Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:29][CH:28]=4)[C:22]4[C:21](=[O:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:24]([C:25]#[N:26])=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:34][C@@H:35]([OH:38])[CH2:36][OH:37])=[CH:31][CH:32]=4)[C:22]4[CH:21]([OH:39])[CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2c(c1-c1ccc(OC[C@@H](O)CO)cc1)C(O)CCC2

Procedure:
25 mg (0.043 mmol) of the compound from Example 3 were initially charged in 1 ml of THF and 0.1 ml of methanol, 0.8 mg (0.022 mmol) of sodium borohydride was added with stirring and the mixture was stirred at RT for 16 h. The reaction solution was diluted with about 2 ml of water and purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][NH:39][CH3:40]>>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][CH2:24][N:39]([CH3:40])[CH3:38])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: CNC
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCCO)CN2c1ccccc1
Product: CN(C)CCCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(3-hydroxy-propyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][C:10]=2[C:23]([F:26])([F:25])[F:24])=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:33][C@H:30]2[CH2:31][CH2:32][C@H:27]([NH2:34])[CH2:28][CH2:29]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)cnc2C(F)(F)F)c(Cl)cn1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)cnc3C(F)(F)F)c(Cl)cn2)CC1
Temperature: 100 °C

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine (0.0178 g, 0.046 mmol) was dissolved in anhydrous DMSO (1.0 ml) and charged to a microwave vial. This was treated with trans-cyclohexane-1,4-diamine (0.052 g, 0.456 mmol). The reaction mixture was then heated at 100° C. for 18 hr. The reaction mixture was allowed to cool to ambient temperature. The material was purified by preparative reverse-phase HPLC to give 0.0086 g (32%) of trans-N1-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)amino-3-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 485.3 (MH+), retention time=0.63 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:19])=[CH:9][C:10]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:31]1([CH2:44][O:45][C:46](Cl)=[O:47])[C:43]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.[13CH4]>C(Cl)Cl.C(OCC)(=O)C.CCCCCC.C(O)(=O)C.C(OCC)(=O)C>[C:11]([C:10]1[CH:9]=[C:8]([Cl:19])[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:46]([O:45][CH2:44][C:31]1[C:43]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1)=[O:47])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(C(=O)O)c(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: C[Si](C)(C)Cl
Agent: [13CH4]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(=O)O)c(Cl)cc1C(=O)c1ccccc1)OCc1cccc2c1Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A solution was prepared by diluting 3-amino-4-benzoyl-6-chlorobenzoic acid (5.59 g, 20.3 mmol) with approximately 70 mL of CH2Cl2. Chlorotrimethylsilane (5.50 g, 51 mmol, 2.5 equivalents) was added by syringe and the resulting white slurry was heated at gentle reflux for 1.5 hours. After cooling the mixture to 0° C., pyridine (3.69 g, 46.7 mmol, 2.3 equivalents) was added by syringe, immediately followed by addition of fluorenylmethoxycarbonyl chloride (5.78 g, 22.3 mmol, 1.1 equivalents). The resulting slurry was stirred for one hour under a nitrogen atmosphere. The reaction solution was then diluted with CH2Cl2 (150 mL) and was extracted three times with 1.0N aqueous sodium bisulfate (100 mL) and once with aqueous sodium chloride (100 mL), then dried over sodium sulfate and concentrated in vacuo to give a viscous oil. Pure product was obtained in 64% yield (6.50 g) as a white solid by flash chromatography with 5 cm×25 cm silica gel and 40:60 ethyl acetate and then 75:25:1 ethyl acetate/hexane/acetic acid as the eluent. The structure was confirmed by proton NMR, carbon-13 NMR, and FAB mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6](Cl)[N:7]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH2:19][CH2:20][CH:21]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([C:17]2[O:18][CH2:19][CH2:20][CH:21]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)[nH]c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1c(C2=CCCO2)nc(N)[nH]c1=O
Temperature: 100 °C
Yield: 27.2 %

Procedure:
To a stirred solution of 200 mg (1.17 mmol) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml dioxane under argon at room temperature were added 463 mg (1.29 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 82 mg (0.12 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 16 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1 then ethyl acetate then 5/95 methanol/ethyl acetate) afforded 65 mg (27%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 205 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Trimethylaluminium (2M solution in toluene) (2.86 mL, 5.71 mmol) was added to 5-fluoropyridin-2-amine in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) in toluene (8 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 24 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq.) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.32 g, 55%). 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 3.60-3.68 (m, 3H), 3.79-3.83 (m, 2H), 3.86 (d, 2H), 4.31-4.35 (m, 1H), 7.34-7.46 (m, 7H), 7.64-7.69 (m, 4H), 8.14 (d, 1H), 8.22-8.28 (m, 1H), 9.18 (s, 1H); m/z (ES+), (M+H)+=483.63; HPLC tR=3.08 min.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[C:24]#[N:25].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C)C>O1CCCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:24]#[N:25]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(C#N)cc1Cl
Yield: 95.9 %

