Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)C(O)=O)([OH:3])=[O:2].[Br:24]Br>CCOCC.C1(C)C(C)=CC=CC=1>[Br:24][CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]([OH:3])=[O:2]
Reactant: O=C(O)C(CC12CC(c3ccccc31)c1ccccc12)C(=O)O
Reactant: BrBr
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: O=C(O)C(Br)CC12CC(c3ccccc31)c1ccccc12

Procedure:
α-Carboxy-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with bromine in ether, and the corresponding brominated compound was refluxed in xylene to give α-bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid. α-Bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with thionyl chloride and then with N-benzyl-N-hydroxyethylamine to give α-bromo-β-(9,10-dihydro-9,10-methano-9anthryl)propionic acid N-benzyl-N-hydroxyethylamide, I.R., 3400, 3060, 3045, 2860, 1640, 1360, 1158, 1048, 1012, 698 cm-1.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1.[H-].[Na+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:29]4[N:25]([CH3:24])[N:26]=[CH:27][N:28]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.125 g, 0.39 mM) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.08 g, 0.47 mM; prepared using the conditions described in EP-A-421210) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 0.47 mM eq) and the reaction mixture was stirred at room temperature for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-dichloromethane to give the required product (0.048 g, m.p.=244-246° C.). 1H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.67-1.84 (8H, m), 2.30 (1H, m), 3.93 (3H, s), 5.70 (2H, s), 7.52-7.62 (3H, m), 8.00 (1H, s), 8.35 (1H, s), 8.38 (2H, m); (Regiochemistry was established using nOe data). MS (ES+) m/e 402 [MH]+. Anal. Found C, 65.71; H, 5.65; N, 24.07. C22H23N7O requires C, 65.82; H, 5.77; N, 24.42%.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].C[O:10][CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[N:26]=C=O>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:22]1[C:21]([NH:26][C:11]([C:12]2([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]2)=[O:10])=[C:20]([CH3:19])[O:24][N:23]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: COCC1(S(N)(=O)=O)CC1
Agent: CC(C)(C)NC(=O)O
Product: Cc1noc(C)c1NC(=O)C1(S(N)(=O)=O)CC1
Yield: 100 %

Procedure:
This compound was obtained in a crude 100% yield according to the procedure described for the synthesis of 1-methoxymethylcyclopropylsulfonylamine tert-butylcarbamate except that 1.20 equivalents of 3,5-dimethylisoxazole-4-isocyanate was used as the electrophile. The compound was taken directly into the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:18]2[NH:22][C:21]([C:23]3[N:28]=[CH:27][C:26]([CH:29]([OH:32])[CH2:30][OH:31])=[CH:25][CH:24]=3)=[CH:20][CH:19]=2)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1SC.O1CCC[CH2:34]1.CO.O[O:41][S:42]([O-:44])=O.[K+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:18]2[NH:22][C:21]([C:23]3[N:28]=[CH:27][C:26]([CH:29]([OH:32])[CH2:30][OH:31])=[CH:25][CH:24]=3)=[CH:20][CH:19]=2)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[S:42]([CH3:34])(=[O:44])=[O:41]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1F
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 1-[6-(5-{1-[3-fluoro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethane-1,2-diol (367 mg) in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) was added Oxone (registered trademark) (593 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (330 mg, 84%) as a pale-yellow amorphous solid. MS: 489 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([F:28])([F:27])[C:24]([F:30])([F:29])[C:23]=2[CH:31]=1.CCCCC>C1(C)C=CC=CC=1>[F:28][C:25]1([F:27])[C:24]([F:30])([F:29])[C:23]2[CH:31]=[C:19]([NH:18][C:13]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[O:14])[CH:20]=[CH:21][C:22]=2[O:26]1
Reactant: NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
Under a dry nitrogen atmosphere a mixture of 0.55 g (0.0035 mole) 2,6-difluorobenzamide, 0.48 g (0.0038 mole) oxalyl chloride, and 70 ml of toluene was heated at reflux for two hours. The mixture was cooled and distilled under reduced pressure to remove excess oxalyl chloride and approximately 60 ml of toluene. To the pot residue were added 30 ml of fresh toluene and 0.72 g (0.0035 mole) 5-amino-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran dissolved in 30 ml of toluene. The resultant mixture was allowed to stir at room temperature for approximately 18 hours. Approximately 100 ml of n-pentane was added to this mixture. A white precipitate formed after stirring for an additional hour. This solid was collected by filtration to yield 0.74 g of N-[[(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-5-yl)amino]carbonyl]-2,6-difluorobenzamide (mp 183°-184.5° C.), Compound 1 of Table 1. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Temperature: 60 °C
Yield: 91.7 %

