Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Cl:14])[C:7]=1[Cl:15])=[O:5])[CH3:2]>S(=O)(=O)(O)O>[CH3:16][CH:3]1[CH:1]([CH3:2])[C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:4]1=[O:5]
Reactant: CC=C(C)C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2C

Procedure:
By following the procedure described in Example 5, Step D, using as the reactants 2-ethylidene-2',3'-dichloro-4'-methoxypropiophenone (30 g.) and sulfuric acid (120 ml.), there is obtained 2,3-dimethyl- 5-methoxy-6,7-dichloro-1-indanone.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1.[Cl:19][CH2:20][C:21](N(C)C)=[O:22].Cl>O1CCCC1>[F:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]2[O:13][C:14]([C:21](=[O:22])[CH2:20][Cl:19])=[CH:15][CH:16]=2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(Oc2ccco2)cc1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(Oc2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.86 g (29.08 mmol) of n-butyllithium (2.5N in n-hexane) are added dropwise to 5.18 g (29.08 mmol) of 2-(4-fluorophenoxy)furan in 40 ml of absolute tetrahydro-furan at -75° C., and the mixture is stirred for 2.5 h. Then 6.14 g (50.51 mmol) of 2-chloro-N,N-dimethylacetamide in 30 ml of absolute tetrahydrofuran are added at -75° C. After 60 min, the mixture is poured into 200 ml of ice-water, neutralized at 0° C. with 2N hydrochloric acid and extracted 5× with 40 ml of ethyl acetate each time. The combined organic phases are washed 2× with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is stripped off. The product is purified by column chromatography (360 g of silica gel 60; solvent: toluene) and recrystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH3:17]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CCCCOc1ccc(CO)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1ccc(CCl)cc1

Procedure:
Was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.42 g, 69.2 mmol), 4-butoxybenzyl alcohol (9.45 g, 52.4 mmol), CH2Cl2 (145 mL).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C[O:6][C:7](=O)[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]>>[C:11]([NH:10][CH2:9][CH2:8][C:7]([NH:4][CH2:3][CH2:1][OH:2])=[O:6])(=[O:13])[CH3:12]
Reactant: NCCO
Reactant: COC(=O)CCNC(C)=O
Product: CC(=O)NCCC(=O)NCCO
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A mixture of 0.42 g of ethanolamine and 1.0 g of N-acetyl-β-alanine methyl ester was heated at 85° C. for 4 hours. The resulting yellow oil solidified upon cooling and was crystallized from acetonitrile, giving 0.75 g of the desired compound as a white solid, mp 122°-125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 3-bromopyridine (10 g, 0.063 mol) in dry THF (200 mL)/hexane (50 mL) was cooled to −90° C. To this cooled solution was added n-BuLi (2.2 M, 32 mL, 0.063 mol) slowly and allowed to stir for 30 min under N2 atmosphere. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 3 h at RT. The reaction mixture was cooled, quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried, concentrated under vacuum and the crude product was purified by column chromatography on silica gel (30% ethyl acetate in pet. ether) which gave the title compound (3.3 g).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNS(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 1, isobutylamine was reacted with 2-chlorobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 2-chloro-N-isobutyl-benzenesulfonamide as a colorless solid. MS: 248.1 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:26]=1)/[CH:5]=[C:6]1/[C:7](=[O:23])[C:8]2[C:13]([CH2:14]/1)=[CH:12][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[C:10]([O:21][CH3:22])[CH:9]=2>CO.[Pd]>[CH3:22][O:21][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:6]([CH2:5][C:4]3[CH:3]=[CH:2][CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=3)[C:7]2=[O:23])=[CH:12][C:11]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Br)cc(OC(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cccc(OC(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607 mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture, then stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 30, which was purified through flash chromatography by using 100-200 mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexane to afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolved in methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude des-brominated compound 31. The crude 31 was purified by flash chromatography using 100-200 mesh silica gel. Compound 31 was eluted as des-brominated compound at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one 31. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[CH:3]=1.O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C>CO>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:10]3[O:17][C:19]([CH3:24])([CH3:20])[O:16][C@@H:11]3[C@@H:12]([CH2:14][OH:15])[CH2:13]2)[CH:3]=1
Reactant: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Solvent: CO
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Yield: 45.9 %