Procedure:
Into a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and 3-chloro-4-hydroxy-benzonitrile (10 g, 65 mmol) was added anhydrous tetrahydrofuran (600 mL). The mixture was stirred briefly under nitrogen, di-tert-butyl azodicarboxylate (24 g, 104 mmol) was then added. The mixture was stirred for a few minutes, followed by addition of anhydrous isopropanol (6.23 mL, 81.4 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The crude product was purified by flash chromatography using 1:4 (v/v) ethyl acetate/heptane as eluent. Fractions were dried to give 3-chloro-4-isopropoxy-benzonitrile (12.2 g, 91%) as a red-orange semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.[Cl:14][C:15]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([Cl:21])[CH:18]=[C:17]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Fc1cccc(Cl)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1cccc(Cl)c1-c1cc(Cl)nc(Cl)n1
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
To a −78° C. solution of 5 mmol of 1-chloro-3-fluorobenzene in 10 mL of dry THF was added 5 mmol (2 mL, 2.5M) nBuLi. After 15 min added 2 mL dry THF solution of 5 mmol of 2,4-dichloropyrimidine. The solution was allowed to come to room temperature. The starting material had disappeared by TLC analysis. The reaction mixture was poured into a biphasic mixture of 0.1% acetic acid in water and ethyl acetate. The organic layer was separated and cooled in an ice bath. To the cooled ethyl acetate solution was added 5 mmol of DDQ and stirred for 15 min. A new product emerged was visible by TLC analysis (5% ethyl acetate/hexanes). The reaction was diluted with an equal portion of hexanes and filtered through silica gel. The resultant eluent was concentrated under reduced pressure and subjected to chromatography on silica gel with 5% ethyl acetate/hexanes to afford 280 mg of 2,4-dichloro-6-(2-chloro-6-fluorophenyl)pyrimidine (X) as a white solid. ESI/MS 276.9901 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+:9](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.N.O1CCOCC1>CN(C)C=O>[NH2:9][C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (180 mg, 0.46 mmol) was added to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-isopropoxyphenyl)propanoic acid (100 mg, 0.3 mmol) (Example 136, step 2) in N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (110 uL, 0.62 mmol). The reaction was stirred for 10 min., and 0.5 M ammonia in 1,4-dioxane (1.2 mL, 0.62 mmol) was added. The reaction was stirred for 1 h. at r.t., and was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, (S)-tert-butyl 1-amino-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate (90 mg, 90%). Analytical LCMS (M+H-Boc)+: m/z=222.9.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Br[CH2:20][C:21]([NH2:23])=[O:22]>ClCCl.CO.C(O)(=O)C>[CH:2]([N:23]([CH:5]([CH3:6])[CH3:4])[C:21](=[O:22])[CH2:20][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=2[F:11])=[CH:13][CH:14]=1)([CH3:7])[CH3:3]
Reactant: NC(=O)CBr
Reactant: O=C(O)c1cc(F)c(-c2ccc(O)cc2)c(F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N(C(=O)COc1ccc(-c2c(F)cc(C(=O)O)cc2F)cc1)C(C)C
Yield: 97.4 %

Procedure:
An alkylation was carried out with 370 mg of the product of Stage D with 428 mg of bromoacetamide (Preparation 9) under the conditions as described in Example 13, Stage D to obtain 282 mg of the expected product with a Rf=0.35 dichloromethane/methanol/ acetic acid 95/4/1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13]C1C=CC=CC=1.[N:20]([O-])=O.[Na+].N>C(O)(=O)C.S(=O)(=O)(O)O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:20]
Reactant: FC(F)(F)c1cc(Cl)c(Nc2ccccc2)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 107.5 %

Procedure:
2,6-Dichloro-4-trifluoromethylphenylaniline (4.3 g) was dissolved with stirring, in glacial acetic acid (23 ml). A solution of sodium nitrite (1.5 g) in concentrated sulphuric acid (11 ml) was then added at 55°-60° C. The solution thus obtained was cooled to 0°-5° C. and a solution of stannous chloride (16.4 g) in concentrated hydrochloric acid (14 ml) was added with vigorous stirring. A cream-colored solid precipitated. The mixture was filtered and the solid obtained was added to a mixture of aqueous ammonia solution and ice. The mixture thus obtained was extracted with diethyl ether (6×500 ml) and the combined ethereal extracts were dried over sodium sulphate, filtered and evaporated to dryness to give 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.7 g) m.p. 54°-56° C., in the form of a colorless crystalline solid.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(OC(N1CCC(OC2C=CC([N+]([O-])=O)=CC=2)(C2C=CC=CC=2)CC1)=O)C>>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:5]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Agent: CCOC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Product: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1

