Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(OC(C)C)(C)C.[C:20]([O:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CCCCCC>[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:30])[O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: C=C(C)C(=O)OCCNC(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 5.5 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
In a three-necked flask having an inner volume of 50 mL equipped with a thermometer and a stirring apparatus were charged 1.66 g (9.98 mmol) of 2-methyl-2-adamantanol, 2.0 mg of 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, 6.7 g of isopropyl ether, and 1.66 g (10.5 mmol) of 2-methacryloyloxyethyl isocyanate. After the mixture was cooled by ice water to an inner temperature of 5° C., 290 mg (3.0 mmol) of methanesulfonic acid was added dropwise. After stirring the reaction mixture for 15 hours with the reaction temperature maintained at 5 to 6° C., 10 g of a saturated aqueous NaHCO3 solution was added dropwise with the inner temperature maintained at 10° C. or less and, after completion of the dropwise addition, the mixture was allowed to stand still for 30 minutes. The organic layer (upper layer) formed was separated and the aqueous layer (lower layer) was extracted twice with 10 g of isopropyl ether. All the separated organic layers were combined, washed with 10 g of distilled water, and the organic layer concentrated under reduced pressure to obtain 2.82 g of a concentrate. The concentrate was dissolved in 15 g of hexane at 30° C. and the solution was cooled to −10° C. at a rate of 10° C./hour. The crystals which precipitated were separated by filtration and the crystals obtained were dried under vacuum (26.7 Pa) at 30° C. for 2 hours to obtain 1.29 g (purity 98.2%, 3.94 mmol, yield: 39.5%) of 2-methyladamantan-2-yl (2-methacryloyloxyethyl)carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=2)[C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)cc(OC)c1

Procedure:
Compound 2 was reacted with 1-fluoro-4-nitrobenzene in the presence of NaH in DMF to give 3-(3,5-dimethoxyphenyl)-2-[4-(4-nitrophenoxy)-phenyl]-acrylic acid (32). Reduction of 32 (10 g, 24 mmol) with zinc dust (15 g, 230 mmol) in acetic acid (100 mL) was accomplished at 120° C. for 15 h, the mixture was cooled to room temperature. Water (250 mL) was slowly added to the reaction mixture. The precipitated product was filtered and washed with water (70 mL) to give crude product. The product was recrystallized from toluene. Yield (33): 9.7 g, 94%.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.C(OC([NH:29][CH:30]([CH2:34][NH:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[Cl:46])(=[O:38])=[O:37])[C:31]([OH:33])=O)=O)C1C=CC=CC=1.[NH2:47][CH:48]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[C:49]([N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[O:50]>CN(C=O)C.C(Cl)CCl>[Cl:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][CH:48]([NH:47][C:31](=[O:33])[CH:30]([NH:29][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:34][NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])(=[O:37])=[O:38])[C:49](=[O:50])[N:51]([CH2:55][CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH:52]([CH3:54])[CH3:53])=[CH:69][CH:68]=1
Reactant: O=C(NC(CNS(=O)(=O)c1ccc(Cl)cc1Cl)C(=O)O)OCc1ccccc1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NS(C)(=O)=O)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 2-benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the solution is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase over sodium sulfate is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=784.186 (calculated); measured value (M−CO2+H)+: 741.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu](I)I.CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:13]2[CH:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=2)=[N:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: Sc1ccc(Br)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Clc1ccc(Sc2ccc(Br)cn2)cn1
Temperature: 80 °C
Yield: 31.7 %

Procedure:
5-Bromo-2-pyridinethiol (633 mg, 3.33 mmol, Combi-Blocks, Inc., San Diego, Calif.), 2-chloro-5-iodopyridine (798 mg, 3.33 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (32 mg, 0.17 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (921 mg, 6.67 mmol), ethylene glycol (0.37 mL, 6.67 mmol), and 2-propanol (8 mL) were added to a reaction vial. The vial was sealed, purged with nitrogen for several minutes, and heated at 80° C. for 16 h. After cooling to room temperature, the solvents were removed under vacuum. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide 5-bromo-2-((6-chloro-3-pyridinyl)sulfanyl)pyridine (318 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[S:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][CH:19]=1)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:23][CH:22]=3)[CH:28]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 150 °C
Yield: 9.8 %

