Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1CCCC1.BrCC1CC1.[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:46])[C@H:21]([NH:25][C:26]([C:28]2[C:36]3[C:31](=[N:32][CH:33]=[C:34](Br)[N:35]=3)[N:30](COCC[Si](C)(C)C)[CH:29]=2)=[O:27])[CH:22]2[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)#[N:13].C([CH:49]1[CH2:54][CH2:53][N:52]([C:55]([C@H:57]([NH:62][C:63](C2C3N=C(Br)C=NC=3N(COCC[Si](C)(C)C)C=2)=O)C(C)(C)C)=O)[CH2:51][CH2:50]1)#N>>[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:46])[C@H:21]([NH:25][C:26]([C:28]2[C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:57]4[N:62]=[CH:63][N:52]([CH:51]5[CH2:50][CH2:49][CH2:54][CH2:53]5)[CH:55]=4)[N:35]=3)[NH:30][CH:29]=2)=[O:27])[CH:22]2[CH2:23][CH2:24]2)[CH2:16][CH2:15]1)#[N:13]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: BrC1CCCC1
Agent: BrCC1CC1
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(C5CCCC5)cn4)nc23)C2CC2)CC1

Procedure:
Prepared according to the procedure outlined in Example 131 substituting bromocyclopentane for (bromomethyl)cyclopropane in Step 1 and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide in Step 3. MS: (M+H)+=487.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:35]1([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH2:37][CH2:36]1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:38][CH:35]3[CH2:37][CH2:36]3)=[C:50]([OH:51])[CH:14]=2)[CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1Sc1ccccc1CC1CC1

Procedure:
The title compound was prepared by Method A using 3'-phenyl acetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 88° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.25 (d, 2H), 0.53 (dd, 2H), 1.14 (m, 1H), 2.67 (d, 2H), 6.94 (m, 1H), 7.03 (s, 1H), 7.11 (m, 2H), 7.33 (m, 1H), 7.44 (d, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.75 (d, 2H), 7.86 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: [S:1]1[C:5]([S:6]([NH2:9])(=[O:8])=[O:7])=[CH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([C:5]2[S:1][C:2]3[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=3[CH:4]=2)(=[O:7])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2s1
Yield: 94.9 %

Procedure:
To a solution of 13.4 g (100 mmol) of benzothiophene, dissolved in 50 ml anhydrous diethyl ether, was added 62.5 ml of a 1.6 M hexanes solution of n-butyllithium (100 mmol). The reaction mixture was refluxed for 4 hours and then cooled to about −20° C. Sulfuryl chloride (16.1 ml, 200 mmol) was added dropwise. This suspension was stirred at ambient temperature overnight and then added to 75 ml of ice water. The ether layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was added to 100 ml of concentrated ammonium hydroxide and the suspension was warmed to 55° C. The solution was diluted with 200 ml of water and stirred at ambient temperature for several hours. Product was collected by filtration under vacuum. The residue was suspended in 150 ml toluene and filtered to provide 9.2 g of 2-benzo[B]thiophenesulfonamide. The sulfonamide (25 mmol) was reacted with 4-chlorophenylisocyanate (27 mmol) as described in Preparation 2 above to obtain 8.7 g of the title product as a solid.
Reaction SMILES: [OH-].[K+].C(O)(C)C.Cl[CH2:8][C:9]([N:11]([CH2:15][CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:12][CH2:13][CH3:14])=[O:10]>O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:16]2[CH2:15][N:11]([CH2:12][CH2:13][CH3:14])[C:9](=[O:10])[CH2:8][O:25]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCCN(CC(O)c1cccc(OC)c1)C(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCN1CC(c2cccc(OC)c2)OCC1=O
Yield: 100 %

Procedure:
Potassium hydroxide (4.2 g, 0.07 mol), isopropyl alcohol (500 ml) and the amide from example 4 (17.8 g, 0.06 mol) were stirred together as an opaque solution with water (15 ml) for 2 hours. The reaction mixture was concentrated in vacuo and the yellow residue dissolved in ethyl acetate (200 ml). This was partitioned with water (200 ml) then brine (200 ml). The organic fraction was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (15.8 g, 0.06 mol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.62 (m, 2H), 3.36 (m, 2H), 3.51 (q, 2H), 3.81 (s, 3H), 4.30-4.62 (bq, 2H), 4.79 (d, 1H), 6.85 (d, 1H), 6.91 (d, 1H), 6.95 (s, 1H), 7.29 (t, 1H). LRMS: m/z 272. Analysis found C, 66.80; H, 7.78; N, 5.52%. C14H19NO3.0.1H2O requires C, 66.96; H, 7.71; N, 5.58%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[N:10][NH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH3:18].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[N:10][N:9]([C:25]3[CH:26]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[CH:22]=[CH:23][CH:24]=3)[C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1cn[nH]c(=O)n1Cc1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-n2ncc(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
According to Scheme 4 Step 2: To a stirred solution of 4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.250 g, 1.1 mmol) in DMF (5 mL) were added 3-acetamidophenylboronic acid (0.28 g, 1.6 mmol), copper(II) acetate (0.19 g, 1 mmol) and pyridine (0.17 g, 2.1 mmol) and the mixture was stirred overnight at 60° C. The reaction was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by C18 reverse phase column, 15 g column: starting from 20% CH3CN and gradually increasing the percentage of CH3CN (10% each 300 ml) the product came out at 60% of CH3CN. 0.160 g (39%) of N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 7(B) were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([O:26][CH3:27])[CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)=[C:19]([O:26][CH3:27])[CH:18]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Cn1ccnc1CNc1cnccc1I
Product: COc1cc(F)ccc1-c1ccncc1NCc1nccn1C