Procedure:
(oil), from 1-methyl-4-(4-nitrophenoxy)-4-phenylpiperidine, intermediate 1-ethoxycarbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine of m.p. 137° to 138° C.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[C:9]([Cl:16])(=[O:10])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(O)cc1

Procedure:
To a solution of coumaric acid (36.3 g) in dichloromethane (1.03 L) were added oxalyl chloride (45.2 mL) and N,N-dimethylformamide (0.6 mL). After foaming calmed down, the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to give the title compound. The obtained compound was used for the next reaction without being purified.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])=[CH2:28])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].S(C)C.[OH-:33].[Na+].OO>C1COCC1.O.CO>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:18]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH2:28][OH:33])[C:19]=4[S:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: [OH-]
Reactant: C=C(C)c1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)sc12
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CSC
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4c(C(C)CO)cccc34)c(C)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 8-(1-ethyl-propyl)-3-(7-isopropenyl-2-methyl-benzo[b]thiophen-3-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.58 g, 1.45 mmol) in THF (20 mL) is cooled to −78° C., and treated with 2.0 M BH3.SMe2 (2.2 mL, 4.3 mmol). The reaction is stirred in the cooling bath, allowed to warm up gradually to RT and stirred at RT overnight. It is cooled to 0° C., treated with CH3OH (10 mL), 5 M NaOH (10 mL), and 30% H2O2 (10 mL). The resulting mixture is stirred at 0° C. for 15 ml, and then at RT for 4 h. It is diluted with H2O (100 mL); extracted with EtOAc (3×100 mL). The combined organic layers is washed with 5% Na2SO3 (100 mL), H2O (100 mL); dried with Na2SO4; filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.35 g, 0.83 mmol, 57%). 1H NMR (CDCl3): δ 0.91 (t, J=7.0 Hz, 3H), 0.92 (t, J=7.0 Hz, 3H), 1.44 (d, J=3.5 Hz, 1.5H), 1.46 (d, J=3.5 Hz, 1.5 Hz), 1.75-1.95 (m, 4H), 2.38 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 3.25-3.40 (m, 1H), 3.40 (bs, 1H), 3.82-4.03 (m, 2H), 6.68 (s, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C25H31N3OS (M+H)+: 422.6. found: 422.3.
Reaction SMILES: [H-].[Na+].[N:3]1[O:7][N:6]=[C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]=12.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.O>CN(C)C=O>[N:3]1[O:7][N:6]=[C:5]2[C:8]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:10]=[CH:11][C:4]=12
Reactant: Oc1cccc2nonc12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OCC2CO2)c2nonc2c1
Temperature: 50 °C

Procedure:
Sodium hydride (620 mg; 60% oil dispersion) was added in portions to benzofurazan-4-ol (1.74g) in dimethyl formamide (30 ml). The mixture was heated at 50° C. for 30 min. Epibromohydrin (1.6 ml) was added and the mixture was heated at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel (50% ethyl acetate/hexane) to give 1-(4-benzofurazanyloxy)-2,3-epoxypropane (1.6 g), mp 75° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[C:24]([N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:30]1(=[O:32])=[O:31])([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C.P(=O)(O)(O)O>CN(C)C=O.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH2:16][O:17][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:30](=[O:32])(=[O:31])[NH:29][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2S1(=O)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
In dimethylformamide (20 ml) is dissolved sodium 7β-(t-butoxycarbonyl)amino-3-hydroxymethyl-3-cephem-4-carboxylate (3.20 g), followed by the addition of N-carboethoxysaccharin (3.20 g) and triethylamine (2.0 ml). The solution is stirred for one hour at room temperature and, after the addition of triethylamine (2.0 ml), stirred further for one hour. The solution is poured into toluene (1 L) and the resultant precipitate is collected by filtration, washed with toluene and dried. The powder thus obtained is dissolved in water (30 ml). After the addition of ethyl acetate (200 ml), the solution is adjusted to pH 4.0 with diluted phosphoric acid. After separation, the ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated. To the concentrate (30 ml), ether (200 ml) is added under stirring and the resultant precipitate is filtered off. The filtrate is concentrated under reduced pressure and to the concentrate (30 ml) is added carbon tetrachloride (100 ml). The resultant precipitate is collected by filtration, washed with carbon tetrachloride and dried over phosphorus pentoxide. The procedure provides 7β-(t-butoxycarbonyl)amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (2.50 g).