Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=1>C(O)CCC.C(OCC)(=O)C.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>[NH2:15][C:10]1[C:9]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[C:20]([F:31])[CH:19]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cccnc2N)cc1F
Temperature: 130 °C
Yield: 42.9 %

Procedure:
A degassed mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.4 g, 10.91 mmol), tert-butyl 4-bromo-2-fluorobenzoate (3.30 g, 12.00 mmol), Pd(PPh3)4 (0.63 mg, 0.0.545 mmol), 2.0 M Na2CO3aqueous solution (10.91 mL) in n-butanol (26 mL) was microwave heated to 130° C. for 10 min. The reaction was diluted with ethyl acetate (30 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (1.35 g, 43% yield). LCMS (m/z): 289.4 (MH+), 0.67 min.
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: CCCCCCCC([O-])=S
Agent: [Na+]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 90 °C
Reaction time: 5 h

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 40° C. and 11 grams of 34.5% HEGCl solution were added. Also, about 296 grams of 3-chloro-1-propyltriethoxysilane were added batch-wise to the reaction mixture. The product was heated further to 90° C. and stirred for 5 hours. At this point, agitation was discontinued and the two-phase system was allowed to separate. The bottom aqueous phase was removed and the top crude product was recovered. The crude layer was purified by stripping the material at 135-145° C. and 5-10 mm Hg. The process yielded about 251 grams of pale yellow and clear product with a typical GC purity of 92-94%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11]
Reactant: OCc1cc2ccccc2[nH]1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of crude (1H-indol-2-yl)methanol 17 (5.37 g, 36.53 mmol) in anhydrous CH2Cl2 (50 mL) at cold-bath temperature (˜10° C.) was added portionwise pyridinium chlorochromate (PCC) (9.44 g, 40.18 mmol). Reaction was stirred at ambient temperature for 2 hours. Reaction was diluted with CH2Cl2 and filtered through a pad of celite and washed with CH2Cl2. After evaporation of solvent, crude product was silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 1H-indole-2-carbaldehyde 18 (1.52 g, 29% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.[BH4-].[Na+].[ClH:30]>CO.O>[ClH:30].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:6][CH2:5][CH2:4][C:3]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:2]=2[CH3:1])=[CH:23][CH:24]=1
Reactant: Cc1[nH]c2ccccc2c1CCN
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)/C=C/c1ccc(CNCCc2c(C)[nH]c3ccccc23)cc1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. The pH of the reaction mixture is adjusted to 8.5 by slow addition of an aqueous hydrochloric acid solution (ca. 37.3 g of a 21.6 m/m % solution in water) at 20-25° C., until the pH of the solution reaches 8.5. The addition needs ca. 30 minutes in this case. After completion of the addition, the reaction mixture is stirred for one hour at 20-25° C. to allow crystallization. At this stage, the solution can be seeded with crystals of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt to accelerate the crystallization. A suspension is obtained. A second portion of aqueous hydrochloric acid (36 g of a 21.6% m/m HCl solution in water) is added to the suspension during 30 minutes at 20-25° C., followed by the addition of a third portion of aqueous hydrochloric acid (167.7 g of a 21.6% m/m HCl solution in water) during 30 minutes at 20-25° C. The suspension is heated to 65° C. Then, the suspension is cooled to −15° C. and stirred for 30 minutes at −10 to −15° C. to complete the crystallization. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[Cl-].[NH4+]>ClCCl>[CH3:32][S:33]([O:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:14][CH2:13]4)[N:8]=[N:9][C:10]=3[C:2]=2[Cl:1])=[CH:20][CH:19]=1)(=[O:35])=[O:34]
Reactant: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]phenyl}methanol (0.71, 2.3 mmol) was dissolved in dichloromethane (7 mL) and treated with N,N-diisopropylethylamine (0.79 mL, 4.5 mmol). The mixture was cooled to 0° C. and treated with methanesulfonyl chloride (0.21 mL, 2.7 mmol) and after 1 hour, the mixture was treated with additional methanesulfonyl chloride (50 uL). After stirring for an additional 30 minutes, the mixture was poured into ammonium chloride (50 mL, aqueous saturated) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
10 g of (R)-1-(phenylmethyl)-3-pyrrolidinol were dissolved in 160 ml of anhydrous toluene. The solution was stirred under a stream of nitrogen, cooled in an ice/ethanol bath and 8.7 ml of triethylamine were added. At a temperature of −5° C. 4,9 ml of a solution of methanesulfonylchloride in 110 ml of anhydrous toluene were added dropwise over 1,5 hours and the reaction mixture was stirred for 1 hour at 0° C. The solid was filtered and washed with ethyl acetate. The filtrate was washed with water, dried and evaporated in vacuo to give 13,9 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine as an almost colourless oil. M.S. (C.I.) (M/Z): 256 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24](O)=[O:25])[S:22][CH:23]=2)=[N:10]1.CC[N:29]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:20]=[C:21]([C:24]([NH2:29])=[O:25])[S:22][CH:23]=2)=[N:10]1
Reactant: O=C(O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (30.0 mg) obtained in Example 37 in DMA (2 mL) were added EDCI hydrochloride (18.5 mg) and HOBt ammonium salt (14.7 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate to ethyl acetate) to give the title compound (21.2 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g of N-chlorosuccinimide was added thereto. The resulting mixture was stirred at room temperature for five hours. 2200 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hour. The white precipitate was collected by filtration, and the white solid was washed with water and, with t-butyl methyl ether. Thus, 117 g of the title compound was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1ncc(F)cn1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Temperature: 50 °C
Yield: 25.4 %

