Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([C:61]#[N:62])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:61]([C:56]1[CH:57]=[N:58][C:59]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[C:51]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]3[CH2:25][CH2:24][C:15]4([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]4)[CH2:14][CH2:13]3)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1)[CH:60]=2)#[N:62]
Reactant: N#Cc1cnc2cc(Br)ccc2c1
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cc(C#N)cnc5c4)cc3F)CC2)OCC1=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (202 mg, 0.47 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (120 mg, 0.47 mmol), and potassium acetate (93 mg, 0.94 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (38.5 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromoquinoline-3-carbonitrile (110 mg, 0.47 mmol) and 2M aq K2CO3 (0.52 mL, 1.04 mmol) were added. The reaction mixture was purged with nitrogen and heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) afforded the title product (138 mg, 55% yield). MS(ES)+ m/e 502 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.65-1.84 (m, 2 H) 1.86-2.04 (m, 2 H) 2.25-2.40 (m, 1 H) 2.55-2.74 (m, 2 H) 2.75-2.87 (m, 1 H) 3.18 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.92-4.11 (m, 2 H) 4.56 (s, 1 H) 5.62 (d, J=3.54 Hz, 1 H) 7.28 (d, J=4.29 Hz, 1 H) 7.49 (t, J=7.71 Hz, 1 H) 7.58 (dd, J=11.12, 1.77 Hz, 1 H) 7.65 (dd, J=8.08, 1.77 Hz, 1 H) 8.00 (dd, J=8.59, 1.77 Hz, 1 H) 8.06 (d, J=8.34 Hz, 1 H) 8.43 (s, 1 H) 8.63 (d, J=2.02 Hz, 1 H) 9.10 (d, J=2.02 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Yield: 92.4 %

Procedure:
A mixture of 29.1 g of 4-chloro-2-fluoroaniline, 29.6 g of phthalic anhydride, and 150 ml of acetic acid was heated under reflux for 2 hours under stirring. After allowing the mixture to cool, the reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was washed with water and dried under reduced pressure to afford 50.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate (350 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][CH2:28][OH:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:30])[CH:10]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[CH3:38][S:39]([O:29][CH2:28][CH2:27][C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:17][C:16](=[O:30])[N:15]([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:19]1)(=[O:41])=[O:40]
Reactant: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.49 mmol) in dry CH2Cl2 (4 mL) was added Et3N (0.234 mL, 1.46 mmol) at 0˜−5° C. A solution of methanesulfonyl chloride (67 mg, 0.59 mmol) in dry CH2Cl2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was complete, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 97%), which was used in the next step without purification.
Reaction SMILES: [PH2](=O)O.C(N(CC)CC)C.C[Si](Cl)(C)C.[Cl-].[CH2:17]([O:24][C:25]([CH:27]([CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:28][P:29](CCCC1C=CC=CC=1)(=[O:31])[OH:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([O:24][C:25]([CH:27]([CH2:41][CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[CH2:28][PH:29](=[O:30])[OH:31])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=[PH2]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 ml of chloroform and treated with triethylamine (155 g, 1.52mol). The mixture was evaporated and transferred to a three liter flask, containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsiyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g of 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28(3:1 Hex./EtOAc 5% TFA);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])C(O)CCC2C=CC=CC=2)[CH2:14][CH2:13]1.[C:31]1([CH2:37]C(O)=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C=CC=CC=1[C@@H](CC)C(O)=O>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)C(O)CCc2ccccc2)CC1
Reactant: O=C(O)Cc1ccccc1
Agent: CC[C@@H](C(=O)O)c1ccccc1O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)Cc2ccccc2)CC1