Procedure:
1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol) (from Example 1, Step 1) was dissolved in N,N-dimethylformamide (60.8 mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassium carbonate (17 g, 120 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether. The organic layers were combined, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0-10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). LCMS calculated for C11H13ClIO2 (M+H)+: m/z=339.0; Found: 339.0.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:30][O:31][C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:18]([NH:17][C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=[C:11]([NH:38][C:37]3[C:32]([O:31][CH3:30])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:16]=2)[CH3:19])=[N:21][CH:22]=1
Reactant: COc1ncccc1N
Reactant: C[C@H](Nc1nc(On2nnc3ccccc32)ncc1C(N)=O)c1ccc(F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1Nc1ncc(C(N)=O)c(N[C@@H](C)c2ccc(F)cn2)n1
Yield: 68.5 %

Procedure:
A solution of (S)-2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl) ethyl amino)pyrimidine-5-carboxamide (Preparation 5c, 30 mg, 0.08 mmol), 2-methoxy pyridin-3-amine (14 mg, 0.11 mmol) and p-toluenesulfonic acid hydrate (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was heated at 120° C. for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (21 mg, 72%) as a solid.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:37])[C@H:31]([CH2:33][C:34](=[O:36])[NH2:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:37])[C@H:31]([CH2:33][C:34](=[O:36])[NH2:35])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NC(=O)C[C@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 50.8 %

Procedure:
Using the procedure described previously, a heterogeneous solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (152 mg, 0.52 mmol, 1.0 eq), L-asparagine N-benzylamide (231 mg, 1.04 mmol, 2.0 eq) and dichloromethane (1.5 mL), was treated with triethylamine (436 uL, 3.1 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (663 uL, 1.04 mL, 2.0 eq), to provide 130.7 mg (51%) of L-asparagine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide as a white foam.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1OC(C(F)(F)F)=CC=1.[CH3:21][O:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][C:26]2[C:31]3([CH2:41][O:42][C:25]=2[CH:24]=1)[C:39]1[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:33][C:32]3=[O:40].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:21][O:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][C:26]2[C:31]3([CH2:41][O:42][C:25]=2[CH:24]=1)[C:39]1[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=1)[N:33]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:32]3=[O:40]
Reactant: BrCc1ccccn1
Reactant: COc1cc2c(cc1C#N)C1(CO2)C(=O)Nc2ccccc21
Agent: Br
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1cc2c(cc1C#N)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (80%): mp 187-189° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57-8.55 (m, 1H), 7.70-7.64 (m, 1H), 7.27-7.20 (m, 3H), 7.12-7.00 (m, 3H), 6.91-6.89 (m, 1H), 6.55 (s, 1H), 4.97 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.7, 165.8, 164.1, 154.9, 149.6, 142.3, 137.1, 131.2, 129.4, 128.8, 123.7, 123.6, 122.9, 122.0, 121.7, 116.7, 109.8, 94.6, 81.2, 56.9, 56.3, 45.9; MS (ES+) m/z 383.8 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:49][CH2:50][F:51])(=O)=O.O>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:49][CH2:50][F:51])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCCF
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCF)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 80 °C