Procedure:
1-bromo-4-chlorobenzene (0.214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate (60a, 0.3 g, 1.01 mmol) in dimethyl acetamide (5 ml) at 25° C. in a tube. A nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added palladium (II) acetate (0.023 gm, 0.102 mmol) under nitrogen atmosphere and the tube was sealed. The reaction mixture was then heated at 150° C. for 20 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure. The residue so obtained was dissolved in ethyl acetate (30 ml). The solution so obtained was then washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.040 gm, 9.70%).
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Br>C(O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[N:6]2[CH2:28][CH:27]([OH:29])[CH2:25]2)=[CH:23][CH:22]=1
Reactant: BrCC1CO1
Reactant: COC(=O)c1ccc([C@@H](N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
1-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, may be prepared by carrying out the procedure in the following manner: 0.605 g of sodium hydrogen carbonate is added to a suspension of 2.0 g of methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate in 30 cm3 of ethanol followed by 0.60 cm3 of epibromohydrin. After stirring for 20 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, height 35 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume for fractions 6 to 10 and then {fraction (60/40)} for fractions 18 to 27, and then {fraction (50/50)}) and collecting 60-cm3 fractions. Fractions 15 to 40 are combined and then concentrated to dryness under reduced pressure (2. 7 kPa). The residue is taken up in 30 cm3 of ethanol and is then supplemented with 0.20 g of sodium hydrogen carbonate and 0.2 cm3 of epibromohydrin. After stirring for 48 hours at 20° C. and then 24 hours at 35° C., the mixture is filtered and the filtrate is concentrated to dryness at 60° C. under reduced pressure (2.7 kPa). 1.76 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, are obtained in the form of a pasty solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:36]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:34][CH:33]=4)=[O:37])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reaction time: 2 h

Procedure:
At room temp. under nitrogen, to a solution of 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol) and diisopropyl(ethyl)amine (209 mg, 1.62 mmol) in acetonitrile (5 mL) is added 4-trifluoromethylphenyl isocyanate (197 mg, 0.97 mmol). The reaction mixture is stirred at room temp. for 2 h, concentrated, and the residue is purified by flash chromatography with CH2Cl2-MeOH to afford the title product.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.00 mmol) and 4-methylmorpholine (6.5 mL, 59.0 mmol) in tetrahydrofuran (150 mL) was added isobutyl chloroformate (6.5 mL, 49.6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour then 3-(aminomethyl)pyridine (5.2 mL, 51.4 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, then concentrated in vacuo. The residue was purified by column chromatography to afford 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide in 52% yield (7.3 g): 1H NMR (300 MHz, CDCl3) δ 8.39-8.80 (m, 2H), 7.80-7.72 (m, 1H), 7.40-7.35 (m, 1H), 6.47 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 312.1, 314.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N+:12]([CH:15]=[C:16](SC)[S:17]([CH3:19])=O)([O-:14])=[O:13].C[O-].[Na+]>C(O)C.CO>[CH3:19][S:17][C:16]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
α-Aminoacetophenone hydrochloride (6.87 g, 0.040 mol) was mixed with 1-nitro-2-methylthio-2-methylsulphinylethylene (7.25 g, 0.040 mol) in 300 ml dry ethanol and warmed at 60°. Sodium methoxide (from 0.92 g sodium, 0.080 g atom) in methanol (25 ml) was added dropwise, with stirring, over about 10 minutes. After addition, the mixture was stirred at 60° for one hour, and then filtered to give 2-methylthio-3-nitro-4-phenylpyrrole 5.66 g, m.p. 259°-261° dec.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([S:20]([C:23]2[C:24]([CH:28]=[O:29])=[CH:25][S:26][CH:27]=2)(=[O:22])=[O:21])[CH:14]=[CH:13]3)=[CH:6][CH:5]=1>CO.C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([S:20]([C:23]2[C:24]([CH2:28][OH:29])=[CH:25][S:26][CH:27]=2)(=[O:22])=[O:21])[CH:14]=[CH:13]3)=[CH:8][CH:9]=1
Reactant: O=Cc1cscc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1cscc1CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.3 %

Procedure:
Sodium borohydride (21 mg, 0.53 mmol) was added to a solution of 4-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}thiophene-3-carbaldehyde (42 mg, 0.11 mmol) in MeOH (5 mL) and CH2Cl2 (2 mL) and the mixture stirred at ambient temperature. After 40 minutes, the mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL) and the organic fraction washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford solid material which was washed with Et2O and further dried in vacuo to yield (4-{[6-(4-fluorophenyl)naphthalen-2-yl]sulfonyl}-3-thienyl)methanol as a white solid (40 mg). 1H NMR (400 MHz, d6-DMSO): δ 8.70 (1H, s), 8.59 (1H, d, J=3.4 Hz), 8.34 (2H, t, J=6.2 Hz), 8.19 (1H, d, J=8.8 Hz), 8.03 (1H, dd, J=1.7, 8.6 Hz), 7.93-7.85 (3H, m), 7.53 (1H, d, J=3.4 Hz), 7.38 (2H, t, J=8.9 Hz), 5.31 (1H, t, J=5.6 Hz), 4.53 (2H, d, J=5.7 Hz). m/z (ES+) 384 [(M-OH)+].
Reaction SMILES: Br[C:2](Br)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:3][O:4][C:5]1[C:12]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:11][C:8]([CH:9]=[CH2:10])=[C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=1.C1COCC1.C([Li])CCC>O>[CH2:24]([O:23][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][CH2:30][CH2:31][CH2:32][CH3:33])[C:12]([C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[CH:11][C:8]=1[C:9]#[CH:10])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCC(Br)(Br)CCCC)cc1OCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCCCCCC)cc1OCCCCCC
Temperature: 25 °C

