Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O)[CH3:2].[O-]CC.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C1=Cc2ccccc2OCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 4-(2-formylphenoxy)butyric acid ethylester (2.4 g) in diethyl carbonate (24 ml), a solution of 20% sodium ethoxide in ethanol (4.1 g) was added at room temperature, and the solution was stirred at 50° C. for 1 hour. The solution was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid. After ethyl acetate extraction, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) and concentration of the appropriate eluate gave colorless oil of 2,3-dihydro-1-benzoxepin-4-carboxylic acid ethylester (1.3 g, yield 61%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl.O>[CH2:7]([O:6][C:1](=[O:5])[C@@H:2]([O:3][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[CH3:4])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-(−)-ethyl lactate (37.4 g, 0.32 mol) in DCM (200 mL) was added imidazole (25.75 g, 0.38 mol) and TBSCl (50 g, 0.33 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with DCM (2×50 mL), the combined organic extracts washed with brine dried (MgSO4) and concentrated in vacuo to give the title product as a colourless oil (100%). 1H NMR (CDCl3, 400 MHz) 4.21 (1 H, q, J=6.73 Hz), 4.14-4.01 (2H, m), 1.29 (3H, d, J=6.79 Hz), 1.18 (3H, t, J=7.09 Hz), 0.80 (9H, s), −0.01 (6H, s).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:40][CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:42]([OH:44])=[O:43].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][CH:24]=1)=[O:4].[CH3:40][CH:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:42]([O-:44])=[O:43]
Reactant: CCCCCCC(C)C(=O)O
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCCCCCC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(C)C(=O)[O-]
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 49 %

Procedure:
Next, 2.02 g (11.4 mmol) of the above (+)-2-methyl octanoyl chloride and 3 ml of nitrobenzene were cooled to 0° C. in a flask and added with 3.06 g (22.9 mmol) of anhydrous aluminum chloride with stirring, which were stirred at room temperature for 30 minutes. Thereafter, 2.89 g (7 mmol) of (+)-biphenyl-2-methyloctanoate biphenyl dissolved in 3 ml of nitrobenzene was added thereto, which was reacted by stirring at room temperature for 140 hours. After the completion of the reaction, 2 normal hydrochloric acid and ice were added and extracted with chloroform. The extract was washed with water, dried on anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified through a column chromatography of silica gel to obtain 1.55 g (yield: 49%) of an oily (+)-4-(2-methyloctanoyl) biphenyl-2-methyloctanoate.
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:8][C:7]([N+:20]([O-])=O)=[C:6]([F:23])[CH:5]=1>[C].[Pd].C1(C)C=CC=CC=1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])=[CH:8][C:7]([NH2:20])=[C:6]([F:23])[CH:5]=1
Reactant: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Hydrogen gas (1.3 liters) was introduced into a mixture of the compound (III) (6.4 g), 5% palladium-carbon (0.32 g) and toluene (64 g) at room temperature while stirring in 1 hour. After removal of the catalyst from the reaction mixture, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline (3.6 g).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].C[O:7][C:8]([C:10]1([CH3:13])[CH2:12][CH2:11]1)=O.CO>C1COCC1.O>[CH3:13][C:10]1([C:8](=[O:7])[CH2:2][C:1]#[N:3])[CH2:12][CH2:11]1
Reactant: CC#N
Reactant: COC(=O)C1(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)CC#N)CC1
Reaction time: 0.17 h