Procedure:
To a solution of 49 (70 mg, 0.111 mmol, scheme 26) in DMF (2 mL) were added K2CO3 (77 mg, 0.555 mmol) and 419 (79 mg, 0.555 mmol). The mixture was heated to 80° C. for 16 hours. Water was added to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 0-20%, (methanol/dichloromethane; SiliaFlash 10 g cartridge]. Title compound 420 was obtained as a white solid (38.9 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.68 (s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (dd, J=13.5, 2.4 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.22-7.17 (m, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.54 (bd, J=2.3 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.54 (s, 2H), 2.89-2.83 (m, 2H), 2.62 (t, J=5.0 Hz, 1H), 2.59-2.51 (m, 1H), 2.56 (t, J=5.1 Hz, 1H), 2.50-2.32 (m, 8H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 565.23 (M+H).
Reaction SMILES: C([NH:8][NH:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:23]=[CH:22][N:21]3[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:25][N:26]=[C:20]3[CH:19]=2)[CH:12]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[N:21]2[CH:22]=[CH:23][C:18]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=3[CH3:17])[C:10]([NH:9][NH2:8])=[O:34])=[CH:19][C:20]2=[N:26][N:25]=1
Reactant: Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NN)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Reaction time: 1.5 h

Procedure:
A solution of N′-boc-3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzohydrazide (300 mg, 0.63 mmol) in 3.0 mL of DCM at RT was treated with 2.0 mL of TFA. After 1.5 h of stirring, the volatiles were evaporated. The residue was dissolved in DCM, washed with 1 N NaOH followed by brine. The DCM layer was dried and concentrated to afford the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 378 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:10][C:11]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccccc2c1O

Procedure:
In step 1 of sequence A, an aniline, substituted by the appropriate R2 group or groups, is condensed with a dialkyl alkoxymethylenemalonate such as diethyl ethoxymethylenemalonate by heating at 120° to 150°C. The intermediate formed is condensed by heating at a temperature of 150° to 300°C. in a high boiling inert solvent such as diphenyl ether or mixtures of diphenyl ether and biphenyl (e.g. Dowtherm A) to give the ethyl 4-hydroxyquinoline-3-carboxylate product of step 1.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][CH:6]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:7](Cl)=[O:8].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]1([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:2]([CH3:4])([CH3:3])[CH2:1][C:7]1=[O:8]
Reactant: C=C(C)C
Reactant: O=C(Cl)C(Cl)CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC1(C)CC(=O)C1(Cl)CC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 60.2 %

Procedure:
In an autoclave, 280 g of isobutylene are added under pressure to 122 g (0.5 mole) of 2,4,4,4-tetrachlorobutyryl chloride in 600 ml of cyclohexane. A solution of 51 g (0.5 mole) of triethylamine in 500 ml of cyclohexane is then pumped in at 65° C. The reaction mixture is then kept for 3 hours at 65° C. The precipitated hydrochloride of triethylamine is collected by filtration and the filtrate is concentrated. The resulting crystals are collected by filtration, affording 79.4 g of 2-chloro-2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutan-1-one with a melting point of 75°-76° C. (60% of theory).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: NCCc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCc1ccncc1
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Methanesulphonyl chloride (3.5 g.) was added slowly to 4-(2-aminoethyl)pyridine (3.6 g.) and triethylamine (3.0 g.) in chloroform (40 ml.). The temperature was maintained below 40° C. during the addition, after which the orange solution was left to stand at room temperature overnight. Water (50 ml.) was then added, the chloroform phase was separated, and the aqueous phase extracted with chloroform (100 ml.). The two chloroform solutions were combined, dried (MgSO4) and taken to dryness in vacuo to give a yellow oil which solidified immediately. This solid was crystallized from ethanol to yield white crystals of 4-(2-methanesulphonamidoethyl)pyridine (1.4 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12]Br)=[CH:4][CH:3]=1.[CH3:14][O:15][P:16]([O:19]C)[O:17][CH3:18]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][P:16](=[O:19])([O:17][CH3:18])[O:15][CH3:14])=[CH:4][CH:3]=1
Reactant: COP(OC)OC
Reactant: Clc1ccc(CBr)c2ccccc12
Product: COP(=O)(Cc1ccc(Cl)c2ccccc12)OC

