Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=1)[CH3:2]
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(CC)CC)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.3 g of diethylamine, 4 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine, and 15 ml of dimethylformamide, giving ethyl 2-diethylaminothiazole-4-carboxylate as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>ClCCl>[F:19][C:20]([F:28])([F:29])[C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:26][CH:27]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
5.0 g of 2-methoxyphenylacetic acid was dissolved in 20 ml dichloromethane, and 4.6 g of oxalyl dichloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent and an excessive oxalyl dichloride were evapoarated, and the residue was dissolved in 20 ml dichloromethane. Under ice-cooling, 14 g of 4-trifluoromethyl aniline was added thereto, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and then the solvent was evpoarated. The resulting solid was collected by filtration and washed with diethyl ether, to give 8.0 g of N-[4-(trifluoromethyl)phenyl]-2-(2-methoxyphenyl)acetamide as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[NH:14][CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([N:26]([CH:36]2[CH2:38][CH2:37]2)CC2C=CC(OC)=CC=2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.ClC(Cl)C>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]3[NH:14][CH2:15][CH2:16][CH:10]3[CH2:9]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20]1[N:25]=[C:24]([NH:26][CH:36]2[CH2:37][CH2:38]2)[C:23]2=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:22]2[N:21]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CC(Cl)Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC3NCCC3C2)c1
Yield: 89 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (58 mg, 0.097 mmol), anisole (0.043 ml, 0.390 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) was heated at 35° C. overnight. Solvent was evaporated in vacuo and the crude was dissolved in acetonitrile (1 ml) and neutralized with 2N ammonia in methanol (1 ml). The crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-12% 2 N ammonia in methanol/dichloromethane). 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (41 mg) was obtained as a white solid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([O:17][CH3:18])[CH:8]=1.[C:19](=[O:21])=[O:20].O>C1COCC1>[CH:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][C:9]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: O=C=O
Reactant: COc1cc(Br)ccc1OC(C)C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Under an atmosphere of nitrogen, tert-butyllithium (2.14 mL of 1.6 M in toluene, 3.42 mmol) was added dropwise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C., then added dropwise to a flask containing CO2 (1.8 g, 40.8 mmol) (solid, dry ice) in THF (2 mL). The reaction mixture was allowed to stir for 30 minutes warming to room temperature. Water (20 mL) was added to the reaction mixture and the volatiles were removed in vacuo. The resultant aqueous layer was acidified with 1N HCl solution to pH 1 and was extracted with ethyl acetate (3×15 mL). The organics were separated and the combined organics were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-isopropoxy-3-methoxy-benzoic acid (310 mg, 85%) as a white solid. ESI-MS m/z calc. 210.1. found 211.1 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH3:7])[CH2:11][C@@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3]
Reactant: c1cn[nH]c1
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Product: C[C@@H](CN(C)C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (S)—N,N dimethyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](B(O)O)[CH:49]=[CH:48]2>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([O:44][C:43]([F:42])([F:59])[F:58])[CH:46]=4)[CH:51]=3)[N:11]([C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:40][CH:41]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1ccc2cc(OC(F)(F)F)ccc2c1
Reactant: C[C@@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1OS(=O)(=O)C(F)(F)F
Solvent: COCCOC
Product: C[C@@H](c1ccc(C(=O)NCCC(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2cc(OC(F)(F)F)ccc2c1
