Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]([C:11](OC)=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:7]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[CH2:16]([O:15][C:9]1[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:7][N:6]2[CH2:5][CH2:4][NH:1][C:11](=[O:12])[C:10]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nn(CCN=[N+]=[N-])c(C(=O)OC)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Temperature: 90 °C

Procedure:
To a solution of dimethyl 1-(2-azidoethyl)-4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (0.84 g, 2.34 mmol) in anhydrous DMF at 0° C. was added triphenylphosphine (0.92 g, 3.50 mmol). Water (300 μL) was added and the reaction was heated to 90° C. for 3 days. The solvent was removed in vacuo, and the resulting white solid was purified by flash chromatography on silica gel using 0-10% MeOH/CHCl3 gradient elution. Collection and concentration of the appropriate fractions afforded an oily solid which was triturated with methanol to yield a white precipitate. The solid was collected by vacuum filtration to afford the title product. ES MS (M+1)=302.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:34][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: COC(=O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (1-1) (1.1 g) in tetrahydrofuran (7 ml) and water (2 ml) is added, at room temperature, lithium hydroxide monohydrate (0.28 g). The mixture is stirred at room temperature for 20 minutes, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (0.82 g, 73%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]1[NH:13][C:12](=O)[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[CH2:9]1.Cl>C1COCC1.[OH-].[Na+].O>[CH3:7][CH:8]1[NH:13][CH2:12][C:11]2[CH:15]=[CH:16][S:17][C:10]=2[CH2:9]1
Reactant: CC1Cc2sccc2C(=O)N1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1Cc2sccc2CN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a suspension of LAH (0.38 g, 10 mmol) in THF (10 ml) a solution of 6-methyl-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (0.5 g, 3 mmol) in THF (10 ml) was added dropwise. The mixture was stirred for 3 h under reflux and cooled to 0° C. with ice. The solution of 0.4 ml of water in 2 ml THF, 25% NaOH (0.4 ml) and water (1.2 ml) were added carefully step by step. The mixture was stirred for 30 min, filtered and concentrated on rotary evaporator. The residue was purified by flash column chromatography on silica gel (eluent: chloroform/methanol—0→20%) to give yellowish oil. Then, 6 N isopropanolic HCl was added to the oil, stirred for 5 min, concentrated on rotary evaporator, triturated with diethyl ether, filtered, washed with ether and dried in vacuo to give 0.37 g of crystalline compound.
Reaction SMILES: Cl.N[CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.[OH2:29].Cl>C(O)(=O)C.O>[C:10]([C:9]1[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[C:5]([OH:18])[C:4]=1[CH:3]=[O:29])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1.25 g (4.60 mmol) of the product of Example 19 (as the hydrochloride salt) in 10 mL of acetic acid-water (11:3) was added 0.75 g (5.35 mmol) of hexamethylenetetramine. The mixture was refluxed for 3 h then treated with 6 mL of water and 3 mL of conc. hydrochloric acid. Heating was continued for 10 min at which point the reaction mixture was cooled and concentrated in vacuo to remove the acetic acid. The residue was partitioned between EtOAc and water, and the aqueous layer was separated and extracted. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:49][C:50]1[CH:58]=[C:57]2[C:53]([C:54]([CH:59]3[CH2:63][N:62]([C:64]4[N:69]=[CH:68][CH:67]=[CH:66][N:65]=4)[CH:61]4[CH2:70][CH2:71][NH:72][CH:60]34)=[CH:55][NH:56]2)=[CH:52][CH:51]=1>CN1C(=O)CCC1.C(OCC)C>[C:12]([O:11][C:9](=[O:10])[NH:1][CH:2]([C:6]([N:72]1[CH2:71][CH2:70][CH:61]2[N:62]([C:64]3[N:69]=[CH:68][CH:67]=[CH:66][N:65]=3)[CH2:63][CH:59]([C:54]3[C:53]4[C:57](=[CH:58][C:50]([F:49])=[CH:51][CH:52]=4)[NH:56][CH:55]=3)[CH:60]12)=[O:8])[CH:3]([CH3:4])[CH3:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1ccc2c(C3CN(c4ncccn4)C4CCNC34)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
To a solution containing Boc-Val-OH (106 mg, 0.48 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (185 mg, 0.48 mmol) and DIPEA (67 mg, 0.52 mmol) were added followed by the addition of crude 71 (150 mg, 0.46 mmol) in anhydrous NMP (3 mL). After 2.5 h, the reaction mixture was diluted with diethyl ether and washed successively with water, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 210 mg (86%) of 72 as a white-colored foam. Mass spectrum, m/z [523] (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[NH2:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1>ClCCl>[Cl:7][CH2:6][CH2:5][O:4][C:2]([NH:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:3]
Reactant: Cc1cccc(N)c1CNc1cccn2c(C)c(C)nc12
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Chloroethyl chloroformate (12.4 g, 81 mmol) dissolved in dichloromethane (40 ml) is added dropwise at RT, during the course of about 30 min, to a solution of 8-(2-amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (19.65 g, 70 mmol) in anhydrous dichloromethane (600 ml). The mixture is then stirred at RT for 16 h and then extracted with sodium hydrogen carbonate (4×200 ml). After extraction of the aqueous phases with dichloromethane (200 ml), the combined organic extracts are washed with water (2×200 ml), dried over magnesium sulfate and concentrated. The crude product which remains (33.9 g) is used directly for the further reaction in Example 1b.
Reaction SMILES: C([N:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:4][CH2:5][NH2:6])=O.[H-].[Na+].[CH:16]([NH:18][CH2:19]CN)=[O:17].BrCC1C=CC=CN=1.CN=C=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:19][NH:18][C:16]([NH:6][CH2:5][CH2:4][NH:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:17]
Reactant: NCCNC=O
Reactant: NCCN(C=O)Cc1ccccn1
Agent: BrCc1ccccn1
Agent: CN=C=O
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)NCCNCc1ccccn1