Procedure:
Following the procedure of Compound 11, 4-chloro-1-bromomethylnaphthalene is reacted with trimethylphosphite.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[H][H].[CH:20]([CH:22]1[CH2:26][CH:25]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:24]([OH:34])[CH:23]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][OH:42])=O>O1CCCC1.C(O)(=O)C>[OH:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:23]1[CH:22]([CH:20]=[CH:4][C:3](=[O:11])[CH:2]([CH3:1])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:26][CH:25]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:24]1[OH:34]
Reactant: CCCCC(C)C(=O)CP(=O)(OC)OC
Reactant: [H][H]
Reactant: O=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of dimethyl 3-methyl-2-oxoheptylphosphonate (2.36 g.) in tetrahydrofuran (20 ml.) was added dropwise to a stirred suspension of sodium hydride (0.24 g.) in tetrahydrofuran (50 ml.). The mixture was stirred at room temperature until the evolution of hydrogen has ceased, then treated dropwise with a solution of 3-formyl-2-(7-hydroxyheptyl)-5-(2-tetrahydropyranyloxy)cyclopentanol [3.28 g.; prepared as described above in Example 2(e)] in tetrahydrofuran (20 ml.) and stirred for a further 2 hours. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvent was removed in vacuo and the residue dissolved in diethyl ether. The ethereal solution was washed with aqueous sodium carbonate solution, dried over magnesium sulphate, and evaporated to dryness to give 2-(7-hydroxyheptyl)-3-(4-methyl-3-oxooct-1-enyl)-5-(2-tetrahydropyranyloxy)cyclopentanol (4.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.Cl.[CH3:13][NH:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]([CH3:15])[CH3:13]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cc1Cl
Yield: 101.1 %

Procedure:
A solution of 3-chloro-4-fluoronitrobenzene (3.0 g, 17.1 mmol), dimethylamine hydrochloride (1.53 g, 18.8 mmol) and K2CO3 (4.96 g, 35.9 mmol) in Me2SO (20 mL) was heated in a sealed tube at 105° C. for 18 h. On cooling the reaction mixture was poured into water (200 mL) and extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated to give 3.47 g of 3-chloro-4-(dimethylamino) nitrobenzene as a yellow solid. An aliquot of this (3.4 g, 16.95 mmol) was dissolved in 20 mL of EtOH/AcOH (1:1, v/v) with warming. Iron powder (−325 mesh, 9.5 g, 170 mmol) was added in small portions. The mixture was then heated on a steam bath for 30 min. The mixture was cooled, filtered through a pad of celite and the filtrate was evaporated to give 3.33 g of 3-chloro-4-(dimethylamino)aniline as a dark solid. A solution of this compound in EtOH (10 mL) was treated with HNO3 (69% aq, 2.6 mL, 40.6 mmol) dropwise, followed by cyanamide (50% solution in water, 5.3 mL, 67.78 mmol). After heating for 18 h at reflux the reaction mixture was cooled to room temperature, poured into Et2O (100 ml) and basified with NaOH solution (2 N, 100 mL). The ethereal layer was separated. The aqueous phase was extracted with Et2O. The combined organic phases were washed with brine, dried on MgSO4, filtered, and evaporated to give a black oil, which solidified on standing to afford 1.6 g of the title compound. RP-HPLC: tR=12.7 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity >95%). 1H-NMR (CD3OD) δ: 2.68 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.75 (s, 6H, CH3), 7.05 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=8.8 Hz, pyrimidinyl-H), 7.49 (dd, 1H, J=8.8, 2.4 Hz, Ph-H), 7.94 (d, 1H, J=2.4 Hz, Ph-H), 8.43 (d, 1H, J=5.4 Hz, pyimidinyl-H). MS (ESI+) m/z=393 [M+Na] (C17H18N6O2S requires 370.4).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1>CN(C)C=O>[N:26]([C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)=[CH:21][CH:22]=1)=[C:1]=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A mixture of thiocarbonyidiimidazole (4.46 g, 25.0 mmol) (Aldrich) and N,N-dimethylformamide (20 mL) was cooled to about −15° C. and a solution of 4-(4-methyl-1-piperazinyl)benzenamine (prepared according to the procedure of Chong, W. K. et al. WO9921845; 4.78 g, 25.0 mmol) was added over a period of 30 min. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was cooled to 0° C. and ice-water was added. After 30 min, the mixture was extracted with ether (3×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-methylpiperazine (4.84 g, 83%) as a pale purple solid.