Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:24][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19][CH2:18]3)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[CH3:1][N:2]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]34[CH2:24][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19][CH2:18]4)=[CH:13][N:12]=2)[CH:4]=[N:3]1
Reactant: Brc1ccc(C23CCCN(CC2)C3)cn1
Reactant: Cn1cc(B(O)O)cn1
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: Cc1ccccc1
Solvent: CCO
Product: Cn1cc(-c2ccc(C34CCCN(CC3)C4)cn2)cn1
Temperature: 105 °C
Yield: 93.2 %

Procedure:
0.162 g (0.78 mmol) of 1-methyl-4-pyrazolylboronic acid, 0.160 g (0.6 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (obtained by reacting 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (−)-hydrobromide (1:1), prepared in step 1.2, with saturated aqueous sodium carbonate solution) are successively introduced into a 10 ml three-necked round-bottomed flask, as a solution in 3 ml of toluene and 0.3 ml of ethanol. 0.035 g (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.6 ml of aqueous 2M sodium carbonate solution are then added and the mixture is heated at 105° C. for 18 hours. It is cooled to room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up in 10 ml of chloroform and filtered through diatomaceous earth. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.15 g of (−)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is obtained, and is dissolved in 2 ml of isopropyl alcohol to add 0.196 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under vacuum.
Reaction SMILES: [OH:1][OH:2].[C:3]([O:8]C)([CH2:6][CH3:7])([CH3:5])[CH3:4]>>[C:3]([O:8][OH:1])([CH2:6][CH3:7])([CH3:5])[CH3:4].[C:3]([O:1][O:2][C:3]([CH2:6][CH3:7])([CH3:5])[CH3:4])([CH2:6][CH3:7])([CH3:5])[CH3:4]
Reactant: OO
Reactant: CCC(C)(C)OC
Product: CCC(C)(C)OO
Product: CCC(C)(C)OOC(C)(C)CC

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.CN(C=O)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CCOCC>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-aminopropanol 8-1 (Aldrich) (15 g, 0.2 mol), NEt3 (42 mL, 0.3 mol) and DMF (400 mL) at 0° C. was added BOC2O (52 g, 0.24 mol). After stirring at 0° C. for 6 h the reaction mixture was diluted with ether and then washed with H2O (2×), sat. NaHCO3, 5% KHSO4 and brine, dried (MgSO4) and concentrated to give 8-2 as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NCCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCCCCCNC(=O)CCl
Reaction time: 1 h
Yield: 96 %

Procedure:
11-Aminoundecanoic acid (10.7 grams; 0.05 mole) was added to 125 ml of ethyl acetate and refluxed with 5 ml of chloroacetyl chloride as above. After one hour no precipitate was noted and the excess chloroacetyl chloride and ethyl acetate was removed by vacuum distillation. 14 Grams (96% yield) of N-chloroacetylamino-11-undecanoic acid was obtained. This compound was confirmed by elemental analysis and infrared spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN1CCCC1=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
4-Bromophenol (1.0 g, 5.78 mmol) was added to a solution of sodium hydride (0.3 g, 7.51 mmol) in N-methylpyrrolidone (10 ml). After stirring for 10 minutes, 4-chloro-2-methylpyridine (0.96 g, 7.51 mmol) was added. The reaction mixture was heated at 250° C. for 45 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with diethyl ether and washed with water. The solution was then extracted with additional diethyl ether, the organic layer dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D10 (1.34 g, 88%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1)#[N:2].[CH3:18][C:19]1[CH:20]=[C:21]([NH2:30])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:18][C:19]1[CH:20]=[C:21]([NH:30][C:15]([C:6]2[C:7]([NH:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:17])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cnc(C#N)nc2NCC(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid (150 mg, 0.640 mmol), 5-Methyl-2-phenyl-2H-pyrazol-3-ylamine (211 mg, 1.28 mmol) and 1-hydroxybenzotriazole (147 mg, 1.28 mmol) in DMF (5 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (199 mg, 1.28 mmol) at ambient temperature. After being stirred for 15 hours at ambient temperature, the reaction mixture is diluted with ethyl acetate, washed with saturated NaHCO3, dried over MgSO4 and concentrated. The crude product is purified by reverse-phase HPLC to give the product. Rf=0.44 (n-hexane:AcOEt=1:1). 1H NMR (400 MHz, CDCl3) δ 0.98(s, 9H), 2.33(s, 3H), 3.37(d, 2H), 6.55(s, 1H), 7.41-7.53(m,5H), 8.24(s, 1H), 9.01(br, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:20][C:21]3[C:28]([CH3:29])=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[CH3:30])[C:13]3[N:18]([CH3:19])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:20][C:21]3[C:22]([CH3:30])=[CH:23][C:24]([C:25]#[N:26])=[CH:27][C:28]=3[CH3:29])[C:13]=2[N:18]([CH3:19])[CH:17]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Br)cn(C)c12
Yield: 56.3 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (58 mg, 0.15 mmol) in CH2Cl2 (8 mL) was added NBS (29 mg, 0.16 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (2:1), to give the product as a yellow solid (40 mg, 57%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH3:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:35][O:36][CH2:37][CH2:38][OH:39]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH2:20][CH3:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:35][O:36][CH2:37][CH2:38][OH:39])=[O:7]
Reactant: CCSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCSc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 65 %

