Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([OH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>CN(C)C=O>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[CH2:25][O:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2)=[O:29]
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A portion (1.15 g) of 60% sodium hydride was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) in an argon atmosphere; 2.0 g of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was dissolved in anhydrous DMF (40 mL) and the solution was added dropwise to the first mentioned solution at room temperature. After stirring for 1 hr at room temperature, a solution of methyl o-bromomethylbenzoate (6.6 g) in anhydrous DMF (40 mL) was added dropwise and the mixture was stirred for 1 hr. The reaction solution was poured into ice water (500 mL), and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as a yellow oil (2.38 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of methyl-(4-formylphenoxy)acetate (100 g, 0.515 mol) in methanol (500 mL) was cooled to 0-5° C. To this was added a solution of hydroxylamine hydrochloride (54 g) and sodium acetate (64 g) in water (500 mL) drop-wise and stirred at rt for 6 h. The reaction mixture diluted with water and filtered off the solid. The solid was washed with water and dried under vacuum to give the title compound (80 g, 74%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=O)=[CH:16][CH:17]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:3][C@@H:2]2[C:1](=[O:9])[O:10][C:6](=[O:8])[C@H:4]2[O:5][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)=[O:20])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)O[C@@H]2C(=O)OC(=O)[C@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a 300 ml reaction vessel equipped with a stirrer, thermometer, condenser and a dropping funnel, 30 g of D-tartaric acid, 70 g of toluene, 0.12 g of ferric chloride and 59.9 g of p-toluic acid were supplied, and the mixture was heated to 90° C. While keeping this temperature, 83.7 g of thionyl chloride was added from the dropping funnel for 6 hours and the resulting mixture was aged at 105°-110° C. for another 1 hour to carry out the reaction. The reaction mixture was then cooled to room temperature and the precipitated crystals were collected by filtration, followed by drying to obtain 67.2 g of O,O'-di-p-toluoyl-D-tartaric anhydride in the form of pale yellow crystals (purity: 100%, yield: 91.3%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([OH:8])[CH2:6][CH3:7].[P:19](=O)([OH:22])([OH:21])[OH:20]>C(O)C>[P:19]([O:8][C@@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:1])[CH3:18])([OH:22])([OH:21])=[O:20]
Reactant: CC[C@@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Reactant: O=P(O)(O)O
Solvent: CCO
Product: CC[C@@](OP(=O)(O)O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Reaction time: 24 h
Yield: 16 %

Procedure:
10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol and treated with stirring with 3 g of 85 wt. % ortho-phosphoric acid. After 24 h, the crystals formed were filtered off under reduced pressure and dried for 24 h in a drying cabinet at 40° C. to a final pressure of 10 mbar. 2.2 g (16% of theoretical) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate were obtained as colourless crystals with an enantiomeric purity of 85%.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc(C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)ccn1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[5-methyl-2-(2-methyl-pyridin-4-yl)-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=495.2 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(OCc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6 g), 2-chloromethylpyridine hydrochloride (80 g) and cesium carbonate (320 g) in DMF (1 L) was stirred at 70° C. for 2 days. The mixture was cooled, poured into water (2 L) and extracted with EtOAC (×6). The organic layers were washed with brine, dried (MgSO4) and filtered to give a tan solid (114 g) which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].Cl.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:21][CH:18]1[CH2:20][CH2:19]1)[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1coc(=O)c2ccc(Br)cc12
Reactant: NCC1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
A mixture of the product of step ii) (5.5 g), cyclopropylmethanamine hydrochloride (2.09 g) and N,N-diisopropylethylamine (5.1 mL) in methanol (40 mL) was heated at reflux for 17 hours. The reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with methanol and dried under vacuum at 60° C. to yield the sub-titled compound (4.55 g)
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][CH:18]([O:28]CC1C=CC=CC=1)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][CH:18]([OH:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(COc1ccc(F)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Yield: 90.9 %

