Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:35]([NH2:38])(=[NH:37])[CH3:36]>C(#N)C.C(Cl)(Cl)Cl>[CH3:36][C:35]1[NH:37][C:8]2[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[N:5]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)=[O:15])[CH2:4][CH2:3][C:2]=2[N:38]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(Br)C(=O)c3ccccc32)cc1OC
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N2CCc3nc(C)[nH]c3-c3ccccc32)cc1OC
Temperature: 90 °C
Yield: 43.7 %

Procedure:
To a suspension of methyl 4-(4-bromo-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl-2-methoxybenzoate (240 mg) and potassium carbonate (767 mg) in acetonitrile (8 ml) was added acetamidine hydrochloride (472 mg) and the mixture was heated at 90° C. for 3 hours. After cooling, the reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2; 30 g, ethyl acetate) to give methyl 4-(2-methyl-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepin-6-yl)carbonyl-2-methoxybenzoate (95 mg).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(O)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Temperature: -20 °C
Yield: 95.5 %

Procedure:
Methyl 2-({3-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.096 g, 0.25 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.039 g, 0.38 mmol) was added drop wise and methanesulfonyl chloride (0.032 g, 0.28 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing The solvent was removed by evaporation giving 0.109 gram of methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenoxy]methyl}benzoate (yield 94.1%).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O.O>C(#N)C.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reaction time: 3 h
Yield: 92 %

Procedure:
In a 25 ml flask, 3-nitro-5-trifluoromethyl-pyridin-2-ol (300 mg, 1.44 mmol) was dissolved in acetonitrile (4.5 ml), and then phosphorus oxychloride (0.4 ml, 4.33 mmol) and benzyltrimethyl ammonium chloride (164 mg, 0.721 mmol) were added thereto. The mixture was stirred for 3 hours at 800. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid (300 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]([CH3:27])[CH2:19][C@@H:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:17][CH:18]([CH3:27])[CH2:19][C@H:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC(C)C[C@H](N)c1nccs1
Product: CC(C)C[C@H](NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine as starting materials, MS (LC/MS): 386.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[I:27])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[I:27])[CH3:18]
Reactant: CCc1[nH]c(C(=O)O)nc1I
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1I
Yield: 86 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (130 mg, 0.56 mmol), 5-ethyl-4-iodo-1H-imidazole-2-carboxylic acid obtained in Example (58b) (95 mg, 0.36 mmol), WSC hydrochloride (220 mg, 1.15 mmol) and HOBT (46 mg, 0.34 mmol), to obtain 146.2 mg of the title compound as a white solid (86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[N:45]=[C:46]([CH3:50])[N:47]([CH3:49])[CH:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[N:45]=[C:46]([CH3:50])[N:47]([CH3:49])[CH:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: Cc1nc(Br)cn1C
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3cn(C)c(C)n3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 4-bromo-1,2-dimethyl-1H-imidazole.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:8](=[O:9])[O:7][CH2:6][C:5]=12.CN(C)C(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>CCO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:8]([C:4]2[C:5]([CH2:6][OH:7])=[N:1][O:2][N:3]=2)=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C1OCc2nonc21
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one (2.00 g, 0.0159 mol) was dissolved in EtOH (80 mL) and N,N-dimethylacetamide (10 mL) and then 3-chloro-4-fluoroaniline (2.5 g, 0.017 mol) was added as a solid. The reaction was heated at 80° C. overnight. The crude reaction mixture was concentrated in vacuo. The oil was extracted twice with EtOAc and washed with water. The organic was dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography eluting with EtOAc:Hexane (1:1) to yield the desired product (3.2 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.30 (dd, J=7.0, 2.7 Hz, 1H), 7.69 (ddd, J=9.1, 4.4, 2.6 Hz, 1H) 7.45 (dd, J=9.1, 9.1 Hz, 1H), 4.86 (d=5.8 Hz, 2H), 5.78 (t, 5.8 Hz, 1H); MF═C10H7ClFN3O3; LCMS calculated for C10H8ClFN3O3(M+H)+: m/z=272.024.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:31][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
2000.0 mg (6.809 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 1417.0 mg (7.490 mmol) of 1-[3-(trifluoromethyl)phenyl]-ethanamine are placed in 10 ml of dimethylformamide and treated with 1104.0 mg (8.171 mmol) of HOBt. After 10 mins' stirring, 1697.0 mg (8.852 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1). A subsequent enantiomer separation by preparative HPLC on chiral phase [Method 14] yields 1460 mg (46% of theory) of the enantiomerically pure target compound (see also Example 81).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1.O>C1COCC1>[CH2:23]([S:24][C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: SCc1ccccc1
Reactant: CCn1ccnc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ccnc(SCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To 250 mg (1.23 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 340.3 mg (2.46 mM) of potassium carbonate in 4 ml of THF were added 159 μl (1.35 mM) of benzylthiol. The reaction mixture was then stirred at room temperature for 16 h. Water was added and the organic phase was extracted with ethyle acetate. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum, to give a solid, which was triturated in diisopropyle oxide, filtrated and dried under vacuum, to give 250 mg of 3-(benzylthio)-1-ethylpyrazin-2(1H)-one. Yield: 82%.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].C(N(CC)CC)C.CS([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13]
Reactant: Cc1c(CO)ccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CCl)ccc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of 10.1 g of 2-hydroxymethyl-1-methylnaphthalene, 14.0 ml of triethylamine and 120 ml of methylene dichloride, cooled in an ice-salt bath was added dropwise 5.5 ml of methanesulfonyl chloride. The reaction mixture was allowed to warm to room temperature, washed with water, dried and concentrated in vacuo to obtain 8.4 g of 2-chloromethyl-1-methylnaphthalene as a waxy solid.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Reaction time: 6.5 h
Yield: 53342.7 %