Procedure:
The title compound was prepared from reaction of the product of Example 27, Step B, 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid triturated with Et2O and washed with pentane to afford 3,4-difluoro-2-[[2-fluoro-4-(ethylthio)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (65%); m.p. (Et2O) 129–132° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.77 (br s, 1 H), 7.41 (ddd, J=9.0, 5.8, 2.1 Hz, 1 H), 7.23 (dd, J=11.8, 2.1 Hz, 1 H), 7.15 (ddd, J=9.9, 8.9, 7.2 Hz, 1 H), 7.04 (ddd, J=8.5, 2.1, 0.9 Hz, 1 H), 6.85 (ddd, J=9.9, 8.5, 4.2 Hz, 1 H), 4.72 (br s, 1 H), 3.85 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 1 H), 2.92 (q, J=7.3 Hz, 2 H), 1.20 (t, J=7.3 Hz, 3 H). Anal. Calcd for C17H17F3N2O3S: C, 52.8; H, 4.4; N, 7.3. Found: C, 53.0; H, 4.7; N, 7.2.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([NH:62][CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([NH:62][CH3:63])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(CC(=O)NC)OCC
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)NC
Yield: 89.7 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in the Reference Example 3-1); 4.60 g, 10.0 mmol), dimethyl sulfoxide (1.99 ml, 28.0 mmol), oxalyl chloride (1.28 ml, 15.0 mmol), triethylamine (6.98 ml, 50.0 mmol), 2-(diethylphosphono)-N-methylacetamide (2.32 g, 11.0 mmol) and 60% sodium hydride (420 mg, 10.5 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 100 ml, elution with hexaneethyl acetate 1:2) to give the title compound (4.60 g, 89.7% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH3:20])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=1[CH3:38])#[N:28]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:5][C:4]2[C:6]([CH3:20])=[CH:7][C:8]([C:10]([F:19])([C:11]([F:14])([F:13])[F:12])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:3]=2[CH2:1][CH3:2])=[O:34])=[CH:31][C:30]=1[CH3:38])#[N:28]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: Cc1cc(C(=O)Cl)ccc1C#N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(C)c1
Temperature: 50 °C
Yield: 84.5 %

Procedure:
2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylaniline (1.7 g) and pyridine (0.88 g) were dissolved in tetrahydrofuran (30 ml). To the solution, the crude product of 4-cyano-3-methylbenzoyl chloride (1.0 g) and 4-dimethylaminopyridine (0.03 g) were added and the mixture was stirred under heating at 50° C. for 2 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate 10%) to obtain 4-cyano-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-methylbenzamide (2.1 g, yield 83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.C(N(CC)CC)C.[C:22](=S)=[S:23].[OH-].[K+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl>C(O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:22]([S:23][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:38])([F:37])[F:27])[CH:30]=4)=[N:14][N:13]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2ccc(C(=O)NN)cc21
Reactant: S=C=S
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cnc2ccc(-c3nnc(SCc4cccc(C(F)(F)F)c4)o3)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution (5 mL) of 1-methyl-1H-benzimidazole-6-carbohydrazide (0.20 g, 1.05 mmol), triethylamine (0.18 mL, 1.26 mmol) and carbon disulfide (0.16 mL, 2.63 mmol) in ethanol was heated under reflux overnight. The reaction mixture was cooled to 0° C., potassium hydroxide (58.9 mg, 1.05 mmol) and 3-(trifluoromethyl)benzyl chloride were added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3) to give the title compound (49.9 mg, yield 12%) as colorless crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC(Cl)C.[CH:29]1([NH:35][C:36]2[N:44]=[C:43]([F:45])[CH:42]=[CH:41][C:37]=2[C:38]([OH:40])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[NH2:46][C:47]1[CH:56]=[C:55]2[C:50]([CH2:51][CH2:52][C:53](=[O:58])[N:54]2[CH3:57])=[CH:49][CH:48]=1>C(N(CC)CC)C>[CH:29]1([NH:35][C:36]2[N:44]=[C:43]([F:45])[CH:42]=[CH:41][C:37]=2[C:38]([NH:46][C:47]2[CH:56]=[C:55]3[C:50]([CH2:51][CH2:52][C:53](=[O:58])[N:54]3[CH3:57])=[CH:49][CH:48]=2)=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(F)nc1NC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(F)nc3NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HATU was added to a dichloroethane solution of 2-(cyclohexylamino)-6-fluoronicotinic acid and triethylamine. After 30 minutes of stirring at room temperature, 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one was added thereto. The reaction liquid was stirred overnight at room temperature and then hearted under reflux for 3 hours. By post-treating the reaction liquid, 2-(cyclohexylamino)-6-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH:18](OCC)=[O:19]>CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([CH:18]=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNCc1ccc(F)cc1
Reactant: CCOC=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NN(C=O)Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.4 %