Procedure:
A mixture of N-formyl-N-(2-pyridylmethyl)ethylenediamine (prepared by adding sodium hydride to N-formylethylenediamine in dry dimethyl formamide, then reacting with 2-bromomethylpyridine at room temperature) and methyl isocyanate in dry chloroform is heated in a pressure vessel at 100° for 18 hours to give after cooling and removing the solvent N-methyl-N'-[2-((N"-formyl-N"-2-pyridylmethyl)amino)ethyl]urea. Acid hydrolysis by the procedure of Example 4 gives the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>C(#N)CC>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[N:7]([CH:12]([CH3:14])[CH3:13])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:46][CH2:47]2)=[CH:38][CH:37]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CC(C)N1CC(=O)Nc2cc(CO)cnc21
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)N1CC(=O)Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
The 7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.452 mmol) suspended in propionitrile (1 mL). To this was added (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followed by DIEA (0.237 mL, 1.356 mmol) and 4-(4-chlorophenyl)piperidine hydrochloride (115 mg, 0.50 mmol). The reaction was stirred at 90° C. overnight. The crude reaction was cooled to room temperature and concentrated to a residue, then taken up in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered and dried in vacuum to afford the title compound (28.3 mg, 16%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.29-7.37 (m, 2H), 7.18-7.29 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.75-4.87 (m, 1H), 3.81 (s, 2H), 3.32 (d, J=12.9 Hz, 3H), 2.88 (d, J=11.1 Hz, 2H), 1.87-2.07 (m, 2H), 1.65-1.77 (m, 2H), 1.57 (dd, J=12.4, 3.3 Hz, 2H), 1.10 (d, 6H). [M+H] calc'd for C22H27ClN4O, 399; found, 399.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>COCCOCCOC.C(Cl)Cl>[F:18][C:14]1([F:19])[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CCOC(=O)C1CCC2(CC1)CC2(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diglyme (3 mL) was added a solution of sodium 2-chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diglyme via syringe pump at 0.5 ml/h at 150° C. The reaction was cooled to rt, then diluted with DCM and washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) ppm 4.09-4.19 (2H, m), 2.29-2.45 (1H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5H, m), 1.45-1.54 (1H, m), 1.31-1.39 (1H, m), 1.21-1.30 (3H, m), 0.84-0.94 (1H, m).
Reaction SMILES: C([BH3-])#[N:2].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16](=O)[CH2:17][O:18][CH3:19])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+].C(=O)([O-])[O-].[Na+].[Na+].S(=O)(=O)(O)O.Cl>CC(O)C.O.CO>[ClH:5].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH:16]([NH2:2])[CH2:17][O:18][CH3:19])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: COCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: COCC(N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 240 h

