Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([C:16]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
To a solution of 4-(trifluoromethyl)thiobenzamide (5.24 g) in ethanol (50 ml) was added 90% ethyl bromopyruvate (5.53 g), and stirred at 80° C. for 2.5 hours. After completion of the reaction, the solvent was evaporated, and water was added thereto. The insoluble matter was collected by filtration, and then dried to give the titled compound (7.56 g) as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11]1[N:12]([S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])[CH3:10])=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].O>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:8][C@@H:9]([C:11]1[N:12]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@@H](C)N)cc1
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
To a solution of (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-1-tosyl-1H-pyrrole-3-carboxylate (702c; 25.11 g, 54.0 mmol) in 120 mL DCM was added TFA (Aldrich; 120 mL, 1621 mmol) slowly in portions (Caution: gas evolution was observed). After complete addition, the dark brown reaction was stirred 5 min, was fitted with a water-cooled reflux condenser and drying tube and was placed in a pre-heated 50° C. oil bath. The reaction was heated at reflux for 3 h; gas evolution was mild. The reaction was cooled and concentrated in vacuo and the solid material was dried in vacuo for 48 h to give (R)-2-(1-aminoethyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (22.83 g, 54.1 mmol, 100% yield). 1H NMR (400 MHz, MeOH-d4) d ppm 7.89 (2H, d, J=8.4 Hz), 7.57 (1H, d, J=3.5 Hz), 7.52 (2H, d, J=8.2 Hz), 6.79 (1H, d, J=3.5 Hz), 5.28 (1H, q, J=6.8 Hz), 2.47 (3H, s), 1.32 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 309.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].Cl.[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:28][CH:27]=3)[CH2:22][CH2:23]2)=[CH:7][CH:8]=1)#[N:13]
Reactant: N#Cc1ccc(NC(=O)CCl)cc1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-cyano-phenyl)-acetamide and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 113-116° C. (diethylether)
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]1([CH2:26][C:27]([NH:29][NH2:30])=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N#N>C(O)CCC>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:27]([CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:29][N:30]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: S=C1CN=C(c2ccccc2)c2cc(I)ccc2N1
Agent: N#N
Solvent: CCCCO
Product: Ic1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cc3ccccc3)n1-2

Procedure:
A stirred mixture of 7-iodo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (3.78 g, 0.01 mol), phenylacetic acid hydrazide (4.5 g, 0.03 mol) and butanol (150 ml) was heated to reflux while N2 was bubbled through the mixture. After refluxing 17 hours the reaction mixture was concentrated under vacuum. The residue was combined with ice water and allowed to stir for a few minutes. The resulting suspension was filtered and the filtered material washed with CH2Cl2. The filtrate was separated into its respective layers and the aqueous layer washed with CH2Cl2. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with EtOAc to yield 1.43 g (30.04%), mp 200°-201° of the subtitled intermediate. The analytical sample was recrystallized from EtOAc and had mp 201°-202°. The IR, NMR and mass spectra supported the proposed structure.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:22](OCC)=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(OCC)C>[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:22][OH:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
First, 0.44 g of lithium aluminium hydride and 50 ml of diethyl ether were placed in a 100 ml flask. Then, 5.4 g of ethyl 2,2-bis(6-benzyloxyhexyl)acetate obtained in Example 2-(d) was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was stirred for 1 hour at room temperature and for 1 hour under reflux. The reaction mixture was poured into cold diluted hydrochloric acid. An ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) to obtain 4.7 g of 2,2-bis(6-benzyloxyhexyl)ethanol (Y: 96%). The compound thus obtained had a purity of 97.1% by GC.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CO>[C:17]([O:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([CH3:9])([OH:10])[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(C)(O)C(F)(F)CCO
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OCCC(F)(F)C(C)(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6.92 g (0.045 mol) of 4-methyl-3,3-difluoro-1,4-pentanediol and 28 mL of pyridine at 0° C. was added 16 mL of acetic anhydride and the mixture was stirred at 0° C. for 1 hr and at 25° C. for 1 hr. The mixture was added to 15 mL of methanol and the solution was evaporated to dryness to yield oily 4-methyl-3,3-difluoro-1,4-pentanediol 1-acetate.
Reaction SMILES: C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[CH3:17][C@@H:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=[O:20].[Si:25]([O:32][C@H:33]1[CH2:42][C@H:41](O)[C@H:40]2[C:35]([CH:36]=[CH:37][C@H:38]([CH3:61])[C@@H:39]2[CH2:44][CH2:45][C@H:46]2[O:51][C:50](=[O:52])[CH2:49][C@H:48]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH2:47]2)=[CH:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1(C2C=CN=CC=2)CCCC1>C1C=CC=CC=1>[Si:25]([O:32][C@H:33]1[CH2:42][C@H:41]([O:20][C:19](=[O:21])[C@@H:18]([CH3:17])[CH2:22][CH2:23][CH3:24])[C@H:40]2[C:35]([CH:36]=[CH:37][C@H:38]([CH3:61])[C@@H:39]2[CH2:44][CH2:45][C@H:46]2[O:51][C:50](=[O:52])[CH2:49][C@H:48]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[CH2:47]2)=[CH:34]1)([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC[C@H](C)C(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC[C@H](C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
690 mg (6.8 mmol) of triethylamine and 713 mg (4.1 mmol) of diethyl chlorophosphate were added to a solution of 400 mg (3.4 mmol) of (S)-2-methylvaleric acid in 15 ml of dry benzene, and the resulting mixture was stirred at room temperature for one hour. 1.58 g (2.9 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 250 mg (1.7 mmol) of 4-(1-pyrrolidinyl)pyridine were then added to the mixture. The mixture was then stirred at room temperature for 24 hours, after which the mixture was diluted with 20 ml of benzene. The diluted mixture was then washed with 20 ml of water, 20 ml of a 10% w/v aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 6:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.38 g (74% yield) of the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:13])[CH2:10][CH:11]=[CH2:12]>O>[CH2:9]([NH:13]/[C:2](=[CH:3]\[CH3:5])/[C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH:11]=[CH2:12]
Reactant: COC(=O)CC(C)=O
Reactant: C=CCCN
Solvent: O
Product: C=CCCN/C(=C\C)C(=O)OC
Temperature: 25 °C