Procedure:
To a solution of tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate (0.6 g, 2.50 mmol, 1.0 equiv) in EtOH (2.5 mL) was added ethyl formate (0.81 mL, 9.99 mmol, 4.0 equiv) and the reaction mixture heated to 50° C. (oil bath). After stirring 4 h, the reaction was cooled to ambient temperature and stirred 3 d. The reaction was then heated to 50° C. (oil bath) for 3 h at which time more ethyl formate (1.0 mL, 12.28 mmol, 4.9 equiv) was added. After stirring a further 4 h, the reaction was concentrated in vacuo. The crude product was purified by silica gel chromatography (elute with 10-70% ethyl acetate/hexane) to provide the title compound (0.11 g, 16% yield) as a colorless oil which slowly crystallized. Unreacted tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate was recovered from the mother liquor. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.20-7.25 (m, 2H), 7.00-7.08 (m, 2H), 6.27 (s, 1H), 4.58 (s, 2H), 1.43 (s, 9H); LCMS (ES+, (M+H)+) m/z 269.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C)C=O.CC(C)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[N:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(F)nc2c1Cl

Procedure:
To a suspension of 3a in chloroform were added 4 equivalents of oxalyl chloride followed by 0.1 equiv. of dimethylformamide. The solution was refluxed for 3 hours and was quenched with 5 M sodium hydroxide solution at 4° C. The chloroform layer was collected, washed with 100 mL water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Product was obtained by recrystallization using acetone. 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 7.45 (1H, dd, J=8.79, 3.02 Hz), 8.54 (1H, dd, J=9.06, 7.41), 9.21 (1H, s). m/z 255.7 (MH+).
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH:12]([OH:21])[C:13]2[S:17][C:16]3=[CH:18][N:19]=[CH:20][N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1>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.CN(C=O)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11]([CH:12]([OH:21])[C:13]4[S:17][C:16]5=[CH:18][N:19]=[CH:20][N:15]5[CH:14]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CNc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4cn5cncc5s4)C3)[C@H](C)[C@H]12
Yield: 10.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (8.4 mg) is added to a solution of 40.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) and 0.045 ml of N-methylaniline in 1. 0 ml of DMF, and the mixture is stirred in an argon atmosphere at room temperature for 35 min. DMF is removed by evaporation under reduced pressure, 3 ml of distilled water is added to the residue, and the mixture is extracted three times with 5 ml of ethyl acetate while removing insolubles. The aqueous layer is concentrated under reduced pressure to distil-off ethyl acetate, and the concentrate is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 3.5 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [OH-:1].[K+].Cl.Cl[CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[CH2:8]([N:7]([CH2:10][CH3:11])[CH2:6][CH2:5][O:1][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[O:19])=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCN(CC)CCCl
Reactant: O=Cc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCOc1ccc(C=O)cc1

Procedure:
4.82 g potassium hydroxide were dissolved in 70 ml ethanol and treated with 8.46 g (2-Chloro-ethyl)-diethyl-amine hydrochloride. The mixture was stirred until everything was dissolved, then 5.0 g benzaldehyde were added and refluxed for 16 hrs. The mixture was diluted with water and extracted with ethyl acetate, and the organic phases washed several times with caustic soda. After drying and evaporation of the solvent the crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:41]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][CH2:45][NH:44][CH:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>C(N(CC)CC)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:44]1[CH2:45][CH2:46][N:41]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[CH2:42][CH:43]1[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Yield: 383.1 %

Procedure:
3-((6-Chloro-2-naphthyl)sulfonyl)propanoic acid (0.33 g), HOBt (2.30 g) and WSC (2.88 g) were added to acetonitrile (50 mL) and mixed for 15 minutes. Then, di-tert-butyl piperazine-1,3-dicarboxylate (2.99 g) and triethylamine (3.03 g) were added thereto, and the mixture was mixed at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (2.40 g) as a colorless powder.