Procedure:
A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, and dried over Na2SO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[CH:17]=1.[F:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][C:24]2[CH:28]=[CH:27][NH:26][C:25]=2[CH2:29]O)=[CH:21][CH:20]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH:10]([CH:14]([CH3:15])[CH3:16])[C:11]([O:13][CH2:29][C:25]3[NH:26][CH:27]=[CH:28][C:24]=3[CH2:23][C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:32][CH:31]=3)=[O:12])=[CH:7][C:6]=2[CH:17]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1[nH]ccc1Cc1ccc(F)cc1
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccc(F)cc1)c1cc2cc(Cl)ccc2s1

Procedure:
The acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid is reacted with 3-(4-fluorobenzyl)-pyrrolylmethyl alcohol in ether as in Example 20 to give 3-(4-fluorobenzyl)-pyrrolylmethyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH:31]([CH3:33])[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-(4-Benzyloxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (40a, 3.0 g, 7.84 mmol) was dissolved in CH2Cl2 (50 mL) and treated with isovaleraldehyde (0.84 mL, 7.84 mmol). The reaction was stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3, and stirred overnight. The reaction was diluted with EtOAc (400 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 6% MeOH/CH2Cl2 to give 3.3 g (93%) of the desired product.
Reaction SMILES: NCCC[OH:5].C1C(=O)N(OC(CC[S:18][S:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)C(=O)C1.OP(O)(O)=O>C(Cl)Cl.CC(O)C>[N:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:19][S:18][OH:5]
Reactant: NCCCO
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Agent: O=P(O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: OSSc1ccccn1
Reaction time: 1.25 h

