Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]12.[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27]C(=O)C)/[C:23](Cl)=[O:24])[N:21]=1.Cl.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].S(=O)(=O)(O)O>ClCCl.O>[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[OH:27])/[C:23]([NH:1][CH:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH:9]=[CH2:10])[CH2:7][S:8][C@H:3]23)=[O:24])[N:21]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1csc(N)n1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 g of 7-amino-3-vinyl-3-cephem-4-carboxylic acid in 400 ml of dichloromethane are treated with 55.7 ml of N,O-bistnmethyl-silylacetamid. The mixture obtained is stirred for ca. 2 hours at room temperature, cooled to 0° and treated with 52.2 g of 2-(Z)-(2-aminothiazol-4-yl) -2-acetoxyiminoacetic acid chloride in the form of a hydrochloride in small portions. The mixture obtained is stirred for ca.90 minutes at 0° and added under stirring to a mixture of 44.55 g of NaHCO3, 600 ml of water und 100 ml of dichloromethane of a temperature of 5°. The pH of the mixture obtained is adjusted to a pH of ca. 7.2-7.3 with a saturated aqueous solution of NaHCO3. The phases formed are separated. To the aqueous phase 300 ml of water are added and 28.7 g of NH4Cl. The pH of the mixture obtained is adjusted to pH 8 by addition of an aqueous 10% K2CO3 solution and the mixture is stirred for ca. 80 minutes. A solution is obtained. The pH of the solution obtained is adjusted to pH 3 by addition of 5 m sulphuric acid. 7-(Z)-[2-(2-amino-thiazol4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid precipitates, is filtrated off, washed with water and dried. 7-(Z)-[2-(2-amino-thiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid in a purity of 94.3 % is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl.[Na+].[Cl-]>O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ClCCCCCl
Reactant: Oc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCOc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A 1 L flask provided with a stirrer was charged with 128.6 g (1.0 mol) of p-chlorophenol (available from Tokyo Chemical Industry Co., Ltd.), 52.0 g (1.3 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 152.4 g (1.2 mols) of 1,4-dichlorobutane (available from Tokyo Chemical Industry Co., Ltd.) and 300 g of water. The content was maintained at 80° C. for 4 hours. Then the reaction liquid was cooled to room temperature, and deposited NaCl, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 177.4 g of the target p-(4-chlorobutoxy)chlorobenzene (yield: 81%, purity: 98%).
Reaction SMILES: [OH:1][C:2]([CH3:14])([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].CO.Cl>O>[OH:1][C:2]([CH3:14])([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C#Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(O)(C#Cc1ccccc1)C(=O)O
Yield: 89 %

Procedure:
A magnetically stirred mixture of 2.20 g (0.01 mole) of twice distilled 2-hydroxy-2-methyl-4-phenylbutynoate, ethyl ester 1.40 g (0.01 mole) of potassium carbonate and 3 ml of methanol in 20 ml of water was heated under a dry nitrogen atmosphere at 75°-80° C. for 1.5 hours, during which time the substrate dissolved to afford a faint yellow solution. After cooling, 20 ml of water was added and the solution was exhaustively extracted with ether. The aqueous phase was then treated with 1.5 g of Darco® activated carbon, filtered with suction through a Celite® pad and acidified in an ice bath with 2.0 ml (0.02 mole) of concentrated hydrochloric acid. The resulting oil was extracted with three 25 ml portions of ether and the combined extracts were washed with three 35 ml portions of water and dried over MgSO4. Filtration and concentration at the stripper provided an almost colorless oil which solidified on cooling. Recrystallization from hexane containing a trace of ether afforded 1.60 g (89% yield) of 2-hydroxy-2-methyl-4-phenylbutynoic acid as colorless plates, m.pt. 104.5°-106.0° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.I[CH:13]([CH3:15])[CH3:14]>CCOC(C)=O.[Ag-]=O>[CH:13]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Product: CC(C)OC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ol (0.5 g, 3.16 mmol) in 2-iodopropane (5.37 g, 31.6 mmol), silver (I) oxide (1.392 g, 6.01 mmol) was added and the reaction mixture was stirred at room temperature. Upon completion the resulting suspension was diluted with EtOAc and the suspension filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give a pale yellow oil. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane to afforded the title compound;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[N:31]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[N:31]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1nccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(C#N)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.081 mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a mixture of 4-amino-2-methylpyrimidine (102 mg, 0.933 mmol) and triethylamine (0.173 mL, 1.24 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred at 25° C. for 24 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 19/1 methylene chloride/methanol) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide (15 mg, 6%) as a white foam: mp 89–94° C. (foam to gel); EI-HRMS m/e calcd for C21H24N4O3S (M+) 412.1569, found 412.1568.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14](OCC)=[O:15].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=[O:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C=O)cc1OC