Procedure:
Add acetonitrile (87 mL, 1.6 mol) to a suspension of sodium hydride (66 g, 1.6 mol) in THF (700 mL) at room temperature and stir 10 minutes. Then add 1-methyl-cyclopropanecarboxylic acid methyl ester (90.0 g, 0.78 mol) and reflux the white slurry for 3 hours. Cool the mixture, then add methanol (200 mL) and pour the mixture over water (500 mL). Separate the phases and reduce the pH of the aqueous phase with 1.0N HCl until pH 3-4. Extract the aqueous phase with diethyl ether (2×350 mL), combine the organic layers and wash with aqueous sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile as yellow oil. 1H NMR (CDCl3): 3.59 (s, 2H), 1.37 (s, 3H), 1.30 (q, J=4 Hz, 2H), 0.86 (q, J=4 Hz, 2H).
Reaction SMILES: O.[NH3:2].[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl>[F:3][CH:4]([F:16])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:2])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Reactant: N
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction had subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yielded 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[C:21]([C:25]#[N:26])[C:20](=[O:27])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)=O.C(O)(=O)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C([BH3-])#N>CO.ClCCl>[OH:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][NH:42][CH2:41][CH2:40][C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:43])[F:44])=[CH:39][CH:38]=4)=[CH:10][CH:11]=3)=[CH:16][S:17][C:18]=2[NH:19][C:20](=[O:27])[C:21]=1[C:25]#[N:26]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4C=O)cc3)csc2[nH]c1=O
Reactant: NCCc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4CNCCc4ccc(C(F)(F)F)cc4)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2′-formyl-1,1′-biphenyl-4-yl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.025 g, 0.067 mmol) in MeOH (1 mL) and dichloromethane (1 mL, with 2% v/v acetic acid) was added 2-(4-trifluoromethyl phenyl)ethyl amine (0.025 g, 0.13 mmol) and shaken at room temperature for 10 min. MP-cyanoborohydride (0.09 g, 0.2 mmol) was then added to the reaction mixture and shaken at room temperature for 24 h. The reaction was filtered, concentrated and purified by RP-HPLC to give the title compound. MS (ESI) m/e 546 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 11.11 (br s, 1H), 8.97 (br s, 2H), 7.66–7.70 (m, 3H), 7.58 (d, 2H), 7.50–7.54 (m, 2H), 7.46 (d, 2H), 7.37–7.40 (m, 1H), 7.30 (d, 2H), 6.76 (s, 1H), 4.24 (s, 2H), 3.17 (br s, 2H), 2.95 (t, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([CH:12]1[CH2:14][CH:13]1[CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]#[N:26])=[O:11]>O1CCCC1>[CH:10]([CH:12]1[CH2:14][CH:13]1[CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]#[N:26])=[O:11]
Reactant: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccc(CC3CC3C=O)cc12
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A suspension of lithium aluminum hydride (0.020 g, 0.53 mmol) in anhydrous tetrahydrofuran (5 ml) at −45° C. was treated with a solution 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide in 5 ml tetrahydrofuran. After 30 min at −45° C. an additional 0.53 mmol lithium aluminum hydride was added. The reaction was quenched with water followed by 1 N sodium hydroxide after another 30 min. The aluminum salts were removed by filtration and the filtrate was concentrated in vacuo to afford 5-(2-Formyl-cyclopropylmethyl)-1H-indole-3-carbonitrile (0.034 g, 57%) as a light yellow film. 1H-NMR (400 MHz, CDCl3) 9.07 (1H, d, J=5.16 Hz), 7.71 (H, s), 7.58 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.22 (1H, m), 6.98 (1H, s), 2.80 (2H, m), 1.86 (2H), 1.40 (1H, m), 1.11 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1I
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
29.30 g (100 mmol) of 2-iodo-5-nitrobenzoic acid are suspended in a mixture of 200 ml of DCM and 1 ml of DMF as solvent. 19.04 g (150 mmol, 1.5 equivalents) of oxalyl chloride are slowly added dropwise at room temperature. The mixture is then stirred at room temperature for two hours and at 30° C. for 30 min. This is followed by evaporation in a rotary evaporator, and the resulting crude product is employed in the following stage.
Reaction SMILES: CC[N:3]([CH:7](C)C)C(C)C.[ClH:10].[NH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[C:17]([CH3:33])[CH:16]=1)[OH:14].C[N:35](C=O)C>CCOCC>[ClH:10].[CH3:21][C:19]1[CH:20]=[C:15]([CH:13]([OH:14])[CH2:12][NH+:11]=[C:7]([NH2:3])[NH2:35])[CH:16]=[C:17]([CH3:33])[C:18]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1cc(C(O)CN)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(C(O)C[NH+]=C(N)N)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reaction time: 14 h
Yield: 68 %

Procedure:
1H-1-Carboxamidine hydrochloride (271 mg,1.85 mmol), and DIPEA (0.5 mL, 3.87 mmol) were added to a vigorously stirring solution of amine 13 (450 mg, 1.42 mmol) in DMF (1.5 ml). The reaction was stirred for 14 hrs then worked up by diluting with Et2O. The viscous oil was repeatedly washed with Et2O, then recrystillized from CH2Cl/MeOH2 giving pure 14 (382 mg, 68%) as a off-white solid: 1H NMR (270 MHz, DMSO-d6) δ8.16(d, J=8.2 Hz, 1H, ArNO2) 8.03(d, J=8.2 Hz ArNO2), 1H, 7.87(t, J=8.2 Hz, 1H ArNO2), 7.66(t, J=8.2 Hz, 1H, ArNO2), 7.45(t, J=5.2 Hz, 1H, RCH2NH), 7.11(s, 2H, Ar—H), 5.80(d, J=4.1 Hz, LH RO—H), 5.14(s, 2H, ArOCH2Ar(NO2)), 4.60 (m, 1H, ArCH(OH)), 3.31 (m, 2H, CH2NH), 2.21(s, 6H, ArCH3) 13C NMR (67.5 MHz, MeOH-d4)δ159.3, 156.3, 148.2, 138.7, 135.1, 135.1, 132.1, 129.9, 129.6, 127.7, 125.8, 73.0, 71.3, 50.0, 16.8;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:16]=[C:17]([Cl:28])[CH:18]=[C:19]3[C:23]=1[N:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:21]=[CH:20]3)[C:9](=[O:29])[CH2:8]2)=[O:4].[OH-].[Li+].O.CO>O1CCCC1>[Cl:28][C:17]1[CH:18]=[C:19]2[C:23](=[C:15]([CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=4)[CH2:8][C:9]3=[O:29])[CH:16]=1)[N:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:21]=[CH:20]2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1ncc2cc(Cl)cc(CN3C(=O)Cc4cc(C(=O)O)ccc43)c21
Temperature: 100 °C