Temperature: 100 °C

Procedure:
tert-Butyl N-{4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate (10 mg, 0.016 mmol), 6-trifluoromethoxy-2-naphthylboronic acid (5.1 mg, 0.02 mmol), and TEA (14 ul, 0.1 mmol) were dissolved in dimethoxyethane (0.5 ml) and deoxygenated by vacuum-N2 fill cycles. The catalyst Pd(PPh3)4 (2 mg, 10% mol) was added and the mixture was deoxygenated again before heated in microwave reactor to 100° C. for 10 min. The mixture was quenched with 1.5 ml of CH3CN:H2O (3:1, with 5% TFA) and product separated through reverse phase preparative HPLC. The collected product was treated with 1 ml of TFA-DCM (1:2) for 30 min, and the residue lyophilized to give N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine as fine powder. NMR (500 MHz, DMSO-d6) δ: 1.91 (d, J=7.0 Hz, 3H); 2.46 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 5.78 (q, J=7.0 Hz, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (s, 1H); 7.57 (t, J=1.9 Hz, 1H; 7.58˜7.60 (m, 2H); 7.72 (d, J=8.4 Hz, 2H); 7.94 (d, J=1.9 Hz, 2H); 8.04 (br s, 1H); 8.06 (br s, 1H); 8.09 (d, J=9.1 Hz, 1H); 8.13 (d, J=8.6 Hz, 1H); 8.44 (t, J=5.5 Hz, 1H). MS C32H24Cl2F3N3O4 Cald: 641.11; Obsd (M+1): 642.22.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:19]#[N:20])[CH2:13][CH:12]1[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:20][CH2:19][C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH:12]1[CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18]
Reactant: CCC(CC)C1CC1(C#N)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(CC)C1CC1(CN)C(=O)O
Reaction time: 3 h
Yield: 10.8 %

Procedure:
To a solution of 1-cyano-2-(1-ethyl-propyl)-cyclopropanecarboxylic acid benzyl ester (1.76 g, 6.5 mmol) in 25 mL THF was added 20% Pd/C (0.2 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 3 hours. 1H NMR analysis indicated the benzyl ester had been completely cleaved. The mixture was filtered and concentrated hydrochloric acid (2 g) was added along with PtO2 (0.42 g) and the mixture was hydrogenated for an additional 16 hours until the nitrile was reduced. The mixture was filtered and concentrated. Flash chromatography of the residue on silica gel (0.25:1.25:3.5 conc. NH4OH (aq):MeOH:CH2Cl2), followed by ion-exchange chromatography on a DOWEX-50WX8-100 resin provided 0.13 g (11%) of 1-aminomethyl-2-(1-ethyl-propyl)-cyclopropanecarboxylic acid as a colorless solid, mp 255–257° C.: 1H NMR (D2O) δ 3.53 (d, J=13.2 Hz, 1H), 2.50 (d, J=13.2 Hz, 1H), 1.30 (m, 3H), 1.08–1.23 (m, 4H), 0.74 (t, J=7.6 Hz, 3H), 0.65 (t, J=7.6 Hz, 3H), 0.54 (m, 1H). LRMS: m/z 184.1 (M−1). Anal. Calcd for C10H19NO2: C, 64.83; H, 10.34; N, 7.56. Found: C, 64.84; H, 10.69; N, 7.44.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([NH:62][C:63]([CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCOC(C)=O.CN(C=O)C>[CH2:55]([NH:62][C:63]([CH:65]1[CH2:70][CH2:69][N:68]([C:17]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=3)[C:15]3[C:10]([C:9]=2[CH3:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:19])[CH2:67][CH2:66]1)=[O:64])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Reactant: Cc1c(C(=O)O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCC(C(=O)NCc3ccccc3)CC2)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following was added to sequentially to DMF (3 mL): 1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylic acid (90 mg, 0.315 mmol), DIPEA (0.170 mL, 0.945 mmol), and HATU (144 mg, 0.378 mmol). This was allowed to stir for 30 min at rt, after which time the crude N-benzylpiperidine-4-carboxamide (˜70 mg, 0.315 mmol) was added. The reaction was stirred at rt for 17 h, at which time the reaction was diluted with 1:1 EtOAc:diethyl ether and washed with 10% aq. sodium carbonate (2×), dried over magnesium sulfate, and concentrated. The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes) to afford the title compound as an oil. Yield: (77 mg, 0.153 mmol, 51%) 1H NMR (400 MHz, CDCl3) 7.59, 7.34-7.14, 7.03, 5.73, 5.57, 5.43-5.32, 4.76, 4.43, 3.77-3.64, 3.10, 2.80, 2.19-1.52
