0.65 mmol) to provide 227 (121 mg, 71% yield) as a tan solid. LC-MS (M+H=394, obsd.=394).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[N:16]O)[CH2:11][CH2:10]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].C(O)C>[N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH:12]([NH2:16])[CH2:11][CH2:10]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ON=C1CCc2cc(N3CCOCC3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCc2cc(N3CCOCC3)ccc21
Yield: 63.2 %

Procedure:
An ethanol (20 mL) suspension of 5-morpholin-4-yl-indan-1-on-oxime (2.76 g) and 10% palladium carbon (48% water content, 1.0 g) was agitated at room temperature under 0.4 MPa hydrogen atmosphere for 6 hours. After filtering the reaction solution and condensing the filtrate under reduced pressure, 1.64 g of the title compound was obtained by purifying the obtained residue by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system). The physical properties of the compound are as follows.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:8])=[CH:4][CH:3]=1.[CH3:16][N:17](C)C=O.Cl>O>[C:16]([C:2]1[S:6][C:5]([C:7]([C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:8])=[CH:4][CH:3]=1)#[N:17]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(Br)s1
Agent: Cl
Solvent: O
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(C#N)s1

Procedure:
A stirred mixture of 4-[(5-bromo-2-thienyl)carbonyl]-5-methyl-1,3-dihydro-2H-imidazol-2-one (10 grams, 0.034 mole), cuprous cyanide (3.0 grams, 0.034 mole) and dimethylformamide (150 ml) are refluxed for 4 hours. The resulting mixture is poured into a solution of 200 grams ferric chloride and 50 ml concentrated hydrochloric acid in 300 ml water. After the reaction mixture is maintained at 60°-70° C. for 20 minutes, the layers were separated. The aqueous layer is extracted with toluene and the combined organic layers are washed with water and dried. Evaporation of solvent gives the title compound which is recrystallized from methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=[O:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
After dissolving 2.04 g of 2-bromoanisole in 22 ml of tetrahydrofuran, 3.6 ml of n-butyllithium (2.66 M, n-hexane solution) was added dropwise while stirring at below −60° C., and after 30 minutes, a solution of 1.58 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (5 ml) was added and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.63 g, 69% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:31][NH2:32]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2ocnc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2ocnc2c1
Yield: 25 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(benzo[d]oxazol-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (0.1 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give 20 mg desired product (25%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.68-6.80 (m, 6H), 6.58-6.64 (m, 4H), 6.49-6.55 (m, 4H). 6.46 (d, J=8.8 Hz, 2H), 5.89 (s, 2H), 4.09 (t, J=5.6 Hz, 2H), 3.97 (t, J=5.2 Hz, 2H), 3.00 (t, J=5.2 Hz, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.39-2.49 (m, 4H), 0.80-1.00 (m, 6H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[CH3:21][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([OH:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)([CH3:24])[CH3:23]>O>[CH3:24][C:22]([NH:25][C:26]1[O:27][C:28]([C:35]([O:37][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Br:12])=[O:36])=[C:29]([C:31]([F:32])([F:34])[F:33])[N:30]=1)([CH3:21])[CH3:23]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2ccccc2Br)o1
Temperature: 25 °C
Yield: 145.4 %

Procedure:
A reaction vessel was charged with 100 ml of dimethylformamide, 6.11 g (50 mmol) of potassium carbonate, and 18 g (72 mmol) of o-bromobenzyl bromide. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 10 g (40 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 18 hours. Then, the mixture was added to water and extracted three times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 24.5 g of a gold oil. This oil was subjected to Kugelrohr distillation (65°-70° C. @ 0.4 mm Hg) to yield 9.7 g of a gold oil. The remaining still residue upon standing at ambient temperature for 30 minutes formed a solid material. Trituration of this solid material in hexane at ambient temperature resulted in 11.48 g of a white solid product (m.p.=74°-77° C.) identified in Table I.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:34][C:35]1[N:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>O1CCCC1.O>[Br:1][C:2]1[N:6]([S:41]([C:38]2[CH:39]=[N:40][C:35]([CH3:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])[CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
To a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 mL) was added sodium hydride (60% in oil, 31 mg) at 0° C., and the mixture was stirred at the same temperature for 10 min. A solution (3 mL) of 15-crown-5 (0.16 mL) and 6-methylpyridin-3-ylsulfonyl chloride (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a brown oil (yield 213 mg, 79%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1Cl>>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc2sc(S)nc2c1
Product: O=C(O)c1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1

Procedure:
2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carboxylic acid (255) was prepared (100%) from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 1,2,3-trichloro-5-nitrobenzene, obtained from Aldrich, in a similar manner as described in example 251.
Reaction SMILES: [Na:1].C(C1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.OCC[CH:50]1[CH2:54][O:53][C:52]([CH3:56])([CH3:55])[O:51]1>>[Na:1].[CH3:55][C:52]1([CH3:56])[O:53][CH:54]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])[CH2:50][O:51]1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: CC1(C)OCC(CCO)O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCCC2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.7 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan to obtain the title compound (412 mg, total yield: 8.7%) as a light yellow solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[C:19]([CH:22]=O)[S:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[C:19]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[S:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: C1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3csc(C=O)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3csc(CN4CCCCC4)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(2-formyl-1,3-thiazol-4-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 39) (21 mg, 0.052 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (7.77 μL, 0.078 mmol) and acetic acid (7.49 μL, 0.131 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (16.63 mg, 0.078 mmol) was added and the mixture was allowed to stir under nitrogen. The mixture was loaded onto a 2 g SCX-column, eluting with MeOH (25 mL) followed by 2M MeOH/NH3 (25 mL). Product-containing fractions were evaporated to dryness to give a solid (18 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 4% 2N methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](N(OC)C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:17].[CH2:18]([Mg]Br)[CH3:19]>>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:12])[CH2:18][CH3:19])[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:17]
Reactant: CON(C)C(=O)c1cc2c(Cl)c(Cl)ccc2s1
Reactant: CC[Mg]Br
Product: CCC(=O)c1cc2c(Cl)c(Cl)ccc2s1