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl formate (1.1 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxopropanenitrile as a brown oil (2.0 g, 9.8 mmol, 89% yield). MS (EI) for C11H11NO3: 206 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>[Cu]=O.O.C1(C)C(C)=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
93 g of aniline, 3.8 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, 2 g of copper(II)oxide and 40 ml of xylene are heated together to 150° C. for 20 minutes in a water separator. 157.5 g of 4-nitrochlorobenzene, 93 g of aniline and 76 g of calcined sodium carbonate (light) are then added. After 12 hours at 193°-196° C., 10 ml of water have collected in the water separator. The weight ratio of nitrobenzene:4-nitrochlorobenzene:4-nitrodiphenylamine in the reaction mixture is 1.5:2.0:96.5. The reaction mixture is cooled to 95° C. and filtered, and the filter cake is washed with 100 ml of hot xylene. Water is added to the filtrate, and unreacted 4-nitrochlorobenzene and aniline are expelled with steam, the 4-nitrodiphenylamine being obtained as granules. It is isolated by filtration, washed with hot water and dried: 210 g of 4-nitrodiphenylamine, purity (HPLC) 91.3%, yield 89.6 % of theory, relative to p-nitrochlorobenzene employed.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[C:7]=1[F:8].[CH3:18][C:19]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:22]2[N:23]=[CH:24][S:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:17][C:5]1[CH:4]=[CH:3][CH:2]=[C:7]([F:8])[C:6]=1[NH:9][C:10]([C:12]1[S:13][C:14]([C:27]2[C:19]([CH3:18])=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)=[CH:15][CH:16]=1)=[O:11]
Reactant: O=C(Nc1c(F)ccc(Br)c1F)c1cccs1
Reactant: Cc1cc2scnc2cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2scnc2cc1-c1ccc(C(=O)Nc2c(F)cccc2F)s1
Temperature: 110 °C
Yield: 84.3 %

Procedure:
A mixture of (5-bromo(2-thienyl)-N-(2,6-difluorophenyl)carboxamide (22 mg, 0.07 mmol), 6-methyl-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))benzothiazole (14) (19 mg, 0.07 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 8 mg) and sodium carbonate (22 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to prep HPLC chromatography to furnish 22.8 mg of N-(2,6-difluorophenyl)[5-(6-methylbenzothiazol-5-yl)(2-thienyl)]carboxamide (15) as white solid (yield: 84.3%; purity>95%). LC-MS: calcd. for C19H12F2N2OS2: 387 (M+1).
Reaction SMILES: C([NH:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15])(=O)C>C(O)C>[NH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15]
Reactant: CC(=O)Nc1c(C(=O)Nc2nnn[nH]2)oc2ccccc12
Solvent: CCO
Product: Nc1c(C(=O)Nc2nnn[nH]2)oc2ccccc12
Yield: 53 %

Procedure:
A mixture of 5.3 g (0.019 mole) of 3-(acetylamino)N-1H-tetrazol-5-yl-2-benzofurancarboxamide in 50 ml of ethanol plus 50 ml of concentrated (12.0 M) hydrochloric acid is stirred at reflux for two hours. The reaction mixture is cooled in ice to precipitate 3-amino-N-1H-tetrazol-5-yl-2-benzofurancarboxamide. The precipitate is filtered, washed with 50% aqueous ethanol, and recrystallized from aqueous 2-methoxyethanol to yield 2.4 g (53% yield) of the analytically pure 3-amino-N-1H-tetrazol-5-yl-2-benzofurancarboxamide, mp 275° C.-dec.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.C([Li])CCC.Cl[C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=1>CCCCCC.C1COCC1>[CH3:1][C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:15])([CH3:14])[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=3)[CH:9]=[CH:10][C:11]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free argon or nitrogen atmosphere. To a solution of 417.6 mg (1.9667 mmol) of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-ethynylnapthalene in 3 ml of dry tetrahydrofuron (THF) at 0° C. was added dropwise 1.3 ml of 1.6M (2.32 mmol) n-butyllithium in hexane. This mixture was stirred at 0° C. for 10 minutes and at room temperature for 15 minutes, cooled again to 0° C. and then treated by double-ended needle with a solution of 290 mg (2.1279 mmol) of fused zinc chloride in 4 ml dry THF. The mixture was stirred at 0° C. for 45 minutes and at room temperature for 15 minutes. A solution of 361.1 mg (1.9455 mmol) of ethyl 6-chloronicotinoate in 4 ml dry THF was transferred by double ended needle into a suspension of 420 mg (0.3635 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry THF, the resultant mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynyl zinc prepared above. The reaction mixture was stirred at room temperature for 70 hours and then quenched with ice and 30 ml of 3N HCl. The resultant mixture was extracted with 3×50 ml of ether, the ether extracts combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). The ether solution was filtered and concentrated in-vacuo. The resultant crude product was purified by flash chromatography (silica, 10% ethyl acetate in hexanes) followed by recrystallization from a mixture of ethylacetate in hexane to give the title compound as a pale cream solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.2 g, 10.4 mmol) and potassium carbonate (2.9 g, 20.8 mmol) in methanol (100 mL) was added Example 21A (2.0 g, 10.