Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[C:10]1([C:8]2[O:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Reactant: C1CCNCC1
Solvent: CO
Product: c1ccc(-c2cc(OCCN3CCCCC3)no2)cc1
Temperature: 0 °C
Yield: 92.2 %

Procedure:
3-(2-Bromoethoxy)-5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 ml), and piperidine (426 mg) was added thereto, followed by reflux of the resulting mixture for 3 hours. After the reaction mixture was added to ice-cold water (20 ml) and extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (251 mg, 92%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[CH:41][C:40]=1[CH2:49]O.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:49][C:40]3[CH:41]=[N:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: OCc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a solution of 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (50 mg) in dioxane (2 ml) was added triphenylphosphine (84 mg), quinoxaline-2-yl-methanol (48 mg) and di-t-butyl-aza-dicarboxylate (73 mg) and the reaction mixture was heated at 60° C. for 18 h. The reaction mixture was poured into 1N NaOH, extracted 3× methylene chloride, dried magnesium sulfate, filtered and concentration Purification via MPLC biotage chromatography provided the title compound (54 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.45 (d, J=6.2 Hz, 2H), 8.10 (m, 2H), 7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=9.1 Hz, 2H), 7.10 (d, J=6.9 Hz, 2H), 7.01 (d, J=8.7, 2H), 5.41 (s, 2H), 3.94 (s, 3H); MS: (M+H m/z=394.4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
4′-(2-Hydroxy ethyl)octanophenone (1.0 g) prepared in the step B was dissolved in dichloromethane (10 ml) to obtain a solution. p-Toluene sulfonyl chloride (923 mg) and pyridine (383 mg) were added to the solution with cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, ice water was added to the solution, the solution was stirred at room temperature for 20 minutes. Dichloromethane layer was washed with 2% hydrochloric acid, sodium bicarbonate solution, and water. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from hexane-ethyl acetate (10:1) to obtain 2-(4-octanoyl phenyl)ethyl p-toluene sulfonate (950 mg) in the form of colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][N:8]=[C:9]=[S:10]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:9]([NH:8][CH3:7])=[S:10])[N:4]=[CH:5][N:6]=1
Reactant: CN=C=S
Reactant: Nc1nc[nH]n1
Solvent: CN(C)C=O
Product: CNC(=S)n1ncnc1N
Yield: 18.3 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (3.91 g), dimethylformamide (20 ml) and methyl isothiocyanate (3.41 g) were used as reagents. After the reaction, the resulting substance was removed by filtration and the filtrate was extracted with ethyl acetate, after which the obtained white solid was recrystallized from ethanol and ethyl acetate to give 1.34 g of yellow crystals (yield 18%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][NH:22][CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethyl amine (1.0 eq) was added to solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I (1.0 mmol) in 10 mL THF. The solution was cooled to 0° C. 4-Methyl-benzenesulfonyl chloride (1.0 mmol) was added slowly with continuous stirring. Reaction mixture was brought to room temperature and stirred for 2 h Reaction mixture was concentrated, diluted with water, extracted dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:1][Cl:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1SCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of 27.2 g of sulfuryl chloride in 50 ml of dry carbon tetrachloride was added dropwise to a cold (ice-salt bath) solution of 25 g of 4-methylbenzenethiol in 50 ml of carbon tetrachloride containing a few drops of pyridine. The solution was stirred for 0.5 hour at ice-salt bath temperature, allowed to warm to room temperature, then heated under gentle reflux for 0.5 hour. The solution was filtered through a layer of anhydrous sodium sulfate and the filtrate concentrated under reduced pressure. The red liquid residue was distilled to give 24.1 g of 2-methylbenzenesulfenyl chloride, b.p. 67°-69° at 2 mm, nD25 1.6015.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:19]CC2C=CC(OC)=CC=2OC)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH3:38][C:39]([CH3:41])=[O:40].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([S:16]([NH2:19])(=[O:17])=[O:18])[C:39]([OH:40])([CH3:41])[CH3:38])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1cccc(OCc2ccccc2)c1)S(N)(=O)=O
Temperature: -75 °C

