Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C@H:26]([C:48]([OH:50])=O)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:35])=[O:34].[NH:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61].Cl.C(N(CC)CC)C>CC(N(C)C)=O>[NH:25]([C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[C@H:26]([C:48]([N:58]1[CH2:67][CH2:66][CH2:65][C@H:59]1[C:60]([NH:62][CH2:63][CH3:64])=[O:61])=[O:50])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:47])[NH:32][S:33]([C:36]1[C:45]([CH3:46])=[C:43]([CH3:44])[C:40]([O:41][CH3:42])=[CH:39][C:37]=1[CH3:38])(=[O:34])=[O:35]
Reactant: CCNC(=O)[C@@H]1CCCN1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)NC(=O)OC(C)(C)C
Yield: 131.6 %

Procedure:
According to the general procedure for HBTU promoted coupling solutions of 31.5 g Boc-Arg(Mtr)-OH in DMAC, 24.79 g HBTU in DMAC, 11.56 g H-Pro-NHEt.HCl in DMAC and 19.60 g triethylamine in DMAC were premixed and fed into the reactor at 50° C. using a residence time of 1.1 min to yield 52 g crude material which was used in the next step without purification. The calculated yield from HPLC analysis was 99%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:7][C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][S:5][CH:6]=1.[Cl:19]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:1].[Cl:19][C:4]1[S:5][CH:6]=[C:2]([Cl:1])[C:3]=1[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=1
Reactant: Fc1cc2nc(Nc3cscc3Cl)[nH]c2cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cl
Product: Fc1cc2nc(Nc3c(Cl)csc3Cl)[nH]c2cc1F
Yield: 74.3 %