Procedure:
2.15 milliliters (2.32 grams, 20.0 millimoles) of methyl acetoacetate was added with stirring to 1.42 grams (20.0 millimoles) of homoallylamine cooled in an ice bath and the stirring continued while the mixture was allowed to warm to room temperature and thereafter for three hours to obtain a methyl 2-(3-butenyl)aminocrotonate intermediate product and water by-product in the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCOc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 2-Phenoxy ethylamine (45 mg, 0.32 mmol). The title compound was obtained as a solid (32 mg, 24% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.11 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 7.27 (2H, m), 6.93 (3H, m), 4.04 (2H, m), 3.56 (2H, m). MS m/z: 468.03, 470.03 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]([O:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]2[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)=[O:4])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(OC(=O)Cc1cccc(F)c1)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.2 %

Procedure:
A mixture of 2-hydroxy-4'-(methylsulfonyl) isobutyrophenone (100 g), 3-fluorophenylacetic acid (83 g), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (225 g) and DMAP (25 g) in CH2Cl2 (2 L) was mechanically stirred for 17 h at r.t. A solution of 1N HCl (1 L) was then added and the organic phase was separated, washed with a saturated solution of Na2 CO3 (0.4 L) and dried over MgSO4. After concentration, the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexane to give the title compound as a white solid (133 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5cc[nH]c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 52.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 53% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:28][CH2:29][O:30][N:31]=[CH:32][C:33]([OH:35])=[O:34])=[C:9]2[CH3:36])[CH:2]=1.FC(F)(F)C(O)=O.[NH:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50]C=2)C=C1.N1C=CC=C(CCl)C=1.[H-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:28][CH2:29][O:30][N:31]=[CH:32][C:33]([OH:35])=[O:34])=[C:9]2[CH3:36])[CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[CH:14][CH:15]=3)[C:10]([CH2:28][CH2:29][O:30][N:31]=[CH:32][C:33]([O:35][C:47]3[CH:52]=[N:44][CH:50]=[CH:49][CH:48]=3)=[O:34])=[C:9]2[CH3:36])[CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cc1c(CCON=CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1cccnc1
Agent: ClCc1cccnc1
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CCON=CC(=O)Oc2cccnc2)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1cccnc1

Procedure:
The title compound is prepared by reaction of glyoxylic acid-O-2-[1-(3-pyridylmethyl)-5-(benzothiazol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime with trifluoroacetic acid to remove the t-BOC group followed by reaction of the indole intermediate with two equivalents of 3-pyridylmethyl chloride in the presence of a suitable base such as NaH to provide the intermediate glyoxylic acid 3-pyridyl ester-O-2-[1-(3-pyridylmethyl)-5-(benzothiazol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime which is subsequently saponified.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([Cl:27])=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (7.1 g) and phosphorus pentachloride (4.1 g) in toluene (100 ml) and tetrahydrofuran (25 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated to dryness to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (8.1 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH:22][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Reactant: C=Cc1ccccn1
Product: C(=Cc1ccccn1)c1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1

