Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O[NH:9][C:10](=[NH:19])[C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:9]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:19]=2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)O1
Reactant: CSc1ccc(C(=N)NO)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(-c2noc(CCC(=O)O)n2)cc1
Temperature: 120 °C

Procedure:
Succinic anhydride (112 mg, 1.12 mmol) and N-hydroxy-4-methylsulfanyl-benzamidine (203 mg, 1.12 mmol) were dissolved in 2.0 mL of DMF and heated at 120° C. overnight. The cooled solution was evaporated and dried to give 3-[3-(4-methylsulfanyl-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid which was used without further purification.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:23]#[N:24]>O.C(O)C.CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]2[NH:28][C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[N:19]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reaction time: 8 h
Yield: 70 %

Procedure:
Sodium metabisulfite (1.66 g, 8.73 mmol) in 10 ml of water was added to 4-fluoro-benzaldehyde (1.86 g, 15 mmol) in 50 ml of ethanol under argon. The mixture was stored at 0-5° C. overnight and the solid filtered, washed with ethanol and dried. The solid and 3,4-diamino-benzonitrile (2.0 g, 15 mmol) were heated in 7 ml of DMF at 130° C. for 4 hours. After cooling, the mixture was poured into water, the solid filtered and purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 2.49 g (70%) of the desired product. MS (mass spectrum): m/e=238.02 (M+H+).
Reaction SMILES: [N+:1]1([O-:10])[O:5][N:4]=[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=12.[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C>[C:11]([C:19]1[C:20]([CH3:21])=[N+:4]([O-:5])[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N+:1]=1[O-:10])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-][n+]1onc2ccccc21
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred suspension of 80 g. (0.59 mol.) of benzofurazan 1-oxide and 95 g. (0.59 mol.) of benzoylacetone in 1,000 ml. of ethanol was added 1.6 g. (0.04 mol.) of finely divided sodium hydroxide. The mixture became clear after about 30 minutes. Stirring was continued for a further 16 hours, and then the solid which had precipitated was collected by filtration. It was washed with ethanol, and dried to afford 153 g. (92% yield) of 2-benzoyl-3-methylquinoxaline 1,4-dioxide, m.p. 229°-231° C.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](Cl)=[O:18])[CH:11]=[CH:10]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:20][CH:21]([C:29]([F:32])([F:31])[F:30])[C:22]([F:28])([F:27])[S:23]([O-:26])(=[O:25])=[O:24].[C:33]1([S+:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:28][C:22]([F:27])([S:23]([O-:26])(=[O:24])=[O:25])[CH:21]([O:20][C:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]=2)[CH:13]=1)=[O:18])[C:29]([F:30])([F:32])[F:31].[C:46]1([S+:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: C=C(C)C(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc2cc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.0 g (11 mmol) of the resulting 6-methacryloyloxynaphthalene-2-carboxylic acid chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(6-methacryloyloxy-naphthalene-2-carbonyloxy)-propane-1-sulfonate was obtained as colorless solid (6.5 g, yield 89%). The compound has the following structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:15]#[N:16].[C-]#N.[K+].O>CN(C)C=O>[C:15]([C:2]1[CH:3]=[C:4]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)#[N:16]
Reactant: CN(c1cccc(Br)c1)S(C)(=O)=O
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc(C#N)c1)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
169 b) A suspension of N-(3-bromo-phenyl)-N-methyl-methanesulfonamide (1.0 g, 3.8 mmol) and copper cyanide (0.78 g, 8.7 mmol) in N,N-dimethylformamide (5 mL) was heated at 150° C. for 18 hours. The mixture was cooled to room temperature. A solution of potassium cyanide (5 g) and water (50 mL) was added to the vigorously stirred dark mixture and was stirred for 1 hour. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×30 mL) then saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to a yellow oil (1.0 g). The residue was purified via flash chromatography (silica gel column and 5%→50% ethyl acetate:hexane). N-(3-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a tan solid (0.184 g, 23%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69-7.64 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.54-7.49 (m, 1H), 3.36 (s, 3H), 2.88 (s, 3H). MS=211 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].Cl>CN(C)C=O>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Yield: 98.2 %

Procedure:
To a solution of (2S,4R)-1-benzyl-2-methoxycarbonyl-4-hydroxypyrrolidine (661 g) in N,N-dimethylformamide (3.3 l) were added successively imidazole (383 g) and t-butyldimethylsilyl chloride (508 g) at 10°~20° C. with stirring and the solution was stirred at ambient temperature for 3 hours. The mixture was poured into 0.1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, water and 10% sodium chloride, dried with anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-benzyl -2-methoxycarbonyl-4-(t-butyldimethylsilyloxy)pyrrolidine (964 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.CN(C)CCN(C)C.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:23][N:22]([CH3:24])[CH:21]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1cccc(Cl)c1
Agent: CN(C)CCN(C)C
Product: CN(C)C=C(C#N)c1cccc(Cl)c1
Yield: 100 %