Procedure:
Compound 14 was prepared in the manner of compound 7 substituting 2-phenylacetic acid for (R)-2-hydroxy-phenylbutyric acid in part C to afford compound 14: Mass spectrum (M+1)=366.40.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=S)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CCN(CC)CC.Cl.[NH2:23][OH:24]>CCO.O>[OH:24][NH:23][C:9](=[N:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=1)[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)(C)C(=S)Nc1ccc(I)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=Nc1ccc(I)cn1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide (example 39, step 2) (5.1 g, 15.9 mmol) was dissolved in 50 ml of EtOH and Et3N (2.9 ml, 20.7 mmol, 1.3 equiv.) and hydroxylamine hydrochloride (1.3 g, 19.1 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 2 hours at room temperature. The suspension was diluted with 100 ml of water and filtered. The crystals were washed with water and dried for 2 hours at 50° C. and <10 mbar. The desired N-hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (4.35 g, 86% yield) was obtained as a white solid, MS: m/e=319.9 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]#[N:27]>CN(C)C=O>[CH2:28]([CH:25]([N:20]1[CH:21]=[C:17]([C:15]([NH:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[N:18]=[CH:19]1)[C:26]#[N:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Reactant: CCCCCCC(Br)C#N
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C#N)n1cnc(C(=O)NC(c2ccccc2)c2ccccc2)c1
Yield: 49.8 %

Procedure:
To a solution of 1.67 g of 4-{[(diphenylmethyl)amino]carbonyl}-1H-imidazole in 100 ml of dimethylformamide were added 5.03 g of potassium fluoride on alumina. With stirring, 1.35 g of α-bromooctanonitrile were added. The solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. NMR indicated a mixture of starting material with desired product, so the residue was dissolved in 200 ml of acetonitrile, and 1 g of α-bromooctanonitrile and 5 g of potassium fluoride on alumina was added. After stirring at room temperature for 2 days, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over SiO2 and the appropriate fractions combined and concentrated in vacuo to provide 1.2 g of the desired titled intermediate, oil. MS: M+ =400
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.[ClH:30]>>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[C:13](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)\[CH2:14][CH3:15])=[CH:10][CH:11]=1.[ClH:30]
Reactant: CC/C(=C(/c1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1
Agent: Cl
Product: CC/C(=C(\c1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1

Procedure:
A method for the production of E-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3 '-hydroxyphenyl)-2-phenyl-1-butene of formula (I) ##STR9## which comprises the steps of a) heating the compound of formula (II) ##STR10## where R is an easily hydrolyzable protecting group at a temperature within the range of 70°-80° C. for a time within the range of 4-6 hours in the presence of an organic solvent and HCl gas and then cooling the reaction to a temperature within a range of -5° to 5° C. for a time within the range of 10-14 hours to obtain E/Z-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene×hydrochloride of formula (IIIa), and ##STR11## b) heating the compound of formula(IIIa) at a temperature within the range of 50°-60° C. for a time within the range of 10-24hours in the absence of an organic solvent and in the presence of 40-50% by volume suifuric acid or 32-37% hydrochloric acid, and alkalinizing the reaction mixture to obtain the compound according to formula (I).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)ccc1F
Yield: 76.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 76.8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[C:16](=[O:18])[CH2:15][CH2:14]3)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:17]=3[C:16](=[O:18])[CH2:15][CH2:14]4)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: O=C1CCc2cccc(Oc3cncc(Cl)n3)c21
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc4c3C(=O)CC4)n2)cc(OC)c1OC
Yield: 4 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-7-oxy)-pyrazine (200 mg, 0.77 mmol) and 169 mg (0.92 mmol) 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (11 mg). Yield: 4%.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:20]=[C:19]2[C:14]([NH:15][CH2:16][C:17](=[O:21])[NH:18]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:27])=[CH:24][CH2:25]Br.O>CN(C)C(=O)C>[CH3:22][C:23]([CH3:27])=[CH:24][CH2:25][N:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:9])=[O:10])=[CH:12][CH:13]=2)[NH:18][C:17](=[O:21])[CH2:16]1
Reactant: O=C1CNc2ccc(S(=O)(=O)Oc3ccccc3)cc2N1
Reactant: CC(C)=CCBr
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)=CCN1CC(=O)Nc2cc(S(=O)(=O)Oc3ccccc3)ccc21