Procedure:
To (4-chloro-thiophen-3-yl)-(5,6-difluoro-1H-benzoimidazol-2-yl)-amine (125 mg) in acetic acid (8 ml) a solution of N-chlorosuccinimide (59 mg) in acetic acid (2 ml) was added. Following the analogous description in example 54c) the desired product (58 mg) was obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>CS(C)=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]#[N:7]
Reactant: C1CNCCN1
Reactant: Cc1cc(C#N)ccc1F
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)ccc1N1CCNCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoro-3-methylbenzonitrile (2.5 g, 18.50 mmol) in DMSO (10.0 mL) was added piperazine (7.97 g, 92 mmol) at 23° C. The reaction was stirred at 140° C. for 16 hr. The reaction mixture was poured into H2O (100 mL) and the reaction vessel was rinsed with H2O (˜50 mL). The resulting suspension was filtered, rinsed with H2O (3×10 mL) and the resulting solid was dried in vacuo to provide the title compound as a white solid (2.593 g, 12.88 mmol, 69.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21-2.30 (m, 3H) 2.57-2.70 (m, 1H) 2.83 (s, 8H) 7.03-7.09 (m, 1H) 7.55-7.62 (m, 2H). ESI-MS: m/z 202.1 (M+H)+.
Reaction SMILES: CP(=O)([O:5][CH3:6])OC.[CH2:8]([Li])CCC.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:30]2[C:29]3[CH2:28][CH2:27][C@@:25]4(C)[C:21](=[CH:22]O[C:24]4=O)[C:20]=3[CH2:19][CH2:18][C:17]=2[CH:16]=1>CCCCCC.O1CCCC1.O>[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]2[C:19]3[CH2:28][CH2:27][C@@:25]4([CH3:24])[C@H:21]([CH:22]=[CH:8][C:6]4=[O:5])[C:20]=3[CH2:29][CH2:30][C:17]=2[CH:16]=1.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]2[C:19]3[CH2:28][CH2:27][C@@:25]4([CH3:24])[C@@H:21]([CH:22]=[CH:8][C:6]4=[O:5])[C:20]=3[CH2:29][CH2:30][C:17]=2[CH:16]=1
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)OC=C12
Reactant: [Li]CCCC
Reactant: COP(C)(=O)OC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)C=C[C@@H]12
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)C=C[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5 g. of dimethyl methylphosphonate in 100 ml. of dry tetrahydrofuran cooled to about -78° under nitrogen, there is added with stirring one equivalent of n-butyl lithium in hexane. After about 10 minutes, there is added one molar equivalent of 3-methoxy-16-oxaestra-1,3,5(10), 8,14-pentaen-17-one in dry tetrahydrofuran while maintaining the temperature at about -78°. The mixture is allowed to warm to room temperature and then left to stand at room temperature for 5 hours. The mixture is diluted with water and then extracted with ether. The ether extracts are combined and concentrated to furnish a residue which is chromatographed on neutral alumina eluting with benzene to afford 3-methoxy-14β-estra- 1,3,5(10),8,15 -pentaen-17-one and 3-methoxy-14α-estra-1,3,5(10),8,15-pentaen-17-one which can be further purified by recrystallization from aqueous methanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CO.[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:17]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CNCCc1ccccc1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
A cold solution (0° C.) of glycine methyl ester hydrochloride (1.0 g, 8 mmol), methanol (25 mL), glacial acetic acid (0.8 mmol, and phenylacetaldehyde (0.481 g, 4 mmol) was treated with sodium triacetoxyborohydride (1.7 g, 8 mmol) in two portions. The reaction mixture was maintained at 0° C. for 1.5 hr, and then quenched with saturated sodium bicarbonate (15 mL). The solution was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and adsorbed onto silica gel (100 mg) and applied to a column prepacked with silica gel. The column was eluted with CH2Cl2 /MeOH (97:3, v:v) to afford titled compound (258 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:25]=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(Cl)Cl.C(O)C>N1C=CC=CC=1>[C:27]([O:21][CH2:20][C@H:19]1[O:22][C@@H:14]([N:13]2[C:23]3[N:24]=[CH:25][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:26])[C:10]=3[N:11]=[CH:12]2)[C@H:15]([OH:16])[C@@H:17]1[OH:18])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2ncn1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H]3O)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 1-benzylinosine (3.58 g, 10 mmol) and trityl chloride (3.3 g, 12 mmol) in pyridine (50 mL is stirred overnight at room temperature. An additional amount of trityl chloride (3.3 g) is charged on the second and third days. The reaction is monitored by thin layer chromatography on silica gel plates using a mixture of chloroform and ethanol (10:1 v/v) as the developing solvent. After all the starting material is consumed, the mixture is concentrated in vacuo, and the residue coevaporated several times with toluene and ethanol, and then chromatographed on a silica column using chloroform-ethanol (19:1 v/v) as the eluent to give 5'-O-trityl-1-benzylinosine which is crystallized from ethanol: 5.40 g (90% yield), mp 208°-209° C. 1H NMR (Me2SO-d6) δ 3.20-3.24 (2H, m, H-5',5"), 4.10-4.29 (2H, m, H-3',4'), 4.61-4.67 (1H, m, H-2', collapsed to dd upon addition of D2O, J1',2' =5.6, J2',3' =5.0 Hz), 5.24 (2H, s, CH2Ph), 5.21-5.27 (1H, m, OH, exchangeable), 5.57 (1H, d, OH), 5.92 (1H, d, H-1'), 7.06-7.32 (2OH, m, Tr, CH2Ph), 8.23, 8.51 (1H each, H-2, H-8). Analyses: calculated for C26H32N4O5 : C, 71.98, H, 5.37, N, 9.33. Found: C, 71.86, H, 5.44, N, 9.18.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:24]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[S:26][C:27]=1[Cl:28]>O1CCOCC1.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:27]1[S:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:23]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
To a 300 mL sealed flask was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.14 g, 39.1 mmol), potassium carbonate (12.98 g, 94 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1,4-dioxane (50 ml) and H2O (6 ml). After stirring for 90 min at 75° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The reaction residue was purified on silica gel [hexanes/EtOAc, 2:1] to give the product [5.7 g, 70%] as a tan solid: LCMS (ES) m/z 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N+:28]=2[O-:37])[CH:24]=[CH:25][CH:26]=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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N+:28]=3[O-:37])[CH:22]=2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: [O-][n+]1c(-c2cccc(Br)c2)cccc1C(F)(F)F
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: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)[n+]3[O-])c2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2-(3-bromo-phenyl)-6-trifluoromethyl-pyridine 1-oxide (1.12 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at room temperature under argon was added 2 N aqueous sodium carbonate solution (5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for two hours and then allowed to cool to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 9:1) to give 2-(4′-benzyloxy-3′-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine 1-oxide as a clear oil, 1.11 g (70%).
Reaction SMILES: Cl[C:2]1C(CCC)[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18].C(Cl)Cl.N(Cl)Cl>C(O)C.O>[NH:17]([C:2]1[N:3]([CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:18]
Reactant: NN
Reactant: CCCC1C(=O)c2ccccc2N=C1Cl
Agent: ClNCl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCn1c(NN)nc2ccccc2c1=O
Yield: 82 %

