Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH2:17])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH:17][S:24]([CH3:27])(=[O:26])=[O:25])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethylamine (4.05 g, 16.2 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. The solution was cooled to 0° C. Pyridine (2.6 mL, 32.4 mmols, 2 eq) was added followed by mesyl chloride (1.25 mL, 16.2 mmols, 1 eq). The reaction was stirred for 18 h during which time it was warmed slowly to RT. The solvent was removed in vacuo, and the residue dissolved in EtOAc. The resulting solution was washed twice with 2 N HCl, once with water, and 3× with brine. After being dried over Na2SO4 the solution was filtered and concentrated. The crude was purified by silica gel chromatography eluting with 50% to 60% EtOAc:hexane to yield the desired compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89.0 mg) and phenylboronic acid (48.8 mg) were dissolved in DME (0.8 mL). A solution of 2M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C., and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.09 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=444.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (m, 1H) 1.74-1.85 (m, 1H) 2.85 (d, J=11.34 Hz, 1H) 3.10-3.26 (m, 2H) 3.32-3.45 (m, 1H) 4.15 (m, J=2.30 Hz, 1H) 4.80 (d, J=3.13 Hz, 1H) 7.25-7.51 (m, 7H) 7.78-7.88 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.30 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Br:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCO.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Br:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3c(Br)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a mixture of 1-[4-bromo-5,6-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.132 g, 0.27 mmol) and EtOH (2 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred for 18 h at 23° C. The resulting white precipitate was filtered and washed with EtOH to yield the titled compound (0.088 g, 81%). MS (ESI/CI): mass calcd. for C13H9BrCl2N4O4, 402.9; m/z found, 403.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.22-13.94 (m, 1H), 8.98 (s, 1H), 8.40 (s, 1H), 7.74 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=2[O:29]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[C:15]([OH:29])[CH:16]=1)([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 42 %

Procedure:
A mixture of 4.2 g. (8.73 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,2,5,6-tetrahydropyridine, 4.0 g. of 10% palladium-on-carbon and 50 ml. of ethanol is stirred under one atmosphere of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth with ethyl acetate, evaporated and the residue again dissolved in ethyl acetate and filtered. The filtrate is evaporated and the residue crystallized in ether to yield 1.1 g. (42%) of the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][NH:29][CH3:30].C1COCC1>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([N:29]([CH3:30])[CH3:28])[S:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CNC
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(N(C)C)n3)n2)ccc(C#N)c1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide (0.247 g, 0.531 mmol) was added into a microwave test tube with dry pyridine. The mixture was bubbled with nitrogen and dimethylamine 2 M in THF (1.329 ml, 2.66 mmol) was added. The reaction mixture was heated with microwaves at 120° C. for 10 h. The crude product was evaporated, diluted with DCM, washed with 1M Na2CO3 and water. The product was purified with Flash-chromatography. Yield 63.2%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.53 (s, 3H), 3.00 (s, 6H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.55 (m, 1H), 6.41 (d, 1H), 7.30 (d, 1H), 7.52 (m, 3H), 7.74 (d, 1H).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[CH:8][N:9]=1)C.Cl.N1C=CC=CC=1>O>[S:10]1[C:7]2=[CH:8][N:9]=[C:4]([OH:3])[CH:5]=[C:6]2[CH:12]=[CH:11]1
Reactant: CCOc1cc2ccsc2cn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2ccsc2cn1
Temperature: 175 °C
Yield: 55.5 %

Procedure:
A mixture of 5-ethoxythieno[2,3-c]pyridine (127 mg, 0.700 mmol), pyridine hydrochloride (827 mg, 7.00 mmol) and H2O (1.2 mL) was heated in a microwave reactor at 175° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by ISCO chromatography (0 to 15% MeOH:DCM) to afford 58.7 mg (55%) of the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ 14.04 (br s, 1 H), 8.12 (s, 1 H), 7.66 (d, J=5.6 Hz, 1 H), 7.07 (dd, J=5.6, 0.4 Hz, 1 H), 6.95 (d, J=0.8 Hz, 1 H); MS (ESI): 152.02 [M+H]+; HPLC tR=0.74 min (TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Solvent: CO
Solvent: O
Product: Cc1cnc(Cl)nc1Nc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To a vial with 6-aminobenzo[d]oxazol-2(3H)-one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol), solvents MeOH (20 mL) and H2O (5 mL) were added. The turbid mixture was stirred at room temperature for 2 days. Precipitate from the reaction mixture was collected by filtration, washing with H2O (3 mL×2) and EtOAc (3 mL×2), and was further drying in vacuo. 6-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as a light tan color solid: 1.59 g (86% yield); 1H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.3, 1H), 7.06 (d, J=8.3, 1H), 2.14 (s, 3H).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.[NH2:33]C1C=CC(C#N)=CN=1>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1)#[N:33]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ccc(C#N)cn2)cc1