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzoyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 10:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (738 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.ClCCl>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=2)[N:20]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: Cc1ccc(NN)cc1
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Heat a mixture of 4,4,5,5,5-pentafluoro-3-oxo-pentanenitrile (4.0 g, 21.4 mmol) and p-tolyl-hydrazine (10 g, 64.1 mmol) in ethanol (20 mL) to 95° C. in a sealed tube apparatus for 15 hours. After cooling to room temperature, remove the solvent under reduced pressure to give a yellow solid. Distribute the solid between dichloromethane (250 mL), distilled water (150 mL) and a saturated aq. sodium bicarbonate solution (50 mL). Isolate the aqueous phase and extract with dichloromethane (100 mL). Dry the combined organic phases over sodium sulfate and concentrate to give a dark gold oil. Subject oil to silica gel chromatography eluting with ethyl acetate and hexanes to give a light brown solid (3.24 g, 52% yield). MS(ES+): m/z=292.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[C:3]=1[C:24]([OH:26])=O.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[C:3]=1[C:24]([N:35]1[CH2:36][CH2:37][CH:32]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:33][CH2:34]1)=[O:26]
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(OC(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(-c2cncnc2)nn1-c1cccc(OC(F)(F)F)c1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a yellow oil (32%). MS: 501.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([NH:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[N:22][C:21]=1Cl)([CH3:18])[CH3:17]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([N:14]([CH3:15])[C:21]2[N:22]=[N:23][CH:24]=[C:25]([Cl:26])[C:20]=2[NH:19][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Nc1c(Cl)cnnc1Cl
Reactant: CNN1CCN(Cc2ccccc2)CC1
Product: CC(C)Nc1c(Cl)cnnc1N(C)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-methylaminopiperazine (EXAMPLE 9, 2.30 g, 11.4 mmol) and 4-isopropylamino-3,5-dichloropyridazine (EXAMPLE 157, 1.0 g, 4.8 mmol) are heated in a sealed tube under a nitrogen atmosphere to 155° for 3 hr. The mixture is then chromatographed (silica gel, 150 g; 50-100% ethyl acetate/hexane) to give the title compound, NMR (300 MHz, CD3OD) 8.43, 7.30, 4.5, 3.51, 2.90, 2.72, 2.05, 1.75 and 1.21δ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[O:18])[C:15]([OH:17])=O)=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C.[CH3:25][C:26]([O:28][CH2:29][C:30]1[CH2:39][S:38][C@@H:33]2[C@H:34]([NH2:37])[C:35](=[O:36])[N:32]2[C:31]=1[C:40]([OH:42])=[O:41])=[O:27]>C(Cl)Cl.CN(C)CCCO.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[O:18])[C:15]([NH:37][CH:34]2[C:35](=[O:36])[N:32]3[C:31]([C:40]([OH:42])=[O:41])=[C:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])[CH2:39][S:38][C@H:33]23)=[O:17])=[CH:11][S:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)O)cs1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CCOC(=O)Cl
Agent: CN(C)CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC(=O)OC(C)(C)C)[nH]3)[C@H]2SC1
Reaction time: 2 h