Procedure:
The hydrogenolysis of 8-methylsulfonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoic acid (1.237 g., 2.43 mmoles) in absolute ethanol (100 ml.) in the presence of 10% palladium on charcoal (0.2 g.) is carried out at 25° C. in an atmospheric-pressure hydrogenator. After hydrogen uptake stops, the catalyst is filtered off and the solvent is evaporated in vacuo to leave the title compound as a colorless oil (0.927 g., 2.21 mmoles, 91%). ir (neat) 2.8~4.0, 5.81, 6.22, 6.65, 6.86, 7.80, 8.30, 8.95, 10.46, 12.04, 13.18μ; pmr (CDCl3) δ 1.1-3.0 (22H, m, containing a methyl singlet at 2.82 δ), 3.6-4.2 (3H, m), 6.2-6.7 (2H, m), 6.7-7.2 (4H, m).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.O>C(#N)C>[C:23]1([CH:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][C:9]4[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:11][CH:10]=4)[CH:14]=3)[O:19]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and pyrrolidine (51 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. N-[6-(2-Phenyl-chroman-6-yloxy) pyridin-3-yl]-2-pyrrolidin-1-yl acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 10.8 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.25 (d, 2H, 5.4 Hz), 3.67-3.55 (m, 2H), 3.20-3.06 (m, 2H), 3.06-2.90 (m, 1H), 2.80-2.65 (m, 1H), 2.23-2.12 (m, 1H), 2.10-1.85 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:19][CH2:18][CH2:17][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:2]1=[O:1])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxopiperidin-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxopiperidin-3-ylcarbamate (Example 7) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2d) in 26% yield.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.COC1C=CC(C[O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C@@H:36]([CH2:46][CH2:47][CH2:48][C:49]4[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=4)[CH2:37][CH2:38][C:39]=3[C:40]#[C:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=[CH:31][CH:30]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:22][CH:23]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C@@H:36]([CH2:46][CH2:47][CH2:48][C:49]3[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=3)[CH2:37][CH2:38][C:39]=2[C:40]#[C:41][Si:42]([CH3:43])([CH3:44])[CH3:45])=[CH:31][CH:30]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(C#C[Si](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCC(O)c1ccc(C2=C(C#C[Si](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
DDQ (160 mg, 0.71 mmol) was added to a solution of 1-2 (392 mg, 0.61 mmol) and H2O (0.9 mL) in CH2Cl2 (18 mL). After 30 minutes, saturated NaHCO3 solution (40 mL) was added and the resulting mixture was extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash unit from Teledyne Isco (0% ethyl acetate/hexanes→40%) to give the title compound (66 mg, 21%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4]
Reactant: CCOc1ccccc1O
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOc1ccccc1OCC

Procedure:
The procedure was similar to that followed in the preparation of example 8 above, except that the reaction involved 150 ml of water, 15.8 ml of 50% sodium hydroxide solution, 25.4 ml (0.2 moles) of 2-ethoxyphenol, and 21.5 ml (0.2 moles) of 1-bromobutane. This compound was labeled as example 9.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][CH:8]([C:10]1[C:19]([C:20](OCC)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9].Cl>>[Cl:7][CH:8]([C:10]1[C:19]([C:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:27])[F:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9]
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(C)Cl)nc2c(C(F)(F)F)cccc2c1O
Agent: Cl
Product: CC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
Using the procedure of Example 4, 1.5 g of 2-aminothiazole and 1.041 g of the product of Step A were reacted and after the addition of N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with ethyl acetate to obtain 2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide which after crystallization from ether melted at ≈190° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]([NH:9][NH2:10])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[CH:12]=O>C(O)C>[C:1]1([C:7]2[S:8][CH:12]([C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC(=O)OCc1ccccc1
Reactant: NNC(=S)c1ccccc1
Solvent: CCO
Product: O=C(OCc1ccccc1)C1NN=C(c2ccccc2)S1

Procedure:
A solution of benzenecarbothioic acid hydrazide (2g) and benzyl glyoxylate (2.6g) in ethanol (5ml) was stirred at room temperature for 18 hours under nitrogen. The solvent was removed by evaporation and the residue was flash chromatographed to yield the sub-title product (3.5g) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([N:16]([CH3:17])[CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
(3-Nitrophenyl)methanesulfonyl chloride (2.36 g, 10 mmol) was dissolved in benzene (30 mL), then to this solution was added 40% aqueous dimethylamine (12.6 mL, 0.1 mol) and the reaction mixture was vigorously stirred for 2 h at room temperature. The benzene layer was separated and the aqueous layer extracted with CH2Cl2 (2×25 mL). The recombined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL) and the solvent removed under reduced pressure to give 2.32 g (95%) of (3-nitrophenyl)-N,N-dimethylmethanesulfonamide as crystals.
Reaction SMILES: I[C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].C(N(CC)CC)C.[CH2:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[C:27]#[CH:28]>CN(C=O)C.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.[Cu]I>[F:32][C:31]([F:34])([F:33])[C:30]([NH:29][CH2:26][C:27]#[C:28][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])=[O:35]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 95 %