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5](I)=[C:6]([NH2:8])[CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=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>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH:11]=[CH2:12])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Br)c(Cl)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c(Br)cc1N
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 5-bromo-4-chloro-2-iodobenzenamine (2.5 g, 7.51 mmol), tributyl(vinyl)stannane (2.4 g, 7.51 mmol), Pd(PPh3)4 (867 mg, 0.75 mmol) in toluene (25 mL) was stirred at reflux under argon for 16 h. The reaction mixture was allowed to cool to room temperature and quenched with aqueous KF solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (1.0 g, 57.4% yield). ESI-MS m/z: 232.2[M+H]+.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH3:4][C:5]1[C:9]([Zr+3:11])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14].[CH3:15][C:16]1[C:17]([CH3:24])=[C:18]([CH3:23])[C:19]([Li])([CH3:21])[CH:20]=1>O1CCCC1>[Cl-:1].[Cl-:1].[CH3:4][C:5]1[C:9]([Zr+2:11][C:19]2([CH3:21])[CH:20]=[C:16]([CH3:15])[C:17]([CH3:24])=[C:18]2[CH3:23])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: [Li]C1(C)C=C(C)C(C)=C1C
Reactant: CC1=C(C)C(C)([Zr+3])C(C)=C1C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1=CC(C)([Zr+2]C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
10.0 g (33.6 mmols) of (pentamethylcyclopentadienyl)zirconium trichloride, and 150 ml of tetrahydrofuran were put into a 300-ml two-neck egg-plant flask. To this, dropwise added was a tetrahydrofuran solution (50 ml) of 4.3 g (33.6 mmols) of (tetramethylcyclopentadienyl) lithium that had been separately prepared at 0° C. This was warmed up to room temperature, and then stirred as such for 8 hours. The solvent was evaporated away, and the residue was extracted in 100 ml of dichloromethane. The resulting extract was concentrated and cooled to −20° C. to obtain 5.8 g of (pentamethylcyclopentadienyl)(tetramethylcyclopentadienyl)zirconium dichloride. A part of this was collected and dissolved in dewatered toluene to prepare a catalyst solution having a concentration of 10 μmols/ml.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Si](CC=C)(C)C)=[CH:10][C:9]=1[O:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C([O-])([O-])=O.[Na+].[Na+].[Al]>C1COCC1.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>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[Si](C)(C)c1ccc(NC(=O)OC(C)(C)C)c(OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.8 %

Procedure:
In a 500 ml three-necked flask under an argon atmosphere, 8 g (23.8 mmol, 1.7 eq) of tert-butyl-N-{4-[allyl(dimethyl)silyl]-2-ethoxyphenyl}carbamate 7 is mixed with 100 ml of anhydrous THF. Then 42.8 ml (21.4 mmol, 1.5 eq) of 0.5 M 9-BBN is added in anhydrous THF. The reaction is allowed to progress at room temperature and under argon for 4 hours. Then 0.5 g (0.42 mmol, 3% eq) of Pd(PPh3)4, 12 ml (1.7 eq) of an aqueous 2 M Na2CO3 solution, and 3.5 g (14 mmol) of bromopolystyrene resin (substituted 4 mmol/g) is added. The flask is wrapped in a sheet of aluminium foil and the THF is heated under a reflux condenser. After 40 hours, 0.5 g (0.42 mmol, 3% eq) of Pd(PPh3)4 catalyst is added and the reaction of THF under a reflux condenser for 24 hours is continued. The mixture is cooled to room temperature, then allowed to settle before filtering the resin on a Buchner funnel. The resin is washed successively with THF (4×40 ml), a 1% solution of diethyldithiocarbamic acid sodium salt in DMF (4×40 ml), a 1:1 mixture of THF/H2O (4×40 ml), then H2O (2×40 ml), MeOH (2×40 ml), DMF (2×40 ml), MeOH (2×40 ml), 3×[3×40 ml CH2Cl2, 3×40 ml MeOH] and, lastly, dried under vacuum (dessicator). 5.86 g of a light orange powder (yield: 80%) is obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:54](=[O:55])[N:25]3[C:26]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:27]([CH:30]=[CH:31][C:32]4[S:36][N:35]=[N:34][C:33]=4[CH3:37])[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.CO.C(Cl)Cl>[NH2:22][CH:23]1[C:54](=[O:55])[N:25]2[C:26]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])=[C:27](/[CH:30]=[CH:31]\[C:32]3[S:36][N:35]=[N:34][C:33]=3[CH3:37])[CH2:28][S:29][C@H:24]12
Reactant: Cc1nnsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.67 h