Procedure:
2.7 g of 2-(2-tert.-butoxycarbonylimino-4-thiazolin-4-yl)-glyoxylic acid containing one molar equivalent of crystal alcohol are activated with a total of 2 ml of chloroformic acid ethyl ester (added in 3 portions) in 40 ml of methylene chloride at -30° C. in the presence of 2.8 ml of triethylamine and 2 drops of 3-dimethylaminopropanol, and the mixture is then combined with a solution of 3.6 g of 7-aminocephalosporanic acid in a mixture of 40 ml of methylene chloride and 3.6 ml of triethylamine. The resulting mixture is then allowed to come to 20° C., after 2 hours the methylene chloride is stripped off, the aqueous solution which remains is washed with ethyl acetate, then acidified (pH 1.5) and extracted with ethyl acetate and the dried organic phase is evaporated in vacuo. The residue is washed with methylene chloride and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:33]=[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]1[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([NH:25][C:44](=[O:45])[C:43]2[CH:42]=[CH:41][C:40]([N:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]3=[O:33])=[CH:48][CH:47]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(-n2ccccc2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)C1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Cis-3-amino-4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (332.1 mg, 0.95 mmol), from Example 112 Part F, was mixed with 10 mL of CH2Cl2 and 96 mg (0.95 mmol) of triethylamine. The resulting solution was cooled with an ice-water bath. Freshly prepared 4-(2-oxopyridin-1(2H)-yl)benzoyl chloride (222 mg, 0.95 mmol), from part A, was added portion wise. Stirring was continued at rt overnight. CH2Cl2 (10 mL) was added, and the solution was washed with water (3×3 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield cis-4-Benzyloxycarbonylamino-3-[4-(2-oxo-2H-pyridin-1-yl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (343.2 mg) as a crude oil, which was further purified by flash chromatography (ISCO system; 10 g cartridge Eluent AcOEt/Hexane 20%). 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 2H), 7.42–7.24 (m, 8H), 7.06 (d, J=6.5 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 6.27 (t, 1H), 5.06 (s, 2H), 4.34 (bs, 1H), 4.08 (bs, 1H), 3.87 (m, 1H), 3.16 (d, J=13.4 Hz, 1H), 2.98 (t, 1H), 1.85 (bs, 1H), 1.65 (m, 1H), 1.39 (m, 9H), ppm. LC-MS (ESI) 569.24 [M+Na]+, tR=6.331 min (Shimadzu Phenomenex S5 ODS 4.6 ×50 mm Luna flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4)).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(N)CC1.O=C1C2C(=CC=CC=2)C(NC=O)CC1.C(N=C=O)(=O)C1C=CC=CC=1.C([NH:46][C:47]([NH:49][CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:60])[CH2:52][CH2:51]1)=[O:48])(=O)C1C=CC=CC=1>>[O:60]=[C:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:50]([NH:49][C:47]([NH2:46])=[O:48])[CH2:51][CH2:52]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCC(=O)c2ccccc21
Agent: NC1CCC(=O)c2ccccc21
Agent: O=C=NC(=O)c1ccccc1
Agent: O=CNC1CCC(=O)c2ccccc21
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
In the manner described in Example 5, (+)-1,2,3,4- tetrahydro-4-oxo-1-naphthylamine, which is obtaind by acid hydrolysis (refluxing in HC1)of (-)-N-(1,2,3,4-tetrahydro-4- oxo-1-naphthyl)formamide followed by neutralization, is allowed to react with benzoyl isocyanate. The resulting 1-benzoyl-3-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)urea is then hydrolyzed with alkali as in Example 6 to afford (-)-1,2,3,4-tetrahydro-4-oxo-1-naphthylurea.
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[CH:47]1([CH2:53][CH2:54][CH2:55]Cl)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH:47]1([CH2:53][CH2:54][CH2:55][N:44]2[CH2:45][CH2:46][N:41]([C:33]3[CH:34]=[C:35]([F:40])[C:36]([O:38][CH3:39])=[CH:37][C:32]=3[F:31])[CH2:42][CH2:43]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: ClCCCC1CCCCC1
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCCC3CCCCC3)CC2)cc1F
Yield: 97.1 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-cyclohexylpropyl chloride (161 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (342 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1c(F)cccc1F
Yield: 81.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,6-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.1 g, 82%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([N:18]([CH3:20])[CH3:19])[C:12]=1[NH2:21]>>[CH3:19][N:18]([CH3:20])[C:13]1[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([F:10])[C:12]=1[N:21]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CN(C)c1cc(F)cc(F)c1N
Product: Cc1cc(O)cc(=O)n1-c1c(F)cc(F)cc1N(C)C
Temperature: 160 °C
Yield: 17.8 %

Procedure:
An intimate mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g, 0.0103 mol), and 3,5-difluoro-N,N-dimethylbenzene-1,2-diamine (1.4 g, 0.008 mol) was heated at 160° C. under argon for 15 min. The dark colored reaction mixture was cooled, triturated with EtOAc (15 ml), and filtered. The solids were washed with warm EtOAc, followed by hexane and dried to give the title compound as a light blue solid (0.4 g, 14%). Analytically pure sample was prepared by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions were combined and freeze-dried to give the title compound: 1H NMR (CD3OD/400 MHz) δ 6.61 (m, 2H), 6.08 (d, 1H, J=2.0 Hz), δ 78 (d, 1H, J=2.0 Hz), 2.69 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 281.1084 (M+H C14H15N2O2F2 requires 281.1096).