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-((1-methyl-1H-imidazol-2-yl)methyl)pyridin-3-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of CH2Cl2:MeOH (100:0 to 85:15). Light yellow solid (95%). MS (ESI): m/z=313.145 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].C1COCC1>C(O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccccc2[N+](=O)[O-])c(OC)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Oc2ccccc2N)c(OC)c1

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene (0.66 mmol; 180 mg) and THF by ethanol, the title compound was prepared in quantitative yield (181 mg) and used without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]([CH:13]([OH:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
1-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethanone (3.67 mmol) in MeOH (5 mL) was treated with sodium borohydride (0.139 g, 3.67 mmol). The reaction was stirred for 20 minutes, and then standard work-up provided the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C1(C)C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[N:3]2[CH:19]=[N:20][CH:21]=[C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)ncc1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)n2cncc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of 5-bromo-1-methylpyrazin-2-one (500.0 mg, 2.65 mmol) and (p-tolylsulfonyl)methyl isocyanide (573.0 mg, 2.94 mmol) in THF (4 mL) was added a suspension of NaH (235.0 mg, 5.9 mmol) in THF (2 mL) at 0° C. under N2. After stirring at 0° C. for 30 min, the mixture was stirred at 30° C. for another 1.5 h. The reaction mixture was quenched with H2O (20 mL) at 0° C., and extracted with EtOAc (30 mL×2). The organic phases were combined, washed with brine (30 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (PE:EA=1/1) to give the title compound (300.0 mg, 50%) as a light yellow solid. 1H NMR (CDCl3 400 MHz) δ 8.06 (d, J=4.4 Hz, 1H), 6.61 (s, 1H), 3.48 (s, 3H). LCMS (M+H)+ 228.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([O:30]CC)=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
After a mixture of ethyl [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (475 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (402 mg, yield: 89%). This was recrystallized from ethanol-hexane. Melting point: 140–141° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([CH3:30])[C:22]=2[N:23]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:31]([OH:33])[CH3:32]>>[CH2:31]([O:33][C:28]([C:26]1[CH:25]=[C:24]([CH3:30])[C:22]2[N:23]=[C:19]([C:13]3[C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:12]=3[NH:11][C@H:3]([CH2:2][OH:1])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:20][C:21]=2[CH:27]=1)=[NH:29])[CH3:32]
Reactant: Cc1cc(C#N)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Reactant: CCO
Product: CCOC(=N)c1cc(C)c2nc(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of (S)-2-[4-(1-hydroxymethyl-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile (0.8 g, 2.0 mmol) in ethanol (anhydrous, 80 mL) was bubbled HCl (anhydrous) at 0° C. until saturation. The mixture became a clear solution after a few minutes of bubbling and the solution was stirred at room temperature for 14 h. After concentration in vacuo, the crude product (0.89 g, 100%) was directly used for the next step without purification. LCMS (M+H)+ m/z 446 (t=1.55 min).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[OH:29])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:49])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2]
Reactant: C[C@]12CCCCC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 70 %

Procedure:
The title compound II-ah was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 70/30). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.61 (1H, s), 3.29 (1H, dd), 2.61-1.03 (19H, m), 0.88 (3H, s), 0.79 (3H, s).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:9][C:8]=1[CH3:13]
Reactant: CCC(=O)Cl
Reactant: Cc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1ccc(Cl)c(C)c1
Temperature: 130 °C