Procedure:
The product from Example 1, Part C (160 mg, 0.5 mmol) and 6-aminonicotinonitrile (89 mg, 0.75 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, the aqueous phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (30 mg, 14%). 1H NMR (400 MHz, CDCl3) δ 8.84 (br s, 1H), 8.55 (d, J=2 Hz, 1H), 8.30 (d, J=9 Hz, 1H), 7.95 (dd, J=9 Hz, 2 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.07 (d, J=15 Hz, 1H), 4.63 (s, 1H), 4.12 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.96 (m, 2H), 1.94 (s, 3H), 1.84 (s, 3H). MS: m/z (MNa+) 445.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture at 0° C. under N2 of sodium azide (1.47 g, 22.6 mmol) in anhydrous DMF (30 mL) was added a solution of 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (6.00 g, 18.8 mmol), prepared as in Example 1178A-D, in anhydrous DMF (10 mL). Reaction stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)s1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) ) of α-ethynyl- 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 371 mg (19%) of the expected methyl ester, with a melting point of 84°-85° C., were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44](Cl)=[O:45]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:47])[CH2:43][C:44]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:45]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: COC(=O)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (22 mg, 0.04 mmol, Example 25: step c ) was dissolved into THF (1 mL) and to this was added chlorocarbonyl-acetic acid methyl ester (9 μL, 0.085 mmol). The reaction was heated to 50° C. for 5 hours and then allowed to stir at RT for 48 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by preparative TLC (SiO2) (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C28H31N3O7S3: 618.1 (M+1) found: 617.9.
Reaction SMILES: [CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Si:30]([O:35][CH3:36])([O:33][CH3:34])[O:31][CH3:32])=[CH2:29]>C1(C)C=CC=CC=1>[CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[CH2:29][CH2:28][Si:30]([O:35][CH3:36])([O:33][CH3:34])[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Reactant: C=C[Si](OC)(OC)OC
Solvent: Cc1ccccc1
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1CC[Si](OC)(OC)OC)N(C)C
Yield: 67 %

Procedure:
14.6 g (40 mmol) of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-1-butanone, 750 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 and 13.4 ml (88 mmol) of vinyltrimethoxysilane were dissolved in 50 ml of toluene and degased using N2. After heating with stirring at reflux for 41 hours, the solvent was distilled off and the product was chromatographed (silica gel, CH2Cl2 /ethyl acetate). 13.8 g (67%) of dark red oil were obtained which were purified by boiling in heptane with active charcoal followed by filtration to give a yellow, viscous oil. 1H-NMR (CDCl3): 0.61 ppm (3H, t, Bu-H4, 3JH,H =7.2 Hz); 1.2 ppm (2H, mc, Et-H2); 1.88 ppm (2H, mc, Bu-H3); 2.37 ppm (6H, s, N(CH3)2); 2.71 ppm (2H, mc, Et-H1); 3.16 ppm (2H, mc, CH2 -Ph); 3.25 ppm (4H, mc, morpholine-N--CH2); 3.63 ppm (9H, s, Si(OCH3)3); 3.85 ppm (4H), mc, morpholine-O-CH2); 6.61 ppm (1H, dd, Ph-H5, 3JH5,H6, =8.6 Hz, 4 JH3, H6 =2.6 Hz); 6.75 ppm (1H, d, Ph-H3); 7.14-7.29 ppm (5H, m, Ph'-H); 8.44 ppm (1H, d, Ph-H6).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:19][CH2:18][CH2:17][Cl:16])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCl
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CC(NCCCl)C(=O)N1Cc1ccccc1

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an RF value of 0.24 (on silica gel using ethyl acetate: petroleum ether=1:1) are obtained.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[O:24][C@@H:23]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:23]1[S:22][CH2:21][C@H:20]([CH2:19][OH:18])[O:24]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO)CS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of cis and trans-5-t-butyldimethylsilyloxymethyl-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 25) (4.00 g, 10.8 mmol) in MeOH (30 mL) was added a few drops of acetyl chloride (200 μL) at 0° C. The mixture was stirred at 0° C. for 1 hr. and at room temperature for 18 hr. A few drops of ammonium chloride was added and the solvent was evaporated under reduced pressure. The crude material was purified by several flash chromatography with a mixture of dichloromethane and methanol (96:4) to give 382 mg of the cis isomer , 1.19 g of the trans isomer and 332 mg of the mixture in a total yield of 80% after the first purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].O1CCOCC1.Cl[CH:21]([F:23])[F:22]>O>[Br:1][C:2]1[C:3]([O:11][CH:21]([F:23])[F:22])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 11 h
Yield: 33.4 %

