Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:25])([CH3:24])[O:4][C:5]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:23])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:8][C:6]=12.[CH2:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>C(#N)C.S(=O)(=O)(O)O>[CH3:25][C:3]1([CH3:24])[C@@H:2]([OH:1])[C@H:7]([O:34][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[CH:8]=[C:9]([NH:12][C:13](=[O:23])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: COc1ccc(CC(=O)Nc2ccc3c(c2)C2OC2C(C)(C)O3)cc1
Reactant: OCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2ccc3c(c2)[C@@H](OCCc2ccccc2)[C@H](O)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-2H-1-benzopyran (200 mg, 0.68 mmol) and phenethyl alcohol (0.32 mL, 2.72 mmol) in acetonitrile (1.0 mL), sulfuric acid (0.01 mL) was added and stirred at the room temperature for 2 hours. Thereto, ice-cooled ethyl acetate was added and the formed crystals were filtered, to obtain the intended substance as white solid (yield:77%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([N:34]=[C:35]=[O:36])=[CH:28][C:27]=2[O:26]1>O1CCCC1>[O:33]1[C:32]2[CH:31]=[CH:30][C:29]([NH:34][C:35]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:36])=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)OCO2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-(methylenedioxy)phenyl isocyanate (199 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (71.9%) of the desired product as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:32]1[CH2:36][CH2:35][O:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:33][N:32]([CH2:36][CH2:35][OH:34])[CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: c1ccc(CN2CCOC2)cc1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Solvent: CCO
Product: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1cc(CN(CCO)Cc3ccccc3)c(O)c(OC)c1)O2
Yield: 57.3 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 20.0 g of 3-benyl-1,3-oxazolidine are held in 200 ml of absolute ethanol for 48 hours at 70° C. and subsequently solvent and excess 3-benzyl-1,3-oxazolidine are removed, finally in vacuum. After purification by means of a chromatographic column there is obtained 17.2 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxy-phenylmethyl)-N-(2-hydroxyethyl)-N-benzylamine, a colourless oil, which solidifies in the manner of glass at oil pump vacuum.
Reaction SMILES: [Na].C1(C)C=CC(S(N)(=O)=O)=CC=1.[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:37][S:36][C@@H:21]2[C@H:22]([NH:25]C(CCC[C@@H](N)C(O)=O)=O)[C:23](=[O:24])[N:20]2[C:19]=1[C:38]([OH:40])=[O:39])=[O:15].CN(C)C1C=CC=CC=1.C[Si](C)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.CO.O.C(N(CC)CC)C>[CH3:13][C:14]([O:16][CH2:17][C:18]1[CH2:37][S:36][C@@H:21]2[C@H:22]([NH2:25])[C:23](=[O:24])[N:20]2[C:19]=1[C:38]([OH:40])=[O:39])=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: C[Si](C)(Cl)Cl
Agent: Cc1ccc(S(N)(=O)=O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 28 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3.07 g of the sodium salt of toluene-p-sulphonamide of cephalosporin C having a titre of 83.8% were suspended in 30 ml of methylene chloride. 1.4 ml of triethylamine and 1.9 ml of N,N-dimethylaniline were then added and then 2.4 ml of dimethyldichlorosilane were added over 5 minutes with stirring. Stirring was maintained for 1 hour at 28° C. The solution was then cooled to a temperature of -60° C., after which a solution of 3.13 g of PCl5 in 30 ml of methylene chloride was slowly added, followed by 2.5 ml of N,N-dimethylaniline. After 2 hours of agitation at -40° C. the temperature was reduced again to -60° C. and 0.34 of N,N-dimethylaniline in 9 ml of methanol were added. After two hours at -40° C., 10 ml of water at 90° C. were added and agitation was continued for 5 minutes at 4° C. The aqueous phase was then recovered and the organic phase was extracted with 10 ml of cool water. The combined aqueous extracts were washed with 10 ml of methylene chloride and the pH was adjusted to 3.6-3.7 by addition of concentrated aqueous ammonia solution, with stirring. After allowing the mixture to rest overnight at a low temperature, the precipitate which formed was filtered, washed with methylene chloride, water, acetone and ether, to give 0.80 g (65%) of 7-aminocephalosporanic acid with a spectrophotometric titre of 94.4%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl.Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])[CH2:23][CH2:24]1
Reactant: CN(C)CC[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-4-[2-(dimethylamino)ethyl]cyclohexanamine dihydrochloride (300 mg, 1.2 mmol) to afford the desired product (140 mg, 36%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.88 (br s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 5.04-4.96 (m, 1H), 2.67 (s, 3H), 2.36-2.22 (m, 4H), 2.24 (s, 6 H), 1.93-1.83 (dd, J=13.9, 3.5 Hz, 2H), 1.49-1.31 (m, 5H), 1.27-1.15 (m, 2H); ESI MS m/z 375 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:37][N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([Cl:57])[CH:53]=3)[CH:48]=2)(=[O:46])=[O:45])[CH2:40][C:39]1=[O:58]>CN(C=O)C>[Cl:57][C:52]1[CH:53]=[C:54]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([S:44]([N:41]1[CH2:42][CH2:43][N:38]([NH:37][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:12][CH2:11]3)=[O:15])[C:39](=[O:58])[CH2:40]1)(=[O:45])=[O:46])[CH:56]=[CH:55]2
