Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>ClCCl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (3.45 g, 0.026 mol) in dichloromethane (20 mL) at 5° C. was added dropwise a solution of 4-bromobiphenyl (2.3 g, 0.010 mol) in dichloromethane (11 mL) followed by the dropwise addition of 3-carbomethoxypropionyl chloride (1.35 mL, 0.011 mol) in dichloromethane (15 mL), and the mixture stirred. After 2 hours at 5° C., the mixture was allowed to warm to room temperature. After 1 day, the reaction was cooled to 5° C. and quenched by the dropwise addition of water (50 mL). The layers were separated, and the organic layer washed with water and brine, dried (MgSO4), and rotary evaporated. The residue was dissolved (CH2Cl2) and purified by column chromatography on silica gel, eluting with dichloromethane to give 2.68 g of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 115.0-116.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.[Cu]I.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>[C:19]1([C:25]#[C:26][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1C#Cc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of methyl 2-bromobenzoate 34 (166 μL, 1.163 mmol) in acetonitrile (2906 μL) was added triethylamine (972 μL, 6.98 mmol) and phenylacetylene 35 (140 μl, 1.279 mmol). Then copper (I) iodide (11.07 mg, 0.058 mmol), and bis(triphenylphosphine)-palladium(II) chloride (20.40 mg, 0.029 mmol), were successively added, degassing between and after each addition of catalysts. The mixture was stirred at 75° C. overnight. The reaction mixture was partitioned between EtOAc and 1M HCl. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with water, brine, dried over MgSO4. The residue was purified via Biotage using EtOAc/Hex ((0:100 to 10:90); 25+S column), to afford compound 36 (157 mg, 57%). LRMS (ESI): (calc.) 236.08 (found) 237.2 (MH)+
Reaction SMILES: [Na].[NH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]=[C:3]1[NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([O-])=[O:15]>CO.CCOCC>[OH:17][C:12]1[N:11]=[C:3]2[NH:2][C:6]3([CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][N:4]2[C:14](=[O:15])[CH:13]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: NC1=NCC2(CCCC2)N1
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(O)nc2n1CC1(CCCC1)N2
Temperature: 100 °C
Yield: 74 %

Procedure:
2.37 g of sodium are added in a fractionated way to 10 mL of MeOH. After total dissolution, 5.68 g of 1,3-diazaspiro[4.4]non-2-en-2-amine solubilized beforehand in 5 mL of MeOH, and then 25.38 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The oil obtained is taken up in ether. The precipitate is filtered and the residue is then taken up in 10 mL of H2O and acidified with conc. HCl until pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 3.97 g (yield=74%) of 7′-hydroxyspiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a beige solid.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[CH2:15]=O>>[CH3:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:15])[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CN1CCCCC1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred ice cold solution of 2-nitropropane (10.0 g, 0.11 mol) and piperidine (11.1 mL, 1 equiv, 0.11 mol) was added dropwise a premixed solution of sodium hydroxide (0.5 mL, 5 N, 2 mol %) and a 37% aqueous solution of formaldehyde (8.4 mL g, 1 equiv, 0.11 mol) over 15 minutes maintaining an internal temperature between 10-15° C. The flask was removed from the ice bath and stirred at room temperature for 1 h. The reaction was then heated at 50° C. for 1 h. The biphasic mixture was cooled to room temperature and poured into a separatory funnel and diluted with ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a yellow liquid (20.0 g). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.35-1.38 (m, 2H), 1.46-1.51 (m, 4H), 1.53 (s, 6H), 2.43-2.46 (t, J=5.2, 4H), 3.10 (s, 3H), 3.42-3.51 (m, 4H), 4.20 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37]1([NH2:40])[CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:32]6[N:33]=[CH:34][CH:35]=[CH:36][N:31]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.16 g, 1.3 mmol). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), 1.59-1.61 (m, 2H), 2.31 (s, 3H), 2.82-2.83 (d, 3H, J=4.8 Hz), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.39-7.45 (m, 4H), 7.59 (s, 1H), 7.76-7.78 (d, 1H, J=8.4 Hz), 7.86-7.87 (d, 2H, J=4.4 Hz), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 8.67-8.68 (d, 2H, J=4.8 Hz), 9.20 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min.
Reaction SMILES: [NH2:1]C1C=C(SC(F)(F)F)C=CC=1O.CCN=C=NCCCN(C)C.[C:25]([OH:33])(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[C:25]([NH2:1])(=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccncc1
Temperature: 80 °C