Procedure:
16 g of propionyl chloride are added dropwise to a mixture of 18 ml of o-chlorotoluene and 22.7 g of aluminum chloride and the reaction mixture is then heated at 130° C. for 3 hours. After cooling to RT, it is poured into a mixture of 100 ml of concentrated HCl and ice, extracted with ether, the organic phase is washed with saturated NaHCO3 solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is distilled off under reduced pressure to give 20.7 g of the expected product which crystallizes. B.p.=95° C. under 5 Pa.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][CH:12]=1)=[O:9].[NH2:21][CH:22]1[C:40](=[O:41])[N:24]2[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[CH2:27][S:28][C@H:23]12>C(Cl)Cl>[CH:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([NH:21][CH:22]2[C:40](=[O:41])[N:24]3[C:25]([C:37]([OH:39])=[O:38])=[C:26]([CH2:29][S:30][C:31]4[N:35]([CH3:36])[N:34]=[N:33][N:32]=4)[CH2:27][S:28][C@H:23]23)=[O:20])[CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1cccc(CC(=O)O)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(NC=O)n3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
A solution of pivaloyl chloride (1.07 g.) in methylene chloride (3 ml.) was added to a solution of 2-(6-Formamidopyridin-2-yl)acetic acid (1.6 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) in methylene chloride (25 ml.) at -20° to -25° C., and stirred at the same temperature for one hour [solution A]. On the other hand, a solution of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.24 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) in methylene chloride (60 ml.) was stirred at room temperature for 10 minutes. To the solution was added the above solution A at -20° to -25° C. and stirred at the same temperature for 1.5 hours. After removing the solvent from the resultant solution, ethyl acetate, water and sodium bicarbonate were added to the residue. The aqueous layer was separated and washed with ethyl acetate. Ethyl acetate (300 ml.) was added to the aqueous solution, adjusted to pH 2 to 3 with 5% hydrochloric acid, and then shaken sufficiently. The ethyl acetate layer was separated, washed with water and concentrated under reduced pressure to give 7-[2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH3:11])=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(C)n1
Solvent: CCO
Solvent: O
Product: Cc1ccn(CC(=O)NN)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (3-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. The mixture was then cooled to rt and the precipitated product was filtered off and crystallized from ethanol. The title compound (>95% purity) was obtained as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.12 (s, 3H), 4.29 (s, 2H), 4.60 (s, 2H), 6.00 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>C(O)C>[OH:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][NH:15][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: NCCOCCO
Solvent: CCO
Product: O=C(NCCOCCO)c1cnc(C(=O)NCCOCCO)cn1
Temperature: 20 °C

Procedure:
A solution of 500 mg of 2,5-dimethoxycarbonylpyrazine and 0.720 cm3 of 2-(2-aminoethoxy)ethanol in 3 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 4 hours. The reaction mixture is cooled to a temperature of 20° C. and the white solid formed is then filtered off and washed with twice 5 cm3 of ethanol. 150 mg of N,N′-bis(2-hydroxyethyloxyethyl)-pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 125° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ at ppm): from 3.35 to 3.65 (mt, 16H: 2×NCH2CH2OCH2CH2O); 4.62 (t, J=5.5 Hz, 2H: 2×OH); 9.00 (t, J=6 Hz, 2H: 2×NHCO); 9.20 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:9]1=2)=O)(C)(C)C.[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])/[CH:23]=[CH:24]/[C:16]1[CH:17]=[N:18][C:9]2[NH:8][CH2:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Br)cnc21
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2
Temperature: 100 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
A solution of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester (494 mg, 1.5 mmol) in propionitrile (12 mL) was treated with N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (685 mg, 3 mmol) and diisopropylethylamine (788 μL, 4.5 mmol) and purged with Argon for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-Tol)3 (92 mg, 0.3 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hours under Argon. Upon cooling, solvent was removed and the residue was purified by Flash chromatography (silica, 1-3% MeOH in CH2Cl2) to afford the title compound (480 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 10.81 and 10.73 (rotamers, 2s, br, 1H), 8.46 and 8.41 (rotamers, 2s, 1H), 7.58 (d, J=15.4 Hz, 1H), 7.51 (m, 3H), 7.23 (d, J=15.4 Hz, 1H), 7.11 (m, 1H), 7.03 (m, 1H), 6.45 and 6.20 (rotamers, 2s, 1H), 5.06 and 4.87 (rotamers, 2s, 2H), 4.32 and 4.28 (rotamers, 2s, 2H), 3.74 and 3.71 (rotamers, 2s, 3H), 3.16 and 3.05 (rotamers, 2s, 3H), 1.44 and 1.42 (rotamers, 2s, 9H). MS (ESI) in/e: 476.2 (M+H)+, 420.2 (M-tert-Bu)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([C:12](Br)=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1([CH2:25][CH2:26][C@@H:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][C:38]=2[S:47]([C:50]([F:53])([F:52])[F:51])(=[O:49])=[O:48])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:11]([C:12]([NH:46][S:43]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C@@H:27]([CH2:28][S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:38]([S:47]([C:50]([F:52])([F:53])[F:51])(=[O:49])=[O:48])[CH:39]=3)(=[O:44])=[O:45])=[N:13][N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nnc(Br)n2CC1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nnc(NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)n2CC1
Temperature: 90 °C
Yield: 44.3 %

Procedure:
3-Bromo-4,5,7,8-tetrahydro-1,2,3a,6-tetraaza-azulene-6-carboxylic acid tert-butyl ester (154 mg, 0.486 mmol), 4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethane sulfonyl-benzenesulfonamide (269 mg, 0.486 mmol), (1S,2S)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.011 mL, 0.146 mmol), cesium carbonate (269 mg, 0.825 mmol), and copper (I) iodide (13.87 mg, 0.073 mmol) were added to a microwave vial followed by toluene (8 mL). The reaction mixture was degassed for 15 minutes under nitrogen, sealed, and then heated conventionally to 90° C. for 14 hours. The crude material was directly purified via flash chromatography on silica gel (0-15% 2N NH3 in methanol in CH2Cl2) to afford the title compound (170 mg, 44% yield). MS [m/z; (M+1)+]: 790.5