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 1-(4-pyridinyl)-4-piperidinecarboxylic acid (102 mg) and HOBt (153 mg) in DMF (25 ml) was combined with WSC (192 mg) at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was combined with 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (170 mg) obtained in Example 3 and stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue obtained was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic phase was washed with saturated aqueous sodium bicarbonate, dried and concentrated to obtain a residue, which was purified by a column chromatography on a basic silica gel (dichloromethane to dichloromethane: methanol=20:1) and crystallized from ethyl acetate/methanol to obtain the title compound (115 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:14]B(O)O.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[Br:1][C:2]1[C:3]([CH3:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(C)c(Br)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
An oven-dried resealable Schlenk tube was charged with ethyl 5,6-dibromonicotinate (preparation 47b, 1.09 g, 3.5 mmol), methylboronic acid (0.24 g, 4.0 mmol), potassium carbonate (1.46 g, 10.6 mmol) and 1,4-dioxane (27 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After 3 days, the mixture was cooled, filtered through Celite® and the filtrate was evaporated. Purification of the residue by flash chromatography (97:3 to 9:1 hexanes/ethyl acetate) gave the title compound (0.41 g, 45%) as a solid.
Reaction SMILES: Cl[C:2]([F:24])([F:23])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[C:25]1([C:31]2[O:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH2:36][OH:37])[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[F:23][C:2]([F:24])([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1)[O:37][CH2:36][C:34]1[N:35]=[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:32][C:33]=1[C:38]([F:41])([F:40])[F:39]
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)Cl)n3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)OCc4nc(-c5ccccc5)oc4C(F)(F)F)n3c2)cc1
Reaction time: 0.17 h

Procedure:
In a 5 mL microwave vial under a nitrogen atmosphere 3-(Chloro-difluoro-methyl)-6-(4-trifluoromethoxy-phenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.275 mmol), (2-phenyl-5-(trifluoromethyl)oxazol-4-yl)methanol (107 mg, 0.440 mmol), and NaH (39 mg, 0.96 mmol) in DMF (3 ml) were combined and stirred for 10 minutes. The reaction mixture was quenched with 1M HCl and concentrated before being purified the product, 4-((difluoro(6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)methyl)-2-phenyl-5-(trifluoromethyl)oxazole, by prep-HPLC(HCl).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[CH:14]1([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)NC2CCCCC2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 3-(chlorosulfonyl)benzoic acid (2.00 g) and dichloromethane (20 ml) under nitrogen at 0° was treated with cyclohexylamine (3.63 ml) and the mixture was stirred at 0° for 0.5 h. The solvent was evaporated in vacuo and the residue was treated with 1M potassium hydrogen sulfate solution (50 ml) and extracted with EtOAc (3×50 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (2.28 g). LCMS RT=3.16 min, ES+ve 284 (MH)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:22][C:12](=[O:14])[C:11]2[CH:15]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: N#Cc1ccc(NC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)cc1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-aminobenzonitrile (CAN 873-74-5, 39.0 mg, 0.33 mmol) as starting materials; off white solid (24 mg, 18.0%). MS (ESI): 402.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
An ice cold solution of N-benzyloxycarbonyl-4-hydroxymethylpiperidine (2.5 g, 10 mmol) in 100 mL CH2Cl2 is treated with pyridinium chlorochromate (3.23 g, 15 mmol). The reaction is stirred at ambient temperature for 3 hours. The mixture was diluted with 100 mL Et2O and filtered through a plug of silica. The filtrate was concentrated in vacuo to provide 2.3 g of the title compound as a pale green liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(F)cc(F)cc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(F)cc(F)cc32)n1

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5,7-difluoro-1,3-dihydro-2H-indol-2-one (1.0 g), 1-methyl-1H-imidazole (0.74 g) and difluoromethanesulfonyl chloride (1.09 g) are reacted in 8 ml of dichloromethane analogously to Example 5. For the work-up, water is added and stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 97% (1.08 g, 82% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])(C1C=CC(C)=CC=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Li+]>CN(C)C=O>[N:27]([CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])=[N+:28]=[N-:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