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 1:5 ethyl acetate/hexane) gave the title compound. MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23]([CH2:25][CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[N:22][N:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([CH2:26][CH2:25][C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)=[CH:28][CH:29]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Reactant: Cc1nnc(CCc2ccc(N)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(CCc2ccc(NC(=O)/C=C/c3cnccc3-c3ccc(F)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.2 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (730 mg), 4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]aniline (640 mg), 1-hydroxy-1H-1,2,3-benzotriazole monohydrate (505 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (733 mg) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 21 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and the obtained solid was recrystallized from water-containing ethanol to give the title compound (941 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[C:55]#[N:56])(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as starting materials in 20% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:3].[C:16]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:49]>C1COCC1>[ClH:49].[C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=[CH:18][C:19]([CH2:22][O:15][C:10]2[CH:9]=[C:8]3[C:13]([CH2:14][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][NH:7]3)=[CH:12][CH:11]=2)=[CH:20][CH:21]=1
Reactant: CN(C)CC1CNc2cc(O)ccc2C1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethylazodicarboxylic acid (348 mg) was added dropwise to a THF solution (20 ml) of 3-(dimethylamino)methyl-1,2,3,4-tetrahydro-7-quinolinol (344 mg), 4-biphenylylmethanol (368 mg), and triphenylphosphine (525 mg). The reaction mixture was stirred at room temperature for one hour, which was poured into 1N hydrochloric acid and washed with ethyl acetate. The aqueous layer was neutralized with 1N aqueous sodium hydroxide solution, to which was added a saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4), converted into its hydrochloride, and then recrystallized from ethanol-IPE to give the entitled compound (214 mg).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br.O>CC(OC)(C)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7]
Reactant: O=C1CCCCN1
Reactant: Fc1ccc(CBr)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Valerolactam (60 g) was dissolved in MTBE (1.5 L) at room temperature. To this solution was added Bu4NSO4 (4.9 g) as a phase transfer catalyst. The cloudy solution was stirred at room temperature for 5 minutes. Then, NaOH (50 wt %; 300 mL) was slowly added as to keep the internal temperature below 30° C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) was then added slowly to this biphasic mixture, again as to keep the internal temperature under control. The reaction was then aged for 4 hours at room temperature. At this time LC showed the reaction to be complete. Water (500 mL) was then added. After phase cut, the organic layer was washed with brine (300 mL), dried under MgSO4 followed by solvent switch to heptane (400 mL). The slurry obtained was stirred at room temperature. for 1 hour and then filtered to afford the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C=O)C>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][CH3:21])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-{3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl}acetamide 2 (12.7 g, 0.055 mol) and sodium hydride (60% in oil) (2.5 g) in DMF (150 ml) under nitrogen was stirred at room temperature for 30 minutes. The solution was then cooled to 0° C., and a solution of ethyl iodide (9.38 g, 0.063 mol) in DMF (50 ml) was added slowly dropwise. The mixture was then stirred at room temperature for one hour. The DMF was removed under high vacuum, water (200 ml) was added to the residue and the mixture was extracted with ethyl acetate (2×200 ml). The combined ethyl acetate extracts were washed with water (150 ml) and brine (100 ml), dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Compound 5 was obtained after recrystallization from hexane (7.9 g). M. P. (Hexane): 109-112° C.