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([CH3:49])=[C:45]([NH2:48])[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37])[CH3:34].[CH3:50][NH2:51]>C1COCC1>[CH3:34][N:33]([CH3:32])[CH2:35][C:36]([N:38]1[C:47]2[C:42](=[CH:43][C:44]([CH3:49])=[C:45]([NH:48][C:3]3[N:16]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH:51][CH3:50])=[O:17])[C:6]4[CH:19]=[CH:20][N:21]([S:22]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)(=[O:24])=[O:23])[C:5]=4[N:4]=3)[CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:37]
Reactant: Cc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2C)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
A slurry of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (300 mg, 0.626 mmol) and 1-[(dimethylamino)acetyl]-6-methyl-1,2,3,4-tetrahydro-7-quinolinamine (155 mg, 0.626 mmol) in THF (50 mL) was heated at 70° C. for 20 h. The resulting mixture was allowed to cool to rt and was treated with a 2M MeNH2 solution in THF (10 mL). The reaction mixture was stirred at rt for 3 days, then concentrated onto Celite and purified by silica gel chromatography using 1-20% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-({2-{[1-(N,N-dimethylglycyl)-6-methyl-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (87 mg, 20%). ESIMS (M+H)+=685.18.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([S:26]([O:29]C)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([O-:29])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:20][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COS(=O)(=O)c1ccccc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=S(=O)([O-])c1ccccc1
Yield: 173.5 %

Procedure:
A mixture of 19.2 g (73.2 mmol) of triphenylphosphine and 12.6 g (73.2 mmol) of methyl benzenesulfonate was allowed to react for 2 hr at 130° C. A total of 27.6 g (63.5 mmol, 86.8%) of the product was obtained after recrystallization from 75:25 toluene-acetonitrile. Analyses: mp 147.6°-149.7° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27].O>CN(C=O)C>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 35.3 %

Procedure:
To a stirred solution of 6-chloro-3-(5-fluoro-2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 24, 97 mg, 0.35 mmol) in DMF (4 mL), sodium bicarbonate (60 mg) and 1-methanesulfonyl-piperidin-4-ylamine (93 mg, 0.52 mmol) were added and the mixture was stirred at 100° C. for 4 hours. The reaction was cooled and the mixture was poured into water (60 mL). The solid was filtered and dried to give a yellow solid, which was purified by reverse phase HPLC to give 52 mg pale yellow solid. Yield, 35%. MS (M+H)+, 421.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:11])[CH:9]=[CH2:10].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51]Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:17]2[C:36]([CH:37]3[CH2:38][CH2:39]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([O:11][CH2:49][O:50][CH3:51])[CH:9]=[CH2:10]
Reactant: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Reactant: COCCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(OCOC)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a solution of 6-(N-(3-chloro-4-(1-hydroxyallyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (210 mg, 0.37 mmol) in THF (7 mL) was added DIEA (0.084 mL, 0.48 mmol) and chloromethyl methyl ether (0.16 mL, 2.12 mmol). The reaction mixture was heated at 50° overnight. Another portion of DIEA (0.32 mL, 1.85 mmol) was added and heating was continued for another 5 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (175 mg, 77%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (q, 1H), 8.10 (s, 1H), 7.93-8.00 (m, 2H), 7.36-7.53 (m, 5H), 7.19 (s, 1H), 5.88 (ddd, 1H), 5.38 (d, 1H), 5.18-5.30 (m, 2H), 4.66 (d, 1H), 4.53 (d, 1H), 3.38-3.46 (m, 3H), 3.23 (s, 3H), 2.83 (d, 3H), 2.08-2.17 (m, 1H), 0.92-1.06 (m, 1H), 0.75-0.91 (m, 2H), 0.39-0.51 (m, 1H). LCMS (m/z, ES+)=613 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6])=[CH:13][CH:12]=1
Reactant: CC(C)(CF)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CF)C(=O)COc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
157 g (0.79 mol) of 1-bromo-3,3-dimethyl-4-fluoro-butan-2-one were added dropwise to a stirred mixture of 102 g (0.79 mol) of p-chlorophenol and 110 g (0.79 mol) of powdered potassium carbonate in 500 ml of acetone at 20° to 30° C., whilst cooling. The mixture was subsequently stirred at 20° C. for 2 hours, the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 175 g (90% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-4-fluoro-butan-2-one of boiling point 112°-119° C./0.05 mm Hg were obtained. ##STR25##
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:9][CH2:10][CH3:11])[O:5][P:6](Cl)Cl)#[N:2].C[Si]([C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)(C)C>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([CH2:9][CH2:10][CH3:11])[O:5][P:6]([C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[N:20]=1)#[N:2]
Reactant: Cc1c[nH]c([Si](C)(C)C)n1
Reactant: CCCC(CC#N)OP(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC(CC#N)OP(c1nc(C)c[nH]1)c1nc(C)c[nH]1
Reaction time: 0.08 h