Procedure:
Sodium cyanoborohydride (4 g) was added to a stirred mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-2methoxyethanone (20 g), ammonium acetate (70 g) and methanol (300 ml) and the mixture allowed to stand at ambient temperature for 10 days. The mixture was poured into water (1 litre), basified with aqueous sodium carbonate solution and extracted with ether. The extract was evaporated to yield an oil which was poured into water, acidified with concentrated sulphuric acid and allowed to stand for 16 hours at ambient temperature and then heated to 90°-95° C. for 1 hour. The cooled mixture was washed with ether, basified and extracted with ether. The extracts were dried and evaporated to give an oil which was treated with concentrated hydrochloric acid and propan-2-ol. Evaporation to dryness gave a solid which was recrystallised from propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethylamine hydrochloride (m.p. 207°-210° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[CH3:14][O:15][CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH:29]([CH:43]([CH3:45])[CH3:44])[CH2:30][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38](C)([CH3:40])C)C3CO3)[CH:26]=2)[N:21]([CH3:46])[CH:20]=1>CS(C)=O>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH:29]([CH:43]([CH3:45])[CH3:44])[CH2:30][CH:31]3[CH:38]([CH2:40][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])[O:37][C:36](=[O:42])[NH:35]3)[CH:26]=2)[N:21]([CH3:46])[CH:20]=1
Reactant: O=C1CCCCN1
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COCCCc1cn(C)c2ccc(CC(CC3NC(=O)OC3CN3CCCCC3=O)C(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.115 g of piperidin-2-one, 0.136 g of potassium tert-butoxide in 3 ml of dimethyl sulphoxide is stirred at room temperature over 30 minutes, admixed with 0.26 g of tert-butyl {3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate (Example 3Ab) and subsequently stirred further at room temperature overnight. The reaction mixture is poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1)([OH:3])=[O:2].Cl.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C>[CH2:14]([O:2][C:1]([CH:4]1[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1)=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)C1Cc2ccsc2CN1
Agent: Cl
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)C1Cc2ccsc2CN1Cc1ccccc1
Yield: 53 %

Procedure:
Obtained according to a procedure analogous to that of Example 7, from 5-carboxy-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (Example 6) and benzyl chloride. Hydrochloride: pale yellow crystals; M.p. 135°-140° C. (isopropanol); Yield: 53%.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:27][CH2:26][S:25][C:24]([CH3:29])([CH3:28])[C@@H:23]3[C:30]([OH:32])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]3[CH2:27][CH2:26][S:25][C:24]([CH3:29])([CH3:28])[C@@H:23]3[C:30]([OH:32])=[O:31])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(CO)cc3)cc2)[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(CNCCO)cc3)cc2)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Crude product from (a) was diluted up in anhydrous THF (1 mL) in a dry environment and then cooled to ˜0° C. To this solution was added ethanolamine (1 mL of a 0.2 M solution in dry THF). This was allowed to warm to room temperature while stirring overnight. Concentration in vacuo, followed by hydrolysis of the ester as described in part (c) of Example 5 gave the title compound.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][N:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:8][C:7]([C:6]1[C:2]([I:1])=[N:3][N:4]([CH:10]([CH3:12])[CH3:11])[CH:5]=1)=[O:9]
Reactant: CC(=O)c1cn(C(C)C)nc1I
Reactant: COC(OC)N(C)C
Product: CC(C)n1cc(C(=O)C=CN(C)C)c(I)n1
Temperature: 155 °C