Procedure:
3 g (5 mmol) of 2',2'-dibromo-2,4-dihexyloxy-5-(1-adamantyl)styrene and 50 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 4 ml (10 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78° C. and the temperature was permitted to increase to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[CH:16][CH:15]=2)[N:13]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccccc2C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 27.4 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol) in DMSO was added 1-iodo-2-(trifluoromethyl)benzene (0.13 g, 0.479 mmol), TBAF (0.301 g, 0.958 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.050 g, 0.071 mmol). The reaction mass was stirred at 110° C. for 5-6 h. The reaction mass was quenched in water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 2.0% EA:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=9.3 Hz, 1H), 7.57-7.73 (m, 6H), 7.82 (br s, 2H), 8.02 (d, J=8.7 Hz, 2H), 12.72 (br s, 1H). MS (m/z): 458.26 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55](O)=[O:56])=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]2)=[O:56])=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1784.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CN2CCOCC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with morpholine (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(morpholinomethyl)nicotinamide. MS (Q1) 450.0 (M)+
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6].[BH4-].[Na+]>CO.ClCCl>[CH3:3][NH:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([CH3:1])[CH2:29][CH2:30]4)[N:16]=3)[S:12][C:11]=2[CH:31]=1)=[O:6]
Reactant: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCNCC4)ncc3C)sc2c1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C)CC4)ncc3C)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.711 mL, 9.60 mmol) is added to a stirred solution of 2-[5-methyl-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid methylamide (346 mg, 0.845 mmol) in CH3OH (10 mL) and dichloromethane (10 mL) at room temperature. The resultant mixture is stirred for 90 minutes. After being cooled to 0° C., the mixture is treated with powdered sodium borohydride (211 mg, 8.00 mmol) and stirred for 60 minutes. The mixture is allowed to stir at room temperature for 3 hours, concentrated and subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-8%, to give the title compound as a yellowish foam (280 mg, 78% yield). ES+(m/z) 424 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:17]O>C(O)(=O)C>[CH3:1][C:2]1[C:10]([S:11]([CH3:12])=[O:17])=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Temperature: 55 °C
Yield: 93.9 %

Procedure:
1.00 g (4.00 mmol) of 2-methyl-3-(methylthio)-4-(trifluoromethyl)benzoic acid was introduced into 10 ml of glacial acetic acid. The mixture was heated to 50-60° C. At this temperature, 0.35 ml (35% strength, 4.00 mmol) of an aqueous hydrogen peroxide solution was added cautiously dropwise. The mixture was stirred at 60° C. for a number of hours until HPLC analysis no longer indicated any reactant. The reaction mixture was cooled and was worked up by washing with an aqueous 10% strength sodium hydrogensulfite solution. Following analytical verification of the absence of peroxides, the mixture was concentrated. The residue was taken up in water and then 1M hydrochloric acid was added. Extraction was carried out three times with ethyl acetate, and the combined organic phases were thereafter dried and freed from the solvents. 1.00 g of the clean product was isolated.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].C([O-])([O-])=O.[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C.CC(=O)OCC>[Cl:4][CH2:3][CH2:2][S:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=1
Reactant: ClCCBr
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(SCCCl)cc1F
Reaction time: 16 h
Yield: 94.2 %

Procedure:
5.7 ml (68.4 mmol) of 1-bromo-2-chloroethane and 1.9 g (13.7 mmol) of K2CO3 were added to a solution of 2.0 g (13.7 mmol) of 3,4-difluorothiophenol in DMF (20 ml). Stirring was then carried out for 5 h at 60° C. and for 16 h at RT. The mixture was then diluted with EA (50 ml) and washed in succession with 1 M aq. Na2CO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. There were obtained as residue 2.7 g (12.9 mmol, 95%) of (2-chloroethyl)-(3,4-difluorophenyl)sulfane, which was reacted further without additional purification.