Procedure:
The crude solid imino chloride of Step C was dissolved in 800 ml of ethanol and 400 ml of hydrazine hydrate and the mixture was refluxed for two hours until TLC indicated (SiO2, CH2Cl2 /2% MeOH) that no imino chloride remained. 500 ml of water were added to the mixture and the mixture was cooled inducing a crystalline precipitate of the product. The precipitation was filtered, washed well with water, then dried over P2O5 under vacuum to obtain 158 g (82% yield) of 2-hydrazino-3-n-propylquinazolin-4(3H)-one in the form of a pale yellow solid melting at 125°-8° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:15]=O)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.CC1C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+]>COCCOC>[CH3:1][C:2]1[N:3]=[C:4]([CH2:15][C:27]#[N:28])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cn(COCC[Si](C)(C)C)c(C=O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cn(COCC[Si](C)(C)C)c(CC#N)n1
Yield: 80.3 %

Procedure:
Same procedure as that described in example 1, stage 1.4, starting from 8.7 g (32.7 mmol) of 4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde, 6.7 g (34.3 mmol) of TOSMIC and 7.3 g (65 mmol) of potassium tert-butylate in solution in anhydrous DME (54 ml). 6.6 g of compound is obtained in the form of a yellow oil as 70/30 mixture of regioisomers tau and Pi.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[NH3:4].[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:31]4[CH:32]=[N:33][NH:34][CH:35]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(-n3ccnc3)cc2)c2nccn12
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: C1COCCO1
Solvent: CN(C)C=O
Product: N
Product: c1cn(-c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)cn1
Yield: 110.6 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-imidazol-1-yl-phenyl)-amine (49.8 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (54.4 mg, 0.280 mmol), Pd(PPh3)4 (39.1 mg, 0.0338 mmol) and 1.5 M Na2CO3 (0.748 mL, 1.12 mmol) in 2:1 DMF-dioxane (1.5 mL). Purification by Isolute Flash SiII cartridge chromatography eluting with 98:2 DCM:NH3 (7M in MeOH), followed by 97:3 DCM:NH3 (7M in MeOH) and 95:5 DCM:NH3 (7M in MeOH) affords the title compound as a white solid (26.5 mg, 55%). LCMS: Rt 1.75 min (96%), m/z (APCI) 343 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 7.13 (1H, s), 7.63 (2H, d), 7.67 (1H, s), 7.73 (1H, s), 7.79 (1H, s), 8.09 (1H, br s), 8.18 (1H, s), 8.22 (1H, s), 8.27 (2H, d), 8.43 (1H, br s), 9.82 (1H, s), 13.39 (1H, br s).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.C(O)[CH2:30][OH:31]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:30][OH:31])=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: OCCO
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCCO)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 9.8 %