Procedure:
3-Aminopropanol (0.76 ml, 10 mmol) was dissolved in a mixture of CH2Cl2 (5 ml) and 2-propanol (3 ml) and cooled in an ice bath. A solution of SPDP (1.23 g, 3.9 mmol) in CH2Cl2 (2 ml) was added dropwise in ca. 1 min. The mixture was stirred in the cooling bath for 1.25 h, and a 13% aqueous solution of NaH2PO4 (15 ml) and 85% H3PO4 (0.5 ml) were added. The products were extracted with ethyl acetate (2×30 ml), the organic layers were washed with 13% NaH2PO4, 15% KHCO3 and dried in vacuo. The crude compound 3 (1.14 g) was purified by flash-chromatography on silica-gel, elution with mixtures of CHCl3 and 2-propanol (100:0 to 100:7 by volume). Yield of pure compound 3 was 1.01 g (94%). TLC of compound 3 (CHCl3-2-propanol, 9:1): one spot, Rf ca. 0.3. 1H NMR of compound 3 (CDCl3), δ, ppm: 1.68 (quint., 6 Hz, 2H), 2.60 (t, 7 Hz, 2H), 3.05 (t, 7 Hz, 2H), 3.4 (br., 1H), 3.42 (q, 6 Hz, 2H), 3.62 (br., 2H), 6.99 (br., 1H), 7.10 (m, 1H), 7.58-7.65 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:31](I)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:31]([N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH:32]([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with isobutyl iodide and cesium carbonate in N,N-dimethylacetamide to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a colorless solid. MS: 548.8 ([M+NH4]+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:26](=[O:28])[CH3:27])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(=O)N[C@@H](CC(C)C)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Yield: 83 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (106 mg) with acetic anhydride (40 uL) provided 89 mg (83%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][CH2:20][Cl:21])=[O:17].C(N(CC)CC)C>ClCCl>[Cl:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[NH:8][C:7]1[CH:9]=[C:10]([I:14])[C:11]([O:12][CH3:13])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C(Cl)OCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(I)cc(NC(=O)OCCCl)cc1C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (0.305 g, 1.0 mmol) in dichloromethane (5.00 mL) was added 2-chloroethyl chloroformate (0.143 g, 1.000 mmol) and triethylamine (0.279 mL, 2.0 mmol) to give a solution. The mixture was stirred for 3 hours and concentrated to give the title compound that was used without purification.
Reaction SMILES: C[O-].[Na+].Cl.[Cl:5][CH:6]=[CH:7][CH2:8][O:9][NH2:10].[C:11]([CH:16]1[C:21](=[O:22])[CH2:20][CH:19]([CH2:23][CH:24]([S:26][CH2:27][CH3:28])[CH3:25])[CH2:18][C:17]1=[O:29])(=O)[CH2:12][CH2:13][CH3:14]>CO>[Cl:5][CH:6]=[CH:7][CH2:8][O:9][N:10]=[C:11]([C@H:16]1[C:21](=[O:22])[CH2:20][C@H:19]([CH2:23][CH:24]([S:26][CH2:27][CH3:28])[CH3:25])[CH2:18][C:17]1=[O:29])[CH2:12][CH2:13][CH3:14]
Reactant: NOCC=CCl
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)CC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)SCC)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.38 g of sodium methoxide, 10 ml of methanol, and 1.0 g of 3-chloroallyloxyamine hydrochloride (H2NOCH2CH=CHCl) were admixed together and then stirred for 10 minutes at room temperature. 2 g of 2-butyryl-5-(2-ethylthiopropyl)cyclohexane-1,3-dione was added and the resulting mixture stirred for about two days at room temperature. The mixture was then concentrated by evaporation and the concentrate mixed with 60 ml of diethyl ether and 40 ml of water. The ether layer was extracted with 40 ml of aqueous 2 wt. % sodium hydroxide solution, washed with 20 ml of water, dried over anhydrous magnesium sulfate and evaporated affording a minor amount of the title compound as the trans isomer.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH2:16][CH2:17][CH3:18])=O.COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH2:16][CH2:17][CH3:18])/[C:35](=[O:36])[N:37]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCCCc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-butyl-quinoline-3-carbonitrile (example 49c), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butyl-quinoline-3-carbonitrile. LC-MS m/e 337 (MH+).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].CI>C1COCC1>[CH3:9][C:10]([CH3:2])([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of LDA (2.9 mL of 2 M) in THF (30 mL) at −78° C. add ethyl 2-methyl-3-[4-(trifluoromethyl)phenyl]propanoate (1 g, 3.85 mmol). Stir for 10 min, then add methyl iodide (1.48 g, 10.4 mmol) and stir for an additional 15 min Quench the reaction with 10 mL of 1 N HCl and allow to warm to ambient temperature. Extract with EtOAc (50 mL). Wash extract with brine, dry over sodium sulfate, filter, and concentrate. Purify the residue by flash chromatography (5% EtOAc in petroleum ether) to give the title compound (475 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 89.5 %

Procedure:
A suspension of NaH (60% in mineral oil, 3.69 g, 92.2 mmol) in dry DMF (70 ml) was cooled to 0° C. A solution of 4-hydroxybenzaldehyde (10.0 g, 82.0 mmol) in dry DMF (35 ml) was added dropwise. The mixture was stirred at 0° C. for 40 minutes. tert-Butyl bromoacetate (12.1 ml, 82.5 mmol) was added and the mixture was stirred at room temperature for 17 h. The mixture was concentrated under reduced pressure. Diethyl ether was added and the mixture was washed with 10% NH4Cl, water and brine. The organic phase was dried (MgSO4), concentrated under reduced pressure and purified by flash-chromatography (10%-20% EtOAc in hexane). This gave tert-butyl (4-formylphenoxy)acetate (17.4 g, 73.4 mmol, 90% yield) as an colourless oil. This intermediate was dissolved in dry toluene (120 ml) and 4-chloroaniline (9.37 g, 73.4 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 20 h, cooled and concentrated under reduced pressure. Hexane was added and the formed precipitate was filtered, washed twice with cold hexane and dried. This afforded 20.0 g (79%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 1.5 (s, 9H), 4.6 (s, 2H), 7.0 (d, 2H), 7.2 (d, 2H), 7.4 (d, 2H), 7.8 (d, 2H), 8.4 (s, 1H). MS (CI) M/z: 368.0 (M++Na, 100), 369.0 (20), 370.0 (30), 371.0 (10).