Procedure:
A mixture of 3-chlorophenylacetonitrile (5 grams, 33.0 mmol), N,N,N′,N′-tetramethyl-ethane-1,2-diamine (0.767 grams, 6.60 mmol), and dimethyl formamide dimethyl acetal (20 mL) were heated at reflux for 4 h. On cooling, the reaction was partitioned between EtOAc and saturated aqueous NH4Cl solution. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with brine and concentrated in vacuo. The crude product was purified by chromatography (ethyl acetate/hexane, 0-10%) on silica gel (24 grams) to give pure product (6.8 grams, 33.0 mmol, 100% yield.).
Reaction SMILES: B(F)(F)F.C[C:6]1(C)[CH2:11][CH2:10][CH2:9][C:8](C)(C)[NH:7]1.C([Li])CCC.[Li][N:21]1[C:26](C)(C)CCC[C:22]1(C)C.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34].Cl>C1COCC1.CO.O>[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([C:6]1[CH:11]=[C:10]([N:21]([CH3:26])[CH3:22])[CH:9]=[CH:8][N:7]=1)=[O:34]
Reactant: [Li]N1C(C)(C)CCCC1(C)C
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C)c1ccnc(C(=O)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of4-dimethylaminopyridine (DMAP) (6.892 g, 56.4 mmol) in dry THF (200 mL) at 0° C. was added BF3 etherate (7.3 mL, 59.4 mmol) dropwise via a syringe. A slightly cloudy colorless solution was obtained. It was stirred at 0° C. for 0.5 hr. To a solution of 2,2,6,6-tetramethyl piperidine (10.0 mL, 59.2 mmol) in dry THF (100 mL) at -78° C. in a second flask was added n-butyllithium (58.5 mL, 1.06 M in hexane, 62.0 mmol) via syringe. It was then warmed to room temperature in about 20 min. The DMAP-BF3 salt solution was cooled to -78° C. upon which a white suspension was formed. To this suspension was added lithium tetramethylpiperidide solution (prepared in the second flask) via cannula in 0.5 hr with vigorous stirring. A clear dark tan solution was observed after the addition was complete and it was stirred for 30 min at -78° C. This solution at -78° C. was then transferred dropwise to a solution of trimethylacetyl chloride (13.9 mL, 112.6 mmol) in dry THF (50 mL) at -78° C. via cannula in 1 hr. The reaction turned orange during the addition. It was allowed to warm slowly to room temperature in 5 hr. The final solution was brown. Water (50 mL), methanol (50 mL) and 6 N HCl (30 mL) were added sequentially to the reaction mixture. The solution was stirred at 35°-40° C. overnight. The volatile solvents were removed by aspirator. The residue was made basic with 6 N NaOH (ca. pH>11) and extracted with diethyl ether (3×150 mL) and THF (150 mL). Combined organic solution was dried with MgSO4. After removal of solvent (aspirator), the residue was purified by flash chromatography on silica gel (20×5 cm), 1:3 EtOAc/hexane eluent to give 7.10 g of 2-Trimethylacetyl-4-dimethylaminopyridine (1) (61% ). Characterization of the product (1) was as follows:
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:21]([P:1]([OH:2])[OH:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: O=[PH2]O
Reactant: C=CCCCCCCCCCCCCCCCC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCP(O)O
Yield: 98.6 %