Procedure:
Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, ethylene glycol (0.50 mL, 9.0 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 1 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0040 g, y. 10%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH2:17])=O)[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]#[N:17])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(N)=O)cs1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(C#N)cs1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a cooled (0° C.) solution of 2-(N-Boc-aminomethyl)thiazole-4-carboxamide (200 mg, 0.78 mmol, see Angew. Chem. Int. Ed. Engl. 1996, 35, 1503) in dichloromethane (7 mL) was added triethylamine (0.32 mL, 2.34 mmol) and acetic anhydride (0.22 mL, 1.56 mmol) and the mixture stirred for 1 h. After the solvent was removed, the residue was purified by column chromatography (EtOAc: n-hexane, 3:7). 2-(N-Boc-aminomethyl)thiazole-4-carbonitrile (150 mg, 0.627 mmol) thus obtained was dissolved in methanol (10 mL) and cooled to 0° C. To this was added dropwise acetylchloride (30 equivalent) and the mixture stirred for 1 h at rt. The solvent was removed in vacuo to give the title compound (90 mg, 81%).
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C12C(=[O:24])C(CCC1)CCC2.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:24]
Reactant: O=C1C2CCCC1CCC2
Reactant: CC(=O)c1ccc2ccccc2c1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 8.29 g (0.06 mole) of bicyclo[3,3,1]nonan-9-one and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene, and the solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of this chromanol compound was heated at 150° C. to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 6.9 g of a chromene compound represented by the following formula: ##STR161##
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:14])[NH:12][CH2:11][CH:10]([CH3:13])[O:9]1.C(N(CC)CC)C.[Br:22][CH:23]([CH2:27][Br:28])[C:24](Cl)=[O:25]>O>[CH3:7][C:8]1([CH3:14])[N:12]([C:24](=[O:25])[CH:23]([Br:22])[CH2:27][Br:28])[CH2:11][CH:10]([CH3:13])[O:9]1
Reactant: CC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Br)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CN(C(=O)C(Br)CBr)C(C)(C)O1

Procedure:
Fourteen milliliters of a benzene solution containing 3.5 g. of 2,2,5-trimethyl oxazolidine was added to 25 ml. of benzene and 3.5 g. of triethylamine. Seven and one-half grams of 2,3-dibromopropionyl chloride was added dropwise with stirring and cooling in an ice bath. When reaction was complete, the mixture was poured into water and the benzene layer separated, dried over anhydrous magnesium sulfate and the solvent stripped under vacuum. The yield was 5.7 g. of an oil, nD30 = 1.5060.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[C:9](O)[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=1)([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:20])=O>>[CH3:1][C:2]([C:5]1[N:10]=[C:9]([Cl:20])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl

Procedure:
Phosphorus oxychloride (30 cm3) was added portionwise to ethyl 2-[2-(1,1-dimethylethyl)-4-hydroxypyrimidin-5-yl]-acetate (15.0 g). An exothermic reaction occurred and the resultant mixture was poured onto ice. After neutralisation with sodium carbonate the mixture was extracted with ethyl acetate and the extracts washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded ethyl 2-[2-(1,1-dimethylethyl)-4-chloropyrimidin-5-yl]acetate (11.35 g, oil, solidified on standing, mp. 42°-44° C.).
Reaction SMILES: CS(C)=O.[NH2:5][C@@H:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH2:13][O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH2:11][S:12][C@H:7]12.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O>C(OCC)(=O)C>[C:28]([O:27][C:26]([NH:5][C@@H:6]1[C:24](=[O:25])[N:8]2[C:9]([C:21]([OH:23])=[O:22])=[C:10]([CH2:13][O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH2:11][S:12][C@H:7]12)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To 500 ml of dimethyl sulfoxide is added 200 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To this 200 g of di-tert-butyl carbonate is added at room temperature and the mixture is stirred for 16 hours. To the reaction mixture are added 200 g of ice, 2 liters of water and 1 liter of ethyl acetate, and the mixture is stirred. After phase separation, the upper layer is discarded. To the aqueous layer is added 1 liter of ethyl acetate, and 129 g of phosphoric acid is added dropwise thereto while stirring (pH 4). After thorough mixing, the upper layer is separated and the lower layer is extracted with 1 liter of ethyl acetate. The organic layers are combined, washed with two 2-liter portions of ice-water and then with 1 liter of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. To the residue is added 100 ml of methylene chloride, and the resulting mixture is concentrated and dried to give 194 g (74% yield) of the above-identified compound as a glassy solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: CN1CCN(CCO)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 2-(4-methyl-1-piperazinyl)ethanol (1.09 g, 7.6 mmol). Sodium hydride (60%) (467 mg, 11.68 mmol) was added portionwise. The reaction was stirred at rt for 30 min at which time the reaction was diluted with ethyl acetate and washed with water and a saturated sodium chloride solution. Solvents were removed under reduced pressure to give 1.7 g of crude 1-methyl-4-(2-{[3-(methyloxy)-4-nitrophenyl]oxy}ethyl)piperazine as a yellow solid. ESIMS (M+H)+=296.