Procedure:
A mixture of Intermediate 1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)ethanone (5.0 g, 18.0 mmol) and N,N-dimethylformamide dimethyl acetal (50 mL) was heated at 155° C. for 20 h. The mixture was concentrated under vacuum to provide the crude title compound. MS m/z 334.0 (M+1).
Reaction SMILES: [H-].[Na+].C([Si](C)(C)[O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[C:16]3[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=3[S:14][CH2:13][C:12]2=1)(C)(C)C.Cl[CH2:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1>CN(C=O)C>[N:37]1([CH2:36][CH2:35][O:34][C:33]2[CH:43]=[CH:44][C:30]([CH2:29][N:18]3[C:17]4[C:16]5[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=5[S:14][CH2:13][C:12]=4[C:11]4[C:19]3=[CH:20][CH:21]=[C:9]([OH:8])[CH:10]=4)=[CH:31][CH:32]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2SC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 144 mg, 1.317 mmoL) was added into 8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (440 mg, 1.197 mmoL) in DMF (5 mL) at 0° C. After 10 minutes, 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (382 mg, 1.317 mmoL) was added dropwise into the reaction at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layers from the two extractions were combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, first EtOAc then CH2Cl2:MeOH 4:1 as eluent) to yield 8-(tert-butyl-dimethyl-silanyloxy)-11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluorine as a pale foam and 11-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol as a yellow solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:23][CH:24]1[C:34](=[O:35])[N:26]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH2:29][S:30][C@H:25]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][Cl:17])[C:10]([NH:23][CH:24]2[C:34](=[O:35])[N:26]3[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH2:29][S:30][C@H:25]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 32.2 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 3.47 g.), N,N-dimethylformamide (1.1 g.) and phosphoryl chloride (2.3 g.) in ethyl acetate (35 ml.), and a solution of 7-amino-3-cephem-4-carboxylic acid (2.5 g.) and bis(trimethylsilyl)acetamide (12.7 g.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 15-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.85 g.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([C:18]([OH:20])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:22]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:27][NH:28][C:18]([C:11]2[C:12]([C:14]([F:15])([F:16])[F:17])=[N:13][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][CH:10]=2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCC1
Reactant: O=C(O)c1cnc(Nc2ccccc2)nc1C(F)(F)F
Agent: Cl
Product: O=C(NCC1CCCC1)c1cnc(Nc2ccccc2)nc1C(F)(F)F
Yield: 82.9 %

Procedure:
In a manner similar to Reference Example 1 (c), 2-(Phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and cyclopentylmethylamine hydrochloride (21 mg) afforded the title compound (32 mg) after purification by trituration with diethylether.
Reaction SMILES: [NH2:1][C:2]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[N:6][CH:5]=1)=[O:3].Cl.[Cl:24]C1C(Cl)=C(C)NC=1C(NC1CCNCC1)=O>>[ClH:24].[NH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[S:8][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][N:6]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(N)=O)s2)CC1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: NC(=O)c1cnc(N2CCC(N)CC2)s1

Procedure:
Title compound was synthesized from tert-butyl 1-[5-(aminocarbonyl)-1,3-thiazol-2-yl]piperidin-4-ylcarbamate (Intermediate 82) by an analogous method to Intermediate 1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:35])[CH:15]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC2(CC1)OCCO2
Yield: 81.1 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene)acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:28][CH:29]=1
Reactant: CCCc1oc(-c2ccccc2Cl)nc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1oc(-c2ccccc2Cl)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25ClN4O3 (m/e) 428, obsd 429 (M+H).