Procedure:
A solution of (1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol (255 mg, 0.982 mmol), p-toluenesulfonic acid monohydrate (187 mg, 0.982 mmol) and 2,2-dimethoxypropane (0.670 mL, 0.545 mmol) in MeOH (5.00 mL) was stirred overnight. The reaction was quenched via addition of saturated aqueous NaHCO3 solution (10 mL) and MeOH was removed in vacuo. The aqueous mixture was extracted with DCM (4×20 mL) and the combined organics were concentrated in vacuo. The crude mixture was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (135 mg, 45.8%). LC/MS: Rt=1.77 min, ES+ 300. (AA standard).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:9]([CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C.O>C(OCC)C>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][CH2:16][CH:17]=[O:18])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)CCC[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@H](CCCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
To a solution of the material from Step 2 (7.51 g, 19.08 mmol) in diethyl ether (95 mL) at −78° C. was slowly added 1.0 M Dibal-H (26.7 mL, 26.7 mmol) in hexanes. The reaction mixture was stirred at −70° C. for 90 minutes. Water (10 mL) was slowly added, and the reaction mixture was allowed to warm up to room temperature and aged for 30 minutes. Additional water (20 mL) was added, aged for 10 minutes with vigorous stirring. 8 g of celite was added to the reaction mixture, aged at room temperature for 5 minutes, filtered on a short pad of celite, rinsed with tert-butyl methyl ether (10×). The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 7.06 g of the title compound that was used without further purification.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[CH2:6]([C:8]1[CH:9]=[CH:10]C(C=C)=[N:12][CH:13]=1)[CH3:7].BrN1C(=O)CCC1=O.[OH-].[Na+]>O>[CH2:9]([C:8]1[CH:6]=[CH:7][C:2]([CH:1]2[CH2:3][O:5]2)=[N:12][CH:13]=1)[CH3:10]
Reactant: C=Cc1ccc(CC)cn1
Reactant: CC(C)(C)O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 750 mL tert-butanol and 2250 mL water, 200 g (1.488 mol) of 5-ethyl-2-vinyl-pyridine was dissolved and under stirring 324 g (1.786 mol) N-bromosuccinimide was added in 30 min. at 25-30° C. Stirring was continued for 1 hr. and 178.6 g (4.46 mol) of NaOH dissolved in 2250 mL water was added into it. Reaction mixture was stirred for 45 min. Product was extracted twice with 1100 mL methyl tert-butyl ether. Organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 206.13 g (92%) of 6.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH:11]([CH3:18])[CH2:10]2
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Reactant: Br[Zn]CC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and tri-t-butylphosphine-BF4 complex (0.072 g, 0.249 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12.44 ml) and 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.11 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zinc (6.22 ml, 3.11 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): δ 8.04 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J=4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J=6.4 Hz, 3H); LC-MS (IE, m/z): 249 [M+1]+.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=[N:11]C=2C=1.[N:15]1([CH2:21][C:22]([OH:24])=O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CN(C=O)C>[N:15]1([CH2:21][C:22]([NH2:11])=[O:24])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
To a solution of [5-(3-amino-ethoxy)-1,3-dihydro-isoindol-2-yl]-(2,4-dihydroxy-5-isopropyl-phenyl)-methasone hydrochloride (100 mg, 0.255 mmoles) in DMF (10 ml) was added EDC (59 mg, 0.306 mmoles), HOBt (41 mg, 0.306 mmoles), morpholin-4-yl-acetic acid (37 mg, 0.255 mmoles) and triethylamine (43 μl, 0.306 mmoles) and stirred at ambient temperature for one hour. To the reaction mixture was added further EDC (20 mg, 0.104 mmoles), HOBt (14 mg, 0.104 mmoles), morpholin-4-yl-acetic acid (12 mg, 0.083 mmoles) and triethylamine (14 μl, 0.100 mmoles) and stirred at ambient temperature for a further 2 hours. Solvent removed in vacuo. The residue was purified by flash chromatography [Biotage SP4: 25 S, flow rate 25 ml/min, gradient 20% DMAW 90 in DCM to 100% DMAW 90] and then by preparative HPLC to give N-{2-[2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yloxy]-ethyl}-2-morpholin-4-yl-acetamide as a colourless viscous oil (40 mg, 33%). 1H NMR (Me-d3-OD) 7.20 (1H, br s); 7.18 (1H, s); 6.90 (2H, br m); 6.40 (1H, s); 4.10 (2H, t); 3.73 (4H, m); 3.63 (2H, t); 3.20 (1H, m); 3.18 (2H, s); 2.60 (4H, m); 1.25 (6H, d). MS: [M+H]+ 484.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (1 g, 5 mmol), in anhydrous CH2Cl2 (10 mL) under argon were added ethane sulfonyl chloride (0.57 mL, 5.99 mmol) and Pyridine (0.60 mL, 7.5 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (3×10 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid. 1H NMR (CDCl3) δ: 1.23 (t, J=7.5 Hz, 3 H), 1.52 (d, J=6.8 Hz, 3 H), 2.77 (q, J=14, 7.5 Hz, 2 H), 4.61–4.72 (m, 2 H), 7.24 (d, J=8.3 Hz, 2 H), 7.51 (d, J=8.3 Hz, 2 H). ESIMS (MH+): 293.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].[CH3:18][O-:19].[Na+]>ClCCl.CO.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:19][CH3:18])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(C(C)=O)cnc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-acetyl-4-chloro-8-nitroquinoline (339 mg) in dichloromethane was added 28% solution of sodium methoxide in methanol (0.52 mg) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 2:3, v/v) to give 3-acetyl-4-methoxy-8-nitroquinoline (239.3 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CNc1nc(Cl)ncc1N
Temperature: 80 °C
Yield: 54 %