Procedure:
Example 7 is repeated with 66 g (0.5 mol) of phosphinic acid, 140.0 g (0.5 mol) of octadecene, 23 mg of tris(dibenzylideneacetone)dipalladium and 32 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 500 g of tetrahydrofuran followed by working up to obtain 157 g (85% of theory) of octadecylphosphonous acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](I)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:13][N:14](C)C=O>C(OCC)(=O)C>[NH2:9][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1I
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4═CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:33]([NH:32][C:24]2[C:23]([CH:20]([CH3:21])[CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:29]([CH3:31])[CH3:30])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1ccc(NCc2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(Cl)c(Cl)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 28.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(3,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.5 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N-(3,4-dichlorophenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (1.2 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH2:21][C:22]([OH:24])=O)[CH2:17][C:18]([OH:20])=O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]([CH2:37][CH2:38][NH2:39])[C@@H:27]1[O:35][C@@H:34]([CH3:36])[C@@H:32]([OH:33])[C@@H:30]([OH:31])[C@@H:28]1[OH:29].[CH2:40](Cl)[CH2:41]Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C@@H:27]1([O:26][CH2:37][CH2:38][NH:39][C:22](=[O:24])[CH2:21][N:16]([CH2:17][C:18](=[O:20])[NH:39][CH2:38][CH2:37][O:26][C@@H:27]2[O:35][C@@H:40]([CH3:41])[C@@H:32]([OH:33])[C@@H:30]([OH:31])[C@@H:28]2[OH:29])[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:25])[O:35][C@@H:34]([CH3:36])[C@@H:32]([OH:33])[C@@H:30]([OH:31])[C@@H:28]1[OH:29]
Reactant: O=C(O)CN(CC(=O)O)C(=O)CCCCC(=O)OCc1ccccc1
Reactant: ClCCCl
Reactant: C[C@@H]1O[C@@H](OCCN)[C@@H](O)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2,2′-{[6-(benzyloxy)-6-oxohexanoyl]imino}diacetic acid (800 mg, 2.277 mmol) in DMF (12 mL) at room temperature was added 2-aminoethyl α-L-fucopyranoside (1.132 g, 5.46 mmol), DMAP (834 mg, 6.83 mmol) and EDC (1.528 g, 7.97 mmol). After stirring at rt for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (120 g), eluting with 0-40% AcCN in water, to give the title compound. LC-MS Method A: m/e=730.26 [M+1]; Rt=1.42 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[N:13][C:14]=1[Cl:15]>>[Br:8][C:9]1[CH:10]=[C:11]([S:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:18])=[O:17])[CH:12]=[N:13][C:14]=1[Cl:15]
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Product: CN1CCN(S(=O)(=O)c2cnc(Cl)c(Br)c2)CC1
Yield: 91 %

Procedure:
The title compound was prepared as described for Example 3 using 1-methylpiperazine and 5-bromo-6-chloropyridine-3-sulfonyl chloride. Yield: 91%: 1H NMR (CDCl3, 400 MHz) δ 8.59 (d, J=2 Hz, 1 H), 7.67 (d, J=2 Hz, 1 H), 3.08-3.01 (m, 4 H), 2.43 (t, J=5 Hz, 4 H), 2.22 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 155.5, 146.8, 141.2, 132.7, 121.4, 54.2, 46.3, 46.1.
Reaction SMILES: C1(C)C=CC=CC=1.O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[CH2:29]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]>N1C=CC=CC=1>[CH2:29]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:44][C:18]2([C:21]([O:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH3:27])=[O:22])[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=3)=[CH:16][CH2:17]2)=[O:43])=[CH:45][CH:46]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]
Reactant: CCC(C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCCCCOc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCCCCCCOc1ccc(C(=O)OC2(C(=O)OCC(C)CC)C=CC(c3ccccc3)=CC2)cc1
Reaction time: 8 h
Yield: 45 %

Procedure:
A toluene solution containing 10 g of 2-methylbutyl 4'-hydroxybiphenyl-4-carboxylate and 3 g of pyridine was added dropwise to the above-described toluene solution of the acid chloride compound. After conclusion of dropping, the temperature was raised, and reaction was carried out for 8 hours at 50° C. After conclusion of the reaction, the product was washed with water and dried over magnesium sulfate, and the dried product was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 8.2 g of the objective ester compound. (Yield: 45%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)C=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 535.25 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (45 g, 0.17 mol) and copper cyanide (34 g, 0.34 mol) in DMF (450 mL) was heated to 150° C. for 24 h. The suspension was cooled, poured into water with stirring. The solid was filtered and dried to give 25 g (70%) of the title compound which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH2:29][C:28](=[O:30])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CC(=O)c3ccccc3O4)nn2)n1

Procedure:
The object product (29 mg, 31%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (50 mg), spiro[chromene-2,4′-piperidin]-4(3H)-one hydrochloride (60 mg) and potassium carbonate (50 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Yield: 51.6 %

Procedure:
Following general procedure F, {6-bromo-4-[(1-methylpiperidin-4-yl)methylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (29 mg, 51%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.13 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.02-7.83 (m, 2H), 7.56-7.37 (m, 2H), 3.84 (d, J=5.9 Hz, 2H), 2.89-2.74 (m, 3H), 2.71 (s, 3H), 2.05 (d, J=13.4 Hz, 3H), 1.65-1.47 (m, 2H), 1.28 (s, 3H), 1.24-1.16 (m, 2H), 1.16-1.02 (m, 2H), 0.88 (d, J=6.9 Hz, 1H); ESI MS m/z [C26H27ClFN3O2+H]+; HPLC>99% (AUC), tR=9.14 min.