Procedure:
The title compound was prepared according to the method in Example 6 using (1H-Indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine (200 mg, 0.52 mmol) and 2-vinylpyridine (65 mg, 67 uL, 0.62 mmol).
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH2:12][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:25]([NH2:27])[CH3:26].Cl>>[CH2:25]([NH:27][C:14]([C:11]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:9][N:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]1)=[O:16])[CH3:26]
Reactant: CCCCCCN1CCC(C(=O)OCC)(c2ccccc2)CC1
Reactant: CCN
Agent: Cl
Product: CCCCCCN1CCC(C(=O)NCC)(c2ccccc2)CC1

Procedure:
This compound was prepared as above form ethyl 1-hexyl-4-phenyl-4-piperidinecarboxylate hydrochloride (3.54 g, 10 mmol) and ethylamine (2.25 g, 50 mmol). Reaction time 2 days. The crude product (1.0 g) was recrystallized from disopropyl ether, yielding 0.81 g with m.p. 92°-94° C. Hydrochloride m.p. 221°-223° C. (form 2% aqueous acetone).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[C:13]=1[CH2:19][OH:20].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[C:13]=1[CH:19]=[O:20]
Reactant: OCc1c(Cl)cccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)cccc1I
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 1037.6 %

Procedure:
To a solution of 3.11 ml (36.2 mmol) oxalyl chloride in 40 ml dichloromethane at −78° C. was added dropwise over 20 min a solution of 5.14 ml (72.4 mmol) dimethylsulfoxide in 15 ml dichloromethane. The mixture was stirred for a further 15 min at −78° C. and then a solution of 8.10 g (3.02 mmol) (2-chloro-6-iodo-phenyl)-methanol in 40 ml dichloromethane was added dropwise over 30 min and stirring continued at −78° C. for a further 45 min. 20.9 ml (151 mmol) triethylamine were then added dropwise and the reaction mixture allowed to warm to room temperature. Water was then added and the phases were then separated. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford 8.35 g (100%) of the title compound as a yellow crystalline solid which was used in the next step without further purification. MS (EI): 268.0 (44%) & 266.0 (100%) (M+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(O)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a flame-dried flask containing a mixture of 811 mg of 4-hydroxycoumarin and 985 mg of 1-phenyl-1-pentanol in 30 mL of dioxane under an argon atmosphere is added 3.0 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 193 mg of the title product as white crystals.
Reaction SMILES: ClN1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:31]=[C:30]([C:40]([F:43])([F:42])[F:41])[C:29]=1[Cl:44].C(=O)(O)[O-].[K+]>CN(C)C=O.O>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]2([C:36]([F:39])([F:37])[F:38])[O:9][N:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=3)[CH2:35]2)[CH:31]=[C:30]([C:40]([F:41])([F:42])[F:43])[C:29]=1[Cl:44]
Reactant: CC(=O)NCc1ccc(C=NO)c2ccccc12
Reactant: C=C(c1cc(Cl)c(Cl)c(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
N-chlorosuccinimide (0.06 g) was added to N-({4-[(hydroxyimino)methyl]naphthalen-1-yl}methyl)acetamide (0.1 g) in N,N-dimethylformamide (10 ml), and the reaction mixture was stirred at room temperature for 2 hours. 1,2-dichloro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)ethenyl]benzene (0.75 g) and potassium bicarbonate (0.13 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 8 hours. Water was poured into the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with brine, and dried over Magnesium sulfate anhydrous. The solvent was evaporated under the reduced pressure, and the residue was purified with silicagel columnchromatography to get N-[(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}naphthalen-1-yl)methyl]acetamide (0.1 g).
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12])#N.[C:14]([OH:17])(=[O:16])[CH3:15].S(=O)(=O)(O)O>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:15]([C:14]([OH:17])=[O:16])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
4-Cyano-3-nitroanisole (52.3 g., 0.294 mole) was slowly added to a cooled solution of 53 ml. each of acetic acid, water and sulfuric acid. The solution was refluxed for 5 hours, and then diluted with 160 ml. water. After cooling, the resulting solid was filtered and dissolved in 10% sodium hydroxide solution. After decolorization with charcoal the solution was acidified with 6 N HCl, cooled and the yellow product (51.0 g., 88% yield) was filtered. An analytical sample was recrystallized from methanol/water, M.P. 196°-7° C.