Procedure:
This compound was prepared similarly. 5-Iodouridine (1.35 mmol, 500 mg) was dissolved in dry DMF (12 mL) and Ar was bubbled through the solution for 10 min. Then, (Ph3P)4Pd (0.1 equiv., 0.1351 mmol, 156 mg) was added and Ar was bubbled through the solution for another 5 min. Triethylamine (2.0 equiv., 2.703 mmol, 273 mg, 0.376 mL) was added via syringe followed by addition of N-propargyltrifluoroacetamide (2.5 equiv., 3.38 mmol, 510 mg and CuI (0.2 equiv., 0.27 mmol, 51.5 mg). The mixture was stirred at 45° C. for 3.5 h, then the solvent was evaporated, and the residue dissolved in MeOH/methylene chloride 1:1 (10 mL). Ion exchange resin (Bio-Rad AG1 X8, HCO331 form, 1.5 g) was added to remove Et3N HI, and the mixture stirred at room temperature for 20 min. The mixture was then filtered through Celite, the solid washed with MeOH/methylene chloride 1:1 (10 mL) and the solvents removed by rotary evaporation. The residue was purified by column chromatography (chloroform/MeOH 8.25:1.75) to yield 5-(3-trifluoroacetamidopropyn-1-yl)-uridine (ca. 95%) as a yellow foam contaminated with some Et3N.HI. Rf : 0.43 (chloroform/MeOH 8.25:1.75). 1H-NMR (DMSO-d6): 3.61 (m, 2H, 5'), 3.86 (m, 1H, 4'), 3.93-4.08 (m, 2H, 2',3'), 4.23 (m, 2H, H-9), 5.08 (d, 1H, OH), 5.19 (t, 1H, OH), 5.41 (d, 1H, OH), 5.75 (d, 1H, 1'), 8.48 (s, 1H, H-6), 10.10 (t, 1H, NH chain), 11.64 (s, 1H, NH cycl.). 13C-NMR (DMSO-d6): 29.5 (C-9), 60.5 (5'), 69.6 (3'), 73.8 (2'), 75.3 (C-8), 85.0 (4'), 87.6, (C-7), 88.3 (1'), 97.8 (C-5), 113.9, 117.7 (q, CF3, J=288.48 Hz), 144.4 (C-6), 149.7 (C-2), 155.9, 156.4 (q, COCF3, J=36.80 Hz), 161.6 (C-4).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15](C1C=CC=CC=1)[C:16](=[O:18])[O-])(=[O:14])=[O:13].[NH2:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[N:27]=1>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[N:27]=1)=[O:18])(=[O:13])=[O:14]
Reactant: COc1cc(C)nc(N)n1
Reactant: COCCOc1ccccc1S(=O)(=O)N(C(=O)[O-])c1ccccc1
Solvent: C1COCCO1
Product: COCCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 20 °C
Yield: 80 %

Procedure:
4.6 g of N-(2-methoxyethoxy-phenylsulfonyl)phenylcarbamate and 1.8 g of 2-amino-4-methoxy-6-methyl-pyrimidine are refluxed in 40 ml of dioxane for 4 hours. The reaction mixture is cooled to a temperature of 20° C., filtrated and evaporated to dryness. The residue is crystallised from a dioxane/ether mixture (1:10) yielding 4.1 g of N-(2-methoxyethoxy-phenylsulfonyl)N'-(4-methoxy-6-methyl-pyrimidin-2-yl)urea with a melting point of 160°-162° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:28][C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:14][CH:13]=1)[C:7]([O:9]C)=[O:8]>CO.O1CCCC1>[CH:23]1[C:22]2[N:21]([CH2:20][CH2:19][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH:6]([C:7]([OH:9])=[O:8])[C:5]([OH:35])=[O:4])=[CH:17][CH:16]=3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 64 h
Yield: 75.5 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (3 mL) was added to a solution of 2-{4-(2-phenoxazine-10-yl-ethoxy)-benzyl]-malonic acid dimethyl ester (150 mg, 0.3 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL). The mixture was stirred for 64 h at room temperature. The title compound (95 mg, 72%) was isolated by filtration and washed with a mixture of MeOH/THF: mp 303-307° C.; 1H NMR (300 MHz, D2O): δ2.96 (d, 2H), 3.35 (t, 1H), 3.75-3.95 (bs, 2H), 4.18 (m, 2H), 6.55-6.90 (m, 10H), 7.15 (d, 2H).
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=1[N:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C@@H:25]([CH3:32])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:18]1=[O:43].Cl.[CH3:45][O:46][NH2:47]>O1CCCC1>[CH3:45][O:46][NH:47][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([CH3:6])=[C:8]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[C@@H:25]([CH3:32])[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:18]2=[O:43])[CH:9]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Reactant: CON
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Yield: 70.2 %

Procedure:
A solution of iso-propylmagnesium chloride (2M in diethyl ether, 1.2 mL) was added dropwise to a stirred mixture of 4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid, methyl ester (Example 158b, 90 mg), O-methylhydroxylamine hydrochloride (65 mg) and tetrahydrofuran (2 mL) at room temperature. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (65 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>C(O)C.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:28][CH2:27][CH2:26][NH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: BrCCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: NCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
A solution of 15.8 grams (0.04 mole) of phenylstearyl bromide and 19.25 grams (0.32 mole) of ethylene diamine in 250 ml of ethanol was refluxed for 3 hours. The alcohol solvent was removed under reduced pressure and the resulting mixture separated into two layers. The lower layer was removed and 100 ml of water added to the top layer. The oily layer which then formed was dissolved in ether and washed free of residual ethylene diamine with water. The ether solution was dried over anhydrous sodium sulfate and the ether stripped off under reduced pressure to yield 13 grams (87% crude mass yield) of N-phenylstearyl ethylene diamine having the following analysis: