Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][CH:23]=[N:24][CH:25]=2)[N:20]=1>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([S:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[NH:27][C:26]2[C:21](=[N:22][CH:23]=[N:24][CH:25]=2)[N:20]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncncc2[nH]1
Reactant: CCCCN
Agent: Cl
Product: CCCCNS(=O)(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Prepared analogously to Example 51 from n-butylamine and 8-(2'-methoxy-4'-chlorosulfonyl-phenyl)-purine hydrochloride. After the reaction finished, the aqueous phase wsa extracted with ethyl acetate. The residue remaining after the ethyl acetate phases were evaporated was digested with ethanol, subjected to suction filtration, and washed with water.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:16][CH2:17][C@@H:18]1[O:22][C@H:21]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:20]([OH:32])[CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>N1C=CC=CC=1>[C:1]([O:32][C@@H:20]1[CH2:19][C@H:18]([CH2:17][O:16][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:22][C@@H:21]1[N:23]1[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])(=[O:3])[CH3:2]
Reactant: O=C(OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(=O)[nH]c2=O)O1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 96 %

Procedure:
Acetic anhydride (0.88 mL, 9.28 mmol) was added under argon to a solution of 15 (2.50 g, 7.14 mmol) in dry pyridine (50 mL) and the resulting mixture was stirred at room temperature for 22 h. Then, ethanol was added and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-2%) in methylene chloride] to give pure 16 (2.69 g, 96%) as a white foam; mp=68-70° C. (foam); UV (ethanol): λmax=239 nm (ε=15000) 267 nm (ε=8800), λmin=248 nm (ε=5600); 1H NMR (DMSO-d6): δ ppm 11.9 (br s, 1H, NH), 8.1-7.5 (m, 6H, C6H5CO and H-6), 6.10 (d, 1H, H-1′, J1′-2′=4.3 Hz), 5.4 (m, 1H, H-2′), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 1H, H-3′), 2.03 (m, 1H, H-3″), 1.86 (s, 3H, CH3CO); MS (matrix GT): FAB>0 m/z 785 (2M+H)+, 393 (M+H)+, 263 (S)+, 131 (BH2)+, 105 (C6H5CO)+; 43 (CH3CO)+; FAB<0 m/z 391 (M−H)−, 129 (B)−, 121 (C6H5CO2)−, 59 (CH3CO2)−; [α]D20=−81 (c, 0.95 DMSO).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[C:22]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (92 mg, 80%); 1H NMR δ (CDCl3): 8.47 (d, J=8.51 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.22 Hz, 1H), 2.53 (t, J=7.08 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.11 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); LCMS m/z: 229.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12]CC)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.[Li+].[BH4-].[CH2:18]1COC[CH2:19]1>>[CH2:18]([CH:10]([OH:12])[CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:15])=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCOC(=O)CCc1ccc(Cl)nc1Cl
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)CCc1ccc(Cl)nc1Cl
Temperature: 0 °C