Procedure:
A mixture of compound 65 (0.021 g, 0.05 mmol), lithium hydroxide (0.09 g, 0.208 mmol) in a mixture of tetrahydrofuran (1.5 mL), water (0.5 mL) and methanol (0.5 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)/[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])/[C:7](/[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
A suspension of (E)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 3, 0.44 g, 1.17 mmol) and N-bromosuccinimide (0.20 g, 1.17 mmol) in carbon tetrachloride (4 mL) at 25° C. was treated with benzoyl peroxide (14.17 mg, 0.058 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The organic phase was then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylamide (115 mg, 22%) as white solid: mp 202-205° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][S:50]([CH3:49])(=[O:52])=[O:51])=[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOS(C)(=O)=O)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred solution of 100 mg (0.172 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-tert-butoxy-4-(2-hydroxyethoxy)benzyl]-L-glutamate, 25.6 mg (0.253 mmol) triethylamine in ca. 1 ml dichloromethane was added 25.5 mg (0.222 mmol) methane sulphonic acid chloride at 0° C. The reaction mixture was stirred at room temperature for 4 hours. Further 25.6 mg (0.253 mmol) triethylamine and 25.5 mg (0.222 mmol) methane sulphonic acid chloride were added. The reaction mixture is stirred for another 4 hours. The reaction mixture is diluted with dichloro methane. The organic phase washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate solution, dried with sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, hexane/ethylacetate gradient: 5:1→1:99). The desired product was obtained in 79.6% yield (99 mg, 0.14 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][C@H:5]([NH:18][C:19](=[O:24])OC(C)=C)[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9].[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([C@@H:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[O:35][CH2:36][CH2:37][NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:31]=[CH:32][CH:33]=1>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:19](=[O:24])[NH:18][C@@H:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:25])[CH3:26])[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])=[O:9])[CH2:44]2)[O:35][CH2:36][CH2:37][NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:31]=[CH:32][CH:33]=1
Reactant: C=C(C)OC(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: C1CCOC1
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
The resulting (S)-prop-1-en-2-yl 5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamate was dissolved in THF (5 mL) and methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (40 mg, 0.1227 mmol, 1.1 equiv) added and the mixture heated to 50° C. overnight. After completion of the reaction, the solution was washed with 0.5 M HCl, brine, then dried over Na2SO4, filtered, and evaporated to afford crude methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate which was taken directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH2:11]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
2-Chloroadenine (1.53 g, 9.0 mmol), 3-bromobenzyl bromide (2.48 g, 9.92 mmol), potassium carbonate (1.38 g, 10 mmol) were combined in DMF (10 mL) and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried with Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether/ethyl acetate 4:1 and filtered giving 9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (Compound 53) (2.3 g) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[ClH:1].[ClH:1].[NH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][CH2:16][CH2:17][CH3:18])[N:3]=2)[CH2:22][CH2:21]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCCNc1nc(Cl)nc2c1ncn2C(C)CC
Product: CCCNc1nc(NC2CCC(N)CC2)nc2c1ncn2C(C)CC
Product: Cl
Yield: 87.5 %

Procedure:
The operation is carried out as in Stage 2 of Example 44 starting from 117 mg of the product obtained in Stage 1 above and 500 mg of trans-1,4-diaminocyclohexane. In this way 80 mg of expected product is obtained in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Yield: 14.7 %

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)-2-pyridinol (0.59 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (146 mg, 15% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH2:33][CH2:34]Cl)[CH2:30][CH2:31]Cl)[CH:23]=1>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:34][CH2:33][N:29]([CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH2:30][CH2:31]2)(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: ClCCN(CCCl)Cc1cccnc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3cccnc3)CC2)cc1
Yield: 5 %

Procedure:
Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(3-pyridinylmethyl)-4-piperidine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 16.9 mmol) and 3-pyridyl methyl [bis(2-chloroethyl)]amine hydrochloride (4.18 g, 18.6 mmol); 370 mg brown oil. Yield 5%; MS: 457.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])[S:5][CH:6]=1
Reactant: Cc1csc(C=O)c1
Reactant: C[N+](=O)[O-]
Product: Cc1csc(C=C[N+](=O)[O-])c1
Yield: 78 %

Procedure:
In close analogy to the procedure described above, 4-Methyl-thiophene-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][CH:29]([CH2:28][C:27]3[CH:34]=[CH:35][C:24]([C:23]([F:22])([F:36])[F:37])=[CH:25][CH:26]=3)[CH2:30]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC(F)(F)c1ccc(CC2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)benzyl]pyrrolidine oxalate (19.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.5 mg). Calcd for C23H21F3N2O2: 414.1555, found 414.1562.