Procedure:
In a similar manner to Example 18, methyl thioglycolate (9.3 ml) was reacted with 2,3-dichloro-6-fluorobenzaldehyde (15.46 g) in dimethylformamide to give methyl 4,5-dichlorobenzo[b]thiophene-2-carboxylate (7.28 g) as an off-white solid which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 4,5-dichloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.96 g) as a colourless solid. Reaction of this amide with ethylmagnesium bromide gave 1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.09 g) as an oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>>[O:38]1[C:42]2([CH2:47][CH2:46][N:45]([C:21]3[N:20]=[C:19]([O:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:29]=[C:30]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)[CH:31]=[C:2]([F:1])[CH:3]=5)=[CH:9][CH:10]=4)[CH:24]=[CH:23][N:22]=3)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1CC2(CCN1)OCCO2
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC4(CC3)OCCO4)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, CDCl3) δ 1.64 (t, J=5.0 Hz, 4 H), 3.26 (t, J=4.3 Hz, 4 H), 3.77 (s, 4 H), 3.88 (t, J=4.7 Hz, 4 H), 3.96 (s, 4 H), 5.98-5.99 (m, 1 H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.8 Hz, 1 H), 7.32-7.34 (m, 2 H), 7.50-7.60 (m, 3 H), 7.90 (d, J=8.2 Hz, 1 H), 8.00 (d, J=8.6 Hz, 1 H), 8.10 (s, 2 H), 8.15-8.17 (m, 1 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]#[N:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[C:28]([F:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(C#N)c(F)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-cyano-phenylboronic acid, 5-(4-cyano-3-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a cream-colored solid (yield=65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[O:29][CH:30]=1>>[F:39][C:36]1[CH:37]=[CH:38][C:33](/[CH:32]=[CH:31]/[C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=3)[N:27]=2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Yield: 70.4 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (291 mg), 65% oily sodium hydride (39 mg) and 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg), the same reaction as Example 2 was carried out to yield the titled compound (347 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].C([O-])(O)=O.[Na+].CO[CH2:40][CH2:41]OC>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:17]=[CH:16][C:15]3[S:14][CH:13]=[N:12][C:40]=3[CH:41]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1scc(-c2ccc3scnc3c2)c1C(=O)O)c1cc2ccccc2o1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 7 (49 mg, 0.1 mmol) in 1,2-dimethoxyethane (DME, 2 mL) and EtOH (1 mL) was added 37 (31 mg, 0.12 mmol), 0.5 M NaHCO3 (1 mL). The suspension was bubbled with argon for 5 min before adding Pd(PPh3) (38, 12 mg, 0.01 mmol). The reaction mixture was heated at 110° C. for 30 min using microwave initiator. The solid was filtered off and the filtrate was extracted with EtOAc (10 ml×2). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The compound 39 was purified by HPLC. The 39 was dissolved in CH2Cl2 (2 ml) and TFA (0.5 ml) was added. The mixture was stirred for 2 h at r.t. The solvent was removed in vacuo. The residue was treated with MeOH (2 mL) and the solid was collected by centrifuge and washed with MeOH. Compound 40 (20 mg, 48%) was obtained as yellow solid. LC-MS: calcd. for C21H12N2O4S2: 419 (M−1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(Cl)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ncc[nH]2)c2cccnc12
Yield: 60 %

Procedure:
5-Chloro-8-quinolinecarbonitrile, 0.50 g, and imidazole, 1.80 g, were dissolved into 30 ml of pyridine. To the solution 0.36 g of anhydrous potassium carbonate was added and the mixture was heated under reflux for 8 hours. After separating indissolved substance by filtration, the solvent was evaporated and the residue was refined by column chromatography on silica gel using chloroform as an eluent. The crystals obtained were recrystallized from ethanol to yield 0.35 g (yield: 60%) of 5-imidazolyl-8-quinolinecarbonitrile (Compound No. 20).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].[CH2:19]([SH:22])[CH2:20][SH:21].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17])[S:22][CH2:19][CH2:20][S:21]3
Reactant: SCCS
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21SCCS1

Procedure:
To a mixture of 0.60 g of 3,4-dihydro-5,8-dimethyl4-oxo-2H-1-benzothiopyran-6-carboxylic acid 1,1-dioxide in 30 mL of methylene chloride was added 0.24 mL of 1,2-ethanedithiol (purchased from Aldrich Chemical Co.) and 0.35 mL of boron trifluoride diethyl etherate (purchased from Janssen Chimica). The mixture was refluxed overnight and then concentrated under reduced pressure to dryness. To the resulting residue was added 10 mL of dilute hydrochloric acid of pH 1. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 0.62 g of the title compound of Step A as an orange solid which had a melting point >250° C. 1H NMR ((CD3)2SO): δ 2.65 (s, 3H), 2.77 (s, 3H), 2.94 (m, 2H), 3.55-3.80 (m, 6H), 7.50 (s, 1H).