Procedure:
To a solution of ethyl 3-(2,6-dichloropyridin-3-yl)propanoate in THF (12 mL) was added LiBH4 (88 mg, 4.03 mmol). The resultant mixture was stirred at ambient temperature for 2.5 h then was cooled to 0° C. and carefully quenched by addition of saturated NH4Cl(aq) solution. The reaction mixture was diluted with EtOAc and the organic layer washed successively with H2O (1×) and brine (1×). The organic extract was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using a gradient of 0-60% EtOAc/Hexanes as eluent provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 7.58 (1H, d, J=7.92 Hz), 7.25 (1H, d, J=7.80), 3.73 (2H, q, J=5.48 Hz), 2.85 (2H, t, J=7.76 Hz), 1.95˜1.88 (2H, m), 1.42 (1H, m). MS (M+H)+: 205.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]([CH2:25][C:26](O)=[O:27])[CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[CH3:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH2:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[CH:38]=1)[C:26](=[O:27])[CH2:25][N:23]([C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:24])[CH3:30]
Reactant: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Reactant: COc1cc(CC(=O)N(C)CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
A solution of ({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetic acid [18.4 g, Reference Example 1] and 3-(3,4-dimethoxy-benzylamino)-propionic acid ethyl ester [13.4 g, Reference Example 2(a)] in dimethylformamide (400 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate] (19.1 g) and diisopropylethylamine (10.5 ml). After stirring at ambient temperature for 20 hours the reaction mixture was evaporated to dryness. The residue was treated with water (800 ml) followed by hydrochloric acid (175 ml 1 M) and the mixture was extracted twice with ethyl acetate (500 ml). The combined organic extracts were washed with hydrochloric acid (500 ml, 1M), then with water (400 ml), then with saturated aqueous sodium bicarbonate solution (500 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give the title compound as a fawn coloured foam (26.4 g), m.p. 97-105° C. [Elemental analysis:- C,63.4; H,6.7; N,8.7% Calculated for C34H42N4O8.0.5H2O:- C,63.3; H,6.8; N,8.8%].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ncc(F)cc4F)c3)cnc2n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid (0.40 g) and 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (0.391 g) was added tetrahydrofuran (5 ml) and 2 N aqueous sodium carbonate (1.5 ml). Tetrakis(triphenylphosphine)palladium(0) (0.07 g) was added, the mixture was thoroughly degassed with nitrogen, and then stirred at 60° C. for 24 h. On cooling to room temperature, the reaction was partitioned between water and ethyl acetate. The organic extracts were evaporated, and the residue was subjected to chromatography (silica gel, 35% EtOAc/CH2Cl2). The product was crystallised from dichloromethane/isohexane, and the resulting pale yellow solid was collected by filtration and dried in vacuo at 60° C. to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.56 (6H, s), 5.76 (1H, s), 7.58 (1H, dd, J 8.8, 10 Hz), 8.17 (1H, m), 8.29-8.36 (2H, m), 8.48 (1H, s), 8.74 (1H, d, J 2.3 Hz), 9.02 (1H, s); MS (ES+) m/z 386 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].ClC1C=C(C=CC=1)C(OO)=[O:14].[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N+:5]([O-:14])[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: C#Cc1ccc[n+]([O-])c1
Reaction time: 2 h

Procedure:
To a solution of 3-ethynylpyridine in methylene chloride (5 mL/mmol) at room temperature was added m-chloroperoxybenzoic acid (m-CPBA, 70% purity, 1.2 eq) and the resulting mixture was stirred for 2 hours. A further amount of m-CPBA was added (0.25 eq) and stirring was continued for 1 hour. Calcium hydroxide was added (2 eq) and after 15 minutes the mixture was filtered through celite and the filtrate was evaporated. The solid residue was stirred in ether for 3 hours and filtered to afford the 3-ethynylpyridine N-oxide compound as a white solid.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5]CC)=[O:4].[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>C1COCC1.C(OCC)(=O)C.[Zn]>[F:9][C:2]([F:8])([CH:13]([OH:14])[C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccccc1C=O
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(O)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A solution of ethyl bromodifluoroacetate (5.6 g) and 2-methylbenzaldehyde (3 g) in THF (25 mL) is added dropwise to a refluxing suspension of activated zinc dust (2.1 g) in THF (25 mL) and refluxing continued for a further 4 hours. The reaction is allowed to cool to ambient temperature, filtered through hyflo and concentrated in vacuo to give a yellow solid. The solid is taken up in ethyl acetate (50 mL) and washed with brine which leads to the formation of a white precipitate which is filtered off then partitioned between ethyl acetate (50 mL) and 1 N HCl (50 mL). The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo to give (RS)-2,2-difluoro-3-hydroxy-3-(2-methylphenyl)propanoic acid as a yellow solid (2.4 g)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH:24][CH3:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][Cl:5])[CH3:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: ClCCCBr
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCCl)cc1OC
Reaction time: 2 h

Procedure:
29 ml of 1-bromo-3-chloropropane were dissolved in 300 ml of dimethylformamide and 24 g of potassium carbonate were added to the solution. A solution of 18 g N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamine in 50 ml of dimethylformamide were added to the reaction mixture with stirring, dropwise within 2 hours. Then the reaction mixture was stirred for another hour. Then the salts formed were filtered off. The filtrate was concentrated at a maximum bath temperature of 50° C. The residue was dissolved in 200 ml of 0.5 m citric acid solution and the solution was extracted to remove unreacted bromochloropropane with methyl-tert-butyl ether. The aqueous phase was then made slightly alkaline by adding sodium hydrogen carbonate and extracted several times with ethyl acetate. Then the combined ethyl acetate extracts were dried with magnesium sulfate and concentrated. 21 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propyl chloride were obtained as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A solution of 2-(4-fluorophenyl)ethanol(10.0 g, 71.3 mmol) in pyridine (100 mL) was stirred at −5° C. and treated with 4-toluenesulfonyl chloride (14.95 g, 78.4 mmol). After 3 hours, water (10 mL) was added slowly, followed by dilution with ice water and extraction with chloroform. The organic phase was washed with cold 0.5 M aqueous sulfuric acid, then with water, then with saturated aqueous sodium chloride, and was dried over sodium sulfate. Concentration under vacuum provided a pale orange oil containing residual pyridine. Further concentration under vacuum provided an oil (17.74 g) containing about 10% by weight of residual alcohol. A portion was purified by flash chromatography, eluting with 20% ethyl acetate in hexane, to provide a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.70 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.20 (t, J=7 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10].N1CCCCC1>C1CCCCC1>[CH:1](=[CH:14][C:13](=[O:15])[CH2:12][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: CC(=O)CC(=O)C=Cc1ccccc1

Procedure:
Theses compounds may be prepared by various methods but are most conveniently prepared by reacting a benzaldehyde with acetyl acetone in the presence of a suitable catalyst and reaction medium, preferably piperidine and cyclohexane, at reflux temperature under continuous azeotropic water removal. The benzaldehyde reactant will be that which corresponds to the desired substitution of the benzylidene derivative of the final benzylidene pentanedione. The crude product resulting from the foregoing reaction may then be purified by crystallization with methanol to produce the desired benzylidene 2,4-pentanedione. Suitable reactions and reaction conditions are set forth in the examples contained herein.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1Cl.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2nc(S)sc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)sc2c1
Yield: 99.4 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 260 (1.9 g, 99%) was obtained as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: Oc1cccc(Cl)c1
Product: O=Cc1ccccc1Oc1cccc(Cl)c1
Yield: 69 %

Procedure:
Preparation analogous to Example 12a) from 2-fluoro-benzaldehyde and 3-chlorophenol. Yield: 69%; yellow oil after bulb tube distillation (150°-180° C., 0.001 torr); 1H-NMR (CDCl3, 200 MHz): 6.92-7.38 (m, 6H); 7.95 (m, 1H); 10.48 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][C:31]=2[C:46](=O)/[CH:47]=[CH:48]/N(C)C)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[NH:53]([CH:55]1[CH2:58][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:56]1)[NH2:54].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[C:5]([F:28])=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:46]1[N:53]([CH:55]2[CH2:56][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58]2)[N:54]=[CH:48][CH:47]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3C(=O)/C=C/N(C)C)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 70 °C
Yield: 280.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-4-({3-[(2E)-3-(dimethylamino)prop-2-enoyl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 39, 504 mg, 0.648 mmol) in ethanol (10 mL) was slowly added a solution of tert-butyl 3-hydrazinoazetidine-1-carboxylate (Preparation 36, 536 mg, 2.86 mmol) in ethanol (10 mL) and acetic acid (0.23 mL) at 0° C. under nitrogen. The reaction was heated to 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was neutralised to pH 7 with saturated aqueous sodium hydrogen carbonate solution (2 mL) and concentrated in vacuo to afford a yellow oil. The oil was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (1.64 g). The oil was partially purified by silica gel column chromatography (0%-10% methanol in dichloromethane) to afford the title compound as a brown oil (419 mg) of 39% purity via LCMS. The compound was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCOC(=O)[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3S)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/heptane as eluent to provide the title compound as white solid. Yield: 276 mg (69%). 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.21, 3.32 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.73 (m, 2 H), 1.73-1.83 (m, 1 H), 1.91-2.01 (m, 1 H), 2.30 (td, J=11.43, 2.93 Hz, 2 H), 2.44 (t, J=11.13 Hz, 1 H), 2.58-2.69 (m, 1 H), 3.28-3.40 (m, 2 H), 3.65-3.74 (m, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.33, 2.93 Hz, 2 H), 4.13 (q, J=7.23 Hz, 2H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.59, 1.76 Hz, 1 H), 8.19 (d, J=1.76 Hz, 1 H). MS (ESI) (M+H)+=492.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C@@H:7]([NH2:13])[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([NH:13][C@@H:7]([C@@H:8]([OH:12])[CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:14])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](O)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A solution of (2S,3S)-2-amino-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (297 mg, 1.37 mmol) and triethylamine (139 mg, 1.37 mmol) in anhydrous methylene chloride (2 ml) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added N-(benzyloxycarbonyloxy)-succinimide (343 mg, 1.37 mmol). The resulting mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was partitioned between ether and water. The organic layer was washed with cold 1N hydrochloric acid and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo, to provide tert-butyl (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoate (445 mg, 96%) as a yellow oil.