Procedure:
7-Phenoxysulfonyl-3,4-dihydroquinoxalin-2(1H)-one (1.52 g, 5.0 mmol) in 20 ml of N,N-dimethylacetamide was stirred for 8 hours at 100° C. with 2 ml of 3-methyl-2-buten-1-yl bromide. After cooling, the mixture was treated with water and extracted with ethyl acetate. The solution was dried using magnesium sulfate and then concentrated, and the residue was chromatographed over a silica gel column using ethyl acetate/heptane=1:1. The fractions which contained the substance were evaporated on a rotary evaporator, and the product was subsequently stirred with pentane and filtered off with suction, melting point 132° C.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: NCC1CC1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylmethylamine; ESI-MS [M+H]+: 496.2
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.S([O-])(=O)(=O)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:26]([O-])=O.BrC1C=C2C(=CC=1)[N:36]=[CH:35]C([N+]([O-])=O)=C2Cl>>[NH:36]1[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:26]=[CH:35]1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(I)cc2c1Cl
Agent: CS(=O)(=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Product: c1ccc2c(c1)ncc1nc[nH]c12

Procedure:
The imidazo[4,5-c]quinoline system is synthesised starting from 4-chloro-3-nitroquinolines D which are activated in the 6-position by a leaving group EWG, for example halogen, triflate or mesylate. Preferably 4-chloro-6-iodo-3-nitro-quinoline (D.1) or 6-bromo-4-chloro-3-nitro-quinoline (D.2) is used.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Li]CCCC.[C:11]([C:17]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=O)#[C:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[C:11]([C:17]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:18]=1[C:19]([N:3]([CH3:2])[O:4][CH3:5])=[O:21])#[C:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC#Cc1cc(OC)ccc1C(=O)OC
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A suspension of N,O-dimethylhydroxylamine hydrochloride (1.11 g, 11.2 mmol), in THF (35 mL) was cooled to −20° C. in a dry ice-acetonitrile bath. To this solution was added nBuLi (1.6 M in hexanes, 14.0 mL, 22.3 mmol). The mixture was stirred until all the salt had dissolved. A solution of methyl 2-(1-hexyn-1-yl)-4-(methyloxy)benzoate (78) (0.55 g, 2.23 mmol) in THF (2 mL) was added slowly. The mixture was allowed to warm up to room temperature and stirred at room temperature for 3 h, quenched with water and extracted with ether (3×50 mL). The combined ether extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (2.5:1) to yield 0.42 g (68%) of 79 as a light brown oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.2 Hz, 3H), 1.40-1.55 (m, 2H), 1.55-1.65 (m, 2H), 2.39 (t, J=7.0 Hz, 2H), 3.28 (br s, 3H), 3.61 (br s, 3H), 3.80 (s, 3H), 6.83 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 276 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:25]1([CH2:31][C:32]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
For example, p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate is reacted with phenylacetyl chloride in cold aqueous acetone containing sodium bicarbonate to provide p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:26])[C:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:26])[C:12]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)C(C)(C)C(=O)Nc2cc(C(C)(C)C)on2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(O)cc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
To a solution of 203 mg (0.53 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-methoxybenzenesulfonyl)-2-methyl-propionamide (Example 43, Table 19, prepared according to method A) in DCM (5 mL) were added 0.3 mL (3.18 mmol) of BBr3 at 0° C. under nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was poured onto a saturated aqueous NaHCO3 solution-ice mixture (20 mL). The aqueous mixture was acidified to pH 5 and extracted with DCM (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was further purified by column chromatography (silica, eluent DCM, 0-20% ethyl acetate) to afford 64 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(4-hydroxy-benzenesulfonyl)-2-methyl-propionamide.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][N:10]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: CCCCOc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1nc(=O)n(C(=O)NCC)s1

Procedure:
1 ml of triethylamine was added to a solution of 17.4 g of 3-hydroxy-5-n-butoxy-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and then 12 ml of ethyl isocyanate were added dropwise with stirring. The mixture was stirred for 2 hours at 20° C and was concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with a 7-3 benzene-ethyl acetate mixture yielded 18.5 g of 2-(N-ethylcarbamoyl)-5-n-butoxy-1,2,4-thiadiazole-3-one.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4Cl)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4Cl)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-chlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 203°-206° C.) and piperazine.