5' -O-Tosyl-2'-deoxyuridine (2.78 gm, 10 mmole) is dissolved in 50 ml of dimethylformamide (DMF) and 0.98 gm (20 mmole) of lithium azide added. The solution is heated at 100° C for 2 hours, then cooled and filtered. DMF is removed in vacuo at 40° and the yellow residue dissolved in 200 ml of 50% aqueous methanol. 20 gm of Dowex 50 (H+) resin are added and the solution stirred at room temperature for 30 minutes. After filtration, the solvent is reduced to 20-30 ml by rotary evaporation. As the solution becomes more and more concentrated, a white precipitate forms. The precipitate is collected by filtration, dried in vacuo over KOH pellets and recrystallized from 2-propanol to yield 2.05 gm (80% yield) of a white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([CH2:32][CH3:33])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][C:23]([CH:29]=[O:30])=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:31])[CH2:14]1)=[O:11])[CH3:8].Cl.C(O)(=O)C(C(C(O)=O)O)O.N>C1COCC1>[CH2:32]([N:9]([CH2:7][CH3:8])[C:10]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][C:23]([CH2:29][OH:30])=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:31])[CH2:14]1)=[O:11])[CH3:33]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C=O)cc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(CO)cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg of lithium aluminum hydride (2 mmol) is suspended in 5 ml of anhydrous, freshly distilled THF and, at room temperature, a solution of 350 mg of 1,1-diethyl-3-(13-formyl-6-methyl-8α-ergolinyl)urea (1 mmol), dissolved in 10 ml of anhydrous, freshly distilled THF, is added thereto. After one hour of stirring at room temperature, the mixture is combined under cooling with 5 ml of 1N hydrochloric acid, 5 ml of 2N tartaric acid solution is added, and the mixture is rendered alkaline with aqueous ammonia, extracted with ethyl acetate, the organic phase dried and evaporated. After chromatography on silica gel, the compound is crystallized from ethyl acetate.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6](Cl)=[O:7])([O-:3])=[O:2].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N+:1]([CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([O-:3])=[O:2]
Reactant: c1ccccc1
Reactant: O=C(Cl)CC[N+](=O)[O-]
Product: O=C(CC[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from benzene and 3-nitropropanoyl chloride, according to example 2, affording compound (15) with 78% yield, mp 72-74° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.[OH-].[Li+].CO>O>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:5]1
Reactant: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (2.0 g, 5.9 mmol), lithium hydroxide (0.56 g, 24 mmol), methanol (100 mL), and water (10 mL) was stirred at rt for 4 h. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 312.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 13.30 (bs, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.64 (d, 2H, J=8.0 Hz), 7.32 (d, 2H, J=8.0 Hz), 5.79 (bs, 1H), 4.52 (s, 2H), 4.30 (bs, 1H), 4.10 (bs, 1H), 3.84 (d, 1H, J=9.6 Hz), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH:42]2[O:44][CH2:43]2)=[CH:36][CH:35]=1>CO>[OH:44][CH:42]([CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[CH2:43][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccc(OC)cc1
Yield: 30 %

Procedure:
In 200 ml of methanol were dissolved 2 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.84 g of glycidyl 4-methoxyphenyl ether, and the solution was refluxed under heating for 3 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (95:5 v/v). Crude crystals were recrystallized from a mixture of methanol and ethyl ether to give 0.85 g of dimethyl 4-[2-[4-[2-hydroxy-3-(p-methoxyphenoxy)propylamino]butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:13])[CH3:12]>>[CH3:10][CH:11]([N:13]=[CH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1)[CH3:12]
Reactant: Nc1nccc(C=O)n1
Reactant: CC(C)N
Product: CC(C)N=Cc1ccnc(N)n1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 2-propyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:29])=[CH:31][CH:32]=3)[N:12]=2)=[CH:33][CH:34]=1
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 86.8 %

Procedure:
4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (2.63 g, 4.85 mmol), tert-butyl (4-aminobutyl)carbamate (1.37 g, 7.27 mmol), HATU (5.53 g, 14.55 mmol), and Hunig's Base (4.24 mL, 24.25 mmol) were stirred in DCM (20 mL) for 3 h. The solvent was removed and the crude material was purified by silica gel chromatography eluting with 20-40-80% ethyl acetate in hexane to give tert-butyl (4-(4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butyl)carbamate (3.0 g, 87%) as product.