Procedure:
Under inert gas, 3.10 g of C-(3-benzyloxyphenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 60 ml of THF, and then, at a temperature of −75° C., 12.00 ml of a 1.8 N phenyllithium solution were added dropwise. The reaction mixture was allowed to come to 0° C. and stirred briefly, then cooled again to −75° C., and 3.80 ml of acetone were added dropwise. After stirring for 10 minutes, 3 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. After the removal of the solvent under reduced pressure, the residue was dissolved in 20 ml of dichloromethane and admixed with 5.00 ml of trifluoroacetic acid. After stirring at room temperature for 2.5 hours, the reaction solution was neutralized cautiously with 2 N aqueous sodium hydroxide solution and then stirred overnight. The precipitate formed was filtered off with suction, washed with dichloromethane and cold water, and coevaporated twice with toluene. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (2.06 g) with a molecular weight of 335.4 g/mol (C17H21NO4S).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:38])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:38])[C@H:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)[NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(O)cc1
Product: CC(=O)SCC(C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1)C(C)c1ccc(O)cc1
Yield: 78 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and tyrosine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]tyrosine benzyl ester is obtained in a 78% yield in the form of a white solid, having the following characteristics: Rf =0.16 [hexane/ethyl acetate (65:35 by volume)].
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:3]3[CH:7]=[CH:6][CH:5]=[CH:4]3)(=[O:29])=[O:30])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cccc3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Sodium hydride (139 mg, 60%, 3.5 mmol) was added to a solution of pyrrole (200 uL, 194 mg, 2.9 mmol) in THF (10 mL). Stirring for 3 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (185 mg, 0.5 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with NH4Cl (5 mL), diluted with EtOAc (50 mL), washed with NaCl (2×20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 70 mg (35%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.36-1.53 (m, 4 H), 1.55 (s, 9 H), 2.18-2.38 (m, 1 H), 3.22-3.35 (m, 2 H), 3.88 (m, 2 H), 4.33 (d, J=7.42 Hz, 2 H), 6.22-6.31 (m, 2 H), 7.13-7.29 (m, 2 H), 7.71 (d, J=8.8 Hz, 1 H), 7.77 (dd, J=8.6, 1.8 Hz, 1 H), 8.13 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=401.8; Anal. Calcd for C21H27N3O3S+0.30H2O (406.94): C, 61.98; H, 6.84; N, 10.33. Found: C, 62.10; H, 6.90; N, 10.43.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1.[C:24]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of Diisopropylamine (7.87 mL, 56.2 mmol) in dry tetrahydrofuran (50 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 22 mL, 55.0 mmol). The resulting solution was warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and treated, via cannula, with a solution of 3-chlorophenylacetic acid (4.0 g, 23.4 mmol) in tetrahydrofuran (20 mL). The reaction was then allowed to warm to 25° C. where it was stirred for 45 minutes and was then re-cooled to −78° C. A solution of cyclohexanone (3.65 mL, 35.3 mL) in tetrahydrofuran (10 mL) was then added via cannula, and the resulting mixture was stirred at −78° C. for 1.5 h. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride, and the tetrahydrofuran was removed in vacuo. The resulting residue was dissolved in a 2N aqueous solution of sodium hydroxide (30 mL) and washed with ethyl acetate (1×30 mL). The aqueous layer was then acidified to pH=1 with the addition of a 2 N aqueous solution of hydrochloric acid. The product was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 6.05 g (96%) of pure (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid as a white solid. HRMS: calcd for C14H17ClO3, 268.0866; found (ESI_FT), 291.0748.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(N[C:29](=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]([CH3:29])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CC(C)C(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and propiophenone (II), MS (m/e) 434, 392, 329, 297, 288, 261,243, 152, 132 and 105; IR (neat) 2983, 1682, 1253, 1027 and 970 cm-1 ; NMR (CDCl3) 8.03, 7.57, 7.47, 4.1, 2.4, 2.0 and 1.29 δ; CMR (CDCl3) 203, 136, 133, 128.6, 128.5, 62, 38, 34, 29, 17 and 16 δ.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]C(C)(C)C.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: CSSC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CSc1cccc2cc[nH]c12
Temperature: 0 °C
Yield: 56.1 %

Procedure:
To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at −78° C. was added tBuLi (1.7 M, 33.8 mL, 57.4 mmol) and the mixture was allowed to warm to 0° C. The reaction was re-cooled to −78° C. and a solution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and the reaction was allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 7-(methylthio)-1H-indole (1.4 g, 55%). 1H NMR (400 MHz, CDCl3) δ=2.50 (s, 3 H), 6.58 (dd, J=3.03, 2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.56 (d, J=7.83 Hz, 1H), 8.45 (br. s., 1 H); MS (ES+): m/z 164.15 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:27][CH2:28][CH2:29][NH2:30])(=[O:26])[CH3:25]>>[C:24]([NH:27][CH2:28][CH2:29][NH:30][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[N:16][CH:17]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: CC(=O)NCCNC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 48 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using N-acetylethylenediamine instead of ethanolamine, to the title compound (120 mg, 48%) which was obtained as a white solid. MS: m/e=413.1 [M−H]−.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([N:15]=[C:16]=[S:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1.O>[C:5]1([N:15]2[C:16](=[S:17])[N:1]=[N:2][NH:3]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: S=c1nn[nH]n1-c1cccc2ccccc12
Temperature: 102 °C
Yield: 63.1 %