Yield: 44.9 %

Procedure:
Phosphorus pentachloride (5.83 g, 28 mmol) was made a methylene chloride (50 ml) suspension, pyridine (7.39 g, 93 mmol) was added at 5°-10° C. and stirring was continued for 40 minutes. Added all at once at 5° C. thereto was benzhydryl 7-phenylacetamido-3-[2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (E/Z=1/3.5, 5.69 g, 9.36 mmol), and the mixture was stirred at the same temperature for 3 hours. Methanol (38 ml) was slowly added to the reaction mixture at -50° C., and it was stirred for 1 hour at -50° to -30° C. Water (7 ml) was added at -10° C. and the reaction temperature was set at 0° C. and then it was stirred for 10 minutes. The reaction solution was adjusted to pH 6 with saturated sodium bicarbonate solution and then extracted with methylene chloride. It was washed with water and then the methylene chloride layer was dried over magnesium sulfate. The solvent was distilled off and then ethyl acetate was added to the residue. Precipitates were filtered and then cleansed with ethyl acetate thereby benzhydryl 7-amino-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (2.06 g, 45% yield) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[OH-].[Na+].Cl>O>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)/[C:3]([OH:21])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2ccccc2/C(=N\O)C(=O)O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) were added methanol (3.5 ml), water (3.5 ml), sodium hydroxide (0.31 g, 0.0077 mole) and the mixture was heated under reflux for one hour. After cooling to room temperature, the resultant was adjusted to pH 1 with 5% of hydrochloric acid. After stirring at room temperature, the crystals were filtered off and washed with water to obtain colorless crystals of E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid (0.90 g, yield: 94.7%).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>C1C=CC=CC=1>[C:16]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: c1ccccc1
Product: CCC(=O)N1c2ccccc2NC(=O)c2cscc21
Reaction time: 8 h

Procedure:
A reaction mixture comprising 9.9 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4.7 g. (4.4 ml.) of propionyl chloride in 100 ml. of benzene is refluxed for 3 hours and allowed to stand overnight. The precipitate is collected, washed with benzene and dried. A 3 g. portion of this solid is heated to boiling in 125 ml. of ethyl acetate, filtered and the filtrate is cooled. The solid is collected, washed with hexane and dried giving the desired product, mp. 222°-224° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1F
Reactant: COS(=O)(=O)OC
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1F

Procedure:
using isopropyl 2,4-difluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-difluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 112°-115° C.,
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][N:8]=[C:9]([C:12]1[C:13](=[O:31])[CH2:14][CH:15]([C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:20]=2[O:29][CH3:30])[CH2:16][C:17]=1[OH:18])[CH2:10][CH3:11])[CH3:6].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(O)C>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O:31][C:13]2[CH2:14][CH:15]([C:19]3[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:20]=3[O:29][CH3:30])[CH2:16][C:17](=[O:18])[C:12]=2[C:9](=[N:8][O:7][CH2:5][CH3:6])[CH2:10][CH3:11])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2OC)CC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(OS(=O)(=O)c2ccc(C)cc2)CC(c2c(C)c(C)c(C)c(C)c2OC)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A solution of sodium ethoxide (1.10 mmole) in ethanol (8.2 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2-methoxy-3,4,5,6-tetramethylphenyl)cyclohex-2-en-1-one (0.40 g, 1.10 mmole) in ethanol (50 ml). The mixture was evaporated to dryness and the residue dissolved in acetone (50 ml). 4-Toluenesulfonyl chloride (0.21 g, 1.10 mmole) was added and the mixture was stirred at room temperature for 2 hours, then evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-(4-toluenesulfonyl)oxy-2-[1-(ethoxyimino)propyl]-5-(2-methoxy-3,4,5,6-tetramethylphenyl)cyclohex-2-en-1-one (0.59 g; 100%) as a yellow oil.