Procedure:
A mixture of 2-chloro-4-(methylamino)-5-nitropyrimidine (3.76 g, 20 mmol, synthesized from the above procedure), tin(II) chloride dihydrate (18.0 g, 80 mmol) in ethanol (200 mL) is heated at 80° C. After heating for 2 hours, the reaction mixture is cooled to room temperature and concentrated. Ethyl acetate and celite is added to the residue and the mixture is basified with saturated sodium carbonate solution to a pH of 9-10. The mixture is filtered through a pad of celite and washed with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. Further purification by column chromatography (silica gel, eluting with ethyl acetate) affords the title compound (1.72 g, 54%).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C=O)C>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([O:16][CH2:27][C:28]#[N:29])[CH:12]=3)[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2

Procedure:
A stirred mixture of 2-cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone (2.9 g., 0.1 mole), potassium carbonate (15.2 g., 0.11 mole) and chloroacetonitrile (7.5 g., 0.10 mole) in DMF (100 ml.) is heated at 55°-60° C. for two hours and poured into water. The 2-cyclopentyl-6-cyanomethoxy-7,8-dichloro-1-tetralone that separates is collected and dried.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-:11].[CH2:12]([N+:14]1([CH2:19][CH3:20])[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:13]>O.C(O)C.CCOCC>[ClH:11].[CH2:1]([S:8][CH2:17][CH:16]([OH:18])[CH2:15][N:14]([CH2:19][CH3:20])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: CC[N+]1(CC)CC(O)C1
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCN(CC)CC(O)CSCc1ccccc1
Product: Cl
Temperature: 75 °C
Yield: 84.6 %

Procedure:
6.20 g of benzylmercaptan and 2 g of NaOH are stirred together in 25 cc of water, under a nitrogen atmosphere, for 5 minutes at which time there is added thereto a solution of 8.28 g of 1,1-diethyl-3-hydroxy azetidinium chloride in 25 cc of ethyl alcohol. The resulting mixture is heated for 1 hour at 75° C. After evaporating to dryness the product thus obtained is taken up in ether. The resulting etherified solution is then dried on sodium sulfate and neutralized by bubbling gaseous HC1 therethrough. The precipitate which forms is filtered and recrystallized in a mixture of ethyl acetate and ethanol, yielding 12.24 g of white crystals melting at 104° C.
Reaction SMILES: [F:1][C:2]([F:30])([C:26]([F:29])([F:28])[F:27])[C:3]([F:25])([F:24])[C:4]([F:23])([F:22])[O:5][C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[O:8][C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:31]([O:36][C:37]1[CH:38]=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[N:41][CH:42]=1)[CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:31]([O:36][C:37]1[CH:42]=[N:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:19])([F:18])[C:6]([F:21])([F:20])[O:5][C:4]([F:23])([F:22])[C:3]([F:25])([F:24])[C:2]([F:30])([F:1])[C:26]([F:29])([F:28])[F:27])([F:17])[F:16])=[CH:47][CH:48]=2)=[N:39][CH:38]=1)[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride (5.17 g of 95% purity, 8.4 mmol) with 5-pentoxy-2-(4-hydroxyphenyl)pyrimidine (2.17 g, 8.4 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation to provide a yield of 3.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O)(=O)C>CO.CN1C(=O)N(C)CCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: COc1ccc(CN)cc1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Solvent: CO
Product: COc1ccc(CNCc2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
273 mg (1.00 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and 156 ml (1.2 mmol) of 4-methoxybenzylamine in 10 ml of methanol, DMPU and 126 μl (2.2 mmol) of acetic acid are stirred at RT for 1 h. 0.1 g of Raney nickel is then added and the mixture is hydrogenated at RT and finally at 50° C. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in ethyl acetate and satd Na2CO3 solution. The aqueous phase separated off is extracted twice with ethyl acetate; the organic phases are washed with satd NaHCO3 solution, and twice with water and brine, dried (MgSO4) and evaporated. Stirring the residue in diethyl ether yields 4-(3-chloroanilino)-6-[(4-methoxybenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=9.5; TLC-Rf=0.17 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=394.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3]C=1.[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:27]1[CH:32]=[CH:31][C:30](S(Cl)(=O)=O)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:24])[CH3:25])[N:22]([C:30]1[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=1)[S:7]([CH2:4][CH3:3])(=[O:9])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccncc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(c1ccncc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 1 h

Procedure:
To 1 gm of valine benzyl ester p-toluene-sulfonic acid salt in 40 ml of CH2Cl2 at 0° C. was added 1.12 gm of 4-pyridylsulfonyl chloride (U.S. Pat. No. 431,504 (1982)) and 1.9 ml of triethylamine. After 1 hour, the solution was washed with water and extracted with CH2Cl2 (2×100 ml), dried and concentrated. Silica gel column chromotography provided 4-pyridyl-ethanesulfonyl-valine benzyl ester which was treated with 10% Pd/C in methanol under hydrogen atmosphere to provide the desired product in 85% overall yield.