Procedure:
To a solution of NaN3 (1.76 g, 27.0 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 mL) was added 1-naphthalenylisothiocyanate (5.00 g, 27.0 mmol) at room temperature. The yellow solution containing a white solid was heated at 102° C. for 2 h. The reaction mixture was then cooled to room temperature and aqueous 1 N HCl solution was added until pH 2 was reached. The aqueous mixture was extracted with EtOAc (250 mL). The organic layer was extracted with aqueous 1 N NaOH solution. The aqueous layer was acidified with aqueous 6 N HCl solution and a white precipitate formed. The suspension was filtered and the resulting solid was triturated with Et2O/hexane (1/1) to give the title compound (3.89 g, 63% yield) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([OH:11])[CH3:10].[CH2:12](C1C([N+]([O-])=O)=CC=CC=1S(O)(=O)=O)[C@H:13]1[O:15][CH2:14]1.[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][CH2:12][C@H:13]1[CH2:14][O:15]1)[CH3:10]
Reactant: Cc1cccc([C@@H](C)O)c1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc([C@@H](C)OC[C@H]2CO2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(1R)-1-(2-bromo-3-methylphenyl)ethanol (2.00 g, 9.30 mmol) obtained in Example 4(4a) and (R)-glycidyl 3-nitrobenzene sulfonic acid (3.13 g, 12.1 mmol) were dissolved in N,N-dimethyl formamide (45 mL), added with sodium hydride (608 mg, content 55%, 14.0 mmol), and stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. After that, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (1.51 g, yield 60%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)c1cc2ccccc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cc2ccccc2n1CCCCl
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.7 %

Procedure:
To a cold solution of tert-butyl 1H-indole-2-carboxylate (1.15 g, 4.94 mmol, 1 equiv) in dimthylformamide sodium hydride (60% dispersion) (237 mg, 5.92 mmol, 1.2 equiv) was added and the reaction stirred until all the sodium hydride has been consumed. 1-bromo-3-chloropropane (1.46 ml, 14.88 mmol, 3 equiv) was added and the reaction stirred at 60° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP, 50 g cartridge, Rf=0.5, gradient—5%-25% ethyl acetate in hexanes) to afford the title compound as an oil (1.52 g, quant); MS for C16H20ClNO2 m/z 293.12 (M+H)+.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.C(O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](N1CCN(c3cccc(C(F)(F)F)c3)CC1)C2
Yield: 36.7 %

Procedure:
A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(α,α,α-trifluoro-m-tolyl)piperazine, and 2 ml of absolute ethanol in 100 ml of xylene is refluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184°-187° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][N:29]3[CH2:32][CH2:31][CH2:30]3)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1
Reactant: CCC(=O)Nc1ccc(Sc2nc(CCBr)cc(Nc3cc(C)[nH]n3)n2)cc1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1ccc(Sc2nc(CCN3CCC3)cc(Nc3cc(C)[nH]n3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(2-bromoethyl)pyrimidin-2-ylthio)phenyl)propionamide (100 mg, 0.21 mmol) and azetidine (36 mg, 0.63 mmol) in dimethylformamide (2 ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml). The organic layer was washed with a saturated solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over magnesium sulfate. The residue was purified by Gilson HPLC to afford the title compound as a bis-trifluoro acetic acid salt (0.5 mg, 1%). 1H NMR (CD3OD): 1.30-1.37 (3H, m), 2.15-2.20 (3H, s), 2.40-2.50 (4H, m), 2.80-2.90 (2H, t), 3.50-3.55 (2H, t), 4.00-4.15 (4H, s), 6.50-6.55 (1H, s), 7.55-7.65 (2H, m), 7.75-7.80 (2H, m). ES+438
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:16][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3n(n2)CCC3)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (44.5 g, 0.22 mol) in 600 mL chloroform is added at 0° C. N-bromosuccinimide (117 g, 0.66 mol). The mixture is stirred 17 h at RT. Thereafter, the mixture is diluted with water and extracted with dichloromethane. The combined organic phases are dried and evaporated. The obtained crude material is purified by column chromatography on silica (6 cm×40 cm, eluent dichloromethane). The obtained product is further purified by trituration with a MTBE-hexane mixture and 38.2 g (61%) of the product are obtained as solid.