Procedure:
Into a 200-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 4.36 g (0.02 mol) of 2-bromo-6-nitrophenol, 16.7 g (0.1 mol) of 24% sodium hydroxide, 20 ml of 1,4-dioxane and 7 ml of water. The mixture was heated to 80° C. The mixture was stirred at that temperature for 11 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. The reaction mixture was cooled and then subjected to extraction two times each using 20 ml of ether. The ether layer was washed with 20 ml of 12% sodium hydroxide and then with the same volume of water. Then, the ether layer was dried over anhydrous sodium sulfate and then subjected to distillation to obtain 1.79 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 33.4%, purity: 98.8%). To the sodium hydroxide washing was added hydrochloric acid to make the washing acidic, and the resulting precipitate was subjected to extraction with ether, to recover 2.2 g of unreacted 2-bromo-6-nitrophenol (recovery ratio: 50%).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[S:9]([CH2:19][CH2:20][CH2:21]S(C1C=CC(C)=CC=1)(=O)=O)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>CN(C=O)C>[S:9]([CH2:19][CH2:20][CH2:21][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)CCCS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCCc2c[nH]c([N+](=O)[O-])n2)cc1
Temperature: 80 °C

Procedure:
To a stirred mixture containing 2-nitroimidazole (1 g, 8.34 mmol) and Cs2,CO3 (2.9 g, 8.90 mmol) in dimethylformaide (DMF, 50 ml), 1,3-ditosylpropane (3.84 g, 9.99 mmol) was added. The reaction was heated at 80° C. for 3 hours. The solvent was evaporated under vacuum and the residue was suspended in ethylacetate. The solid was filtered, the solvent was concentrated, loaded on a silica gel-packed column and eluted with hexane:ethylacetate (1:1). The product, 3-tosylpropyl-(2-nitroimidazole), was isolated (1.67 g, 57.5%) with m.p. 108-111° C. 1H-NMR (CDCl3) δ 2.23 (m, 2H), 2.48 (S, 3H), 4.06 (t, 2H, J=5.7 Hz), 4.52 (t, 2H, J=6.8 Hz), 7.09 (S, 1H), 7.24 (S, 1H), 7.40 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz).
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[OH:14]C1C=C2C(C(=O)CCO2)=CC=1>>[OH:14][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[O:10][CH2:9][CH2:8][C:7]2=[O:13]
Reactant: COc1ccc2c(c1)OCCC2=O
Reactant: O=C1CCOc2cc(O)ccc21
Product: O=C1CCOc2ccc(O)cc21

Procedure:
By the same method, 7-methoxy-4-chromanone was converted to 7-hydroxy-4-chromanone.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:12]([C:13]#[N:14])=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NC2N(C[O:36]CC[Si](C)(C)C)N=CC=2C#N)C=CC=CC=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:1]1([NH:7][C:8]2[C:12]([C:13]([NH2:14])=[O:36])=[CH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(Nc2ccccc2)n1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1c[nH]nc1Nc1ccccc1
Temperature: 0 °C

Procedure:
To a solution containing a mixture of 3-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2.6 g, 7.8 mmol) in EtOH (40.3 mL) was added 2N aqueous HCl (40.3 mL). The resulting mixture was heated at 0° C. for 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 3N aqueous Na2CO3 until pH ˜9. The solution was further diluted with H2O (400 mL), the layers were partitioned and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O.C(OC(C)C)(C)C>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(C=O)c1

Procedure:
10 mmol of 5-hydroxy-2-nitrobenzaldehyde dissolved in dimethylformamide are added dropwise to 20 mmol of potassium carbonate suspended in a mixture of dimethyl-formamide and isopropyl ether, and then the reaction mixture is heated at reflux for 2 hours. After the mixture has returned to ambient temperature, 10 mmol of 2-chloro-N,N-dimethylethanamine hydrochloride are added dropwise, and then the reaction mixture is heated at reflux again for one night. After returning to ambient temperature, the mixture is filtered and the solvents of the filtrate are evaporated off to yield the expected product in the form of an oil.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Na+].[Cl-]>[CH2:16]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: OCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To the oil of monodispersed tetraethylene glycol (19.4 g, 0.10 mol) was added a solution of NaOH (4.0 g in 4.0 mL) and the reaction was stirred for 15 mm. Then benzyl chloride (3.54 mL, 30.8 mmol) was added and the reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, diluted with sat. NaCl (250 mL), and washed CH2Cl2 (2×200 mL). The organic layers were combined, washed sat. NaCl, dried MgSO4, and chromatographed (silica, ethyl acetate) to afford the monodispersed compound 23 as a yellow oil (6.21 g, 71% yield).