Procedure:
To toluene (5 ml) there were added 0.267 g (1.25 mmol) of 2-cyano-1-n-propylethoxydichlorophosphine and 0.425 g (2.75 mmol) of trimethylsilyl-4-methylimidazole under an argon atmosphere at room temperature, and reaction was conducted for 5minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 10 minutes at room temperature, the residual toluene and excess trimethylsilyl-4-methylimidazole were removed under reduced pressure for 2 hours at 35° C. to obtain 2-cyano-1-n-propylethoxybis (4-methylimidazolyl)phosphine as a colorless transparent oil. This was dissolved in 2.5 ml of chloroform-d, and the solution (0.5 M) was added to 0.678 g (1.25 mmol) of 5′-O-(4,4′-dimethoxytrityl)thymidine that had been dried under reduced pressure for 2 hours, under an argon atmosphere at room temperature. Upon reaching homogeneity, the mixture was allowed to stand overnight for reaction to obtain a phosphorazolide compound represented by the formula (1-18) above.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[NH2:30])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[C:24]5[CH:29]=[CH:28][N:27]=[CH:26][C:25]=5[N:30]=[CH:31]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)OC
Reactant: Nc1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O=CO
Product: c1cc2c(cn1)ncn2CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 24 h
Yield: 65 %

Procedure:
N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (280 mg, 0.68 mmol), trimethylorthoformate (5 mL) and formic acid (0.5 mL) were stirred at 40° C. for 18 hours then at 60° C. for 24 hours, then at 80° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound as a clear viscous oil (185 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H), 1.91-2.03 (m, 4H), 2.15-2.20 (m, 2H), 2.52 (m, 4H), 2.61 (t, 2H), 3.44 (m, 2H), 3.82 (m, 2H), 4.00 (t, 2H), 4.19 (s, 2H), 6.82 (d, 2H), 6.86-6.93 (m, 3H), 7.08 (s, 1H), 8.30 (d, 1H), 9.01 (s, 1H). HRMS ESI+ m/z 421.2590 [MH]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[I:12]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([I:12])[CH:10]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: OCCCc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-hydroxypropyl)phenol (2.00 g, 13.14 mmol) in MeOH (10 ml) under nitrogen at RT was added silver sulfate (4.10 g, 13.14 mmol) followed by iodine (3.34 g, 13.14 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then, the solids were filtered washing with MeOH. The filtrate was concentrated and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.51 (d, J=2.1 Hz, 1H); 7.02-6.97 (m, 1H); 6.73 (d, J=8.2 Hz, 1H); 3.53 (t, J=6.5 Hz, 2H); 2.59-2.51 (m, 2H); 1.80-1.71 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:41][N:40]([CH:37]1[CH2:36][CH2:35][N:34]([CH2:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:39][CH2:38]1)[C:18](=[O:20])[C:17]1[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=1[O:15][CH3:14]
Reactant: CNC1CCN(CC2CCCCC2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)C1CCN(CC2CCCCC2)CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Triethylamine (4.2 ml; 0.03 moles) and a solution of ethyl chloroformate (2.85 ml; 0.03 moles) in anhydrous tetrahydrofuran (35 ml) were added successively to a solution of 2-methoxy-4-amino-5-chlorobenzoic acid (6.04 g; 0.03 moles) in N,N-dimethylformamide (225 ml) whilst maintaining the temperature at -10° C. After stirring at this temperature for 2 hours, a solution of 1-cyclohexylmethyl-4-methylaminopiperidine (6.15 g; 0.03 moles) in anhydrous tetrahydrofuran (35 ml) was added, and the temperature was allowed overnight to reach room temperature. The mixture was poured into an aqueous solution of sodium bicarbonate, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was recrystallized from a mixture of ethanol and diethyl ether. N-methyl-N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (9.6 g) was obtained.
Reaction SMILES: CC(C)([O-])C.[Na+].C1COCC1.CN(C=O)C.[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20].[Br:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>CC(OC)(C)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:20][CH2:19][C:18]([F:22])([F:21])[F:17])=[CH:26][C:25]=1[C:31]([F:32])([F:33])[F:34]
Reactant: OCC(F)(F)F
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a 2.4 M solution of sodium-tert-butoxide in THF (156.3 mL, 375 mmol, Chemetall) was added DMF (38.5 mL, 500 mmol) and then 2,2,2-trifluoroethanol (41.27 g, 413 mmol). After the addition of 2-bromo-5-fluorobenzotrifluoride (60.8 g, 250 mmol) the reaction mixture was heated to reflux and stirred at ˜80° C. for 7 h. After cooling to 25° C., TBME (800 mL) was added and the reaction mixture was washed with 1M HCl (400 mL), 5% NaHCO3 (400 mL) and 10% brine (400 mL). The organic layer was dried (Na2SO4), filtered and evaporated to dryness (60° C./≧5 mbar), affording the crude title product (80.0 g, 99.1%) as a yellow oil which was used without purification in the next step 1H NMR (CDCl3, 400 MHz) δ 4.38 (q, J=7.9 Hz, 2H), 6.98 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([C:13]#[N:14])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1.[OH-:19].[Na+]>>[CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([C:13]([NH2:14])=[O:19])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1
Reactant: CN(C)C1CC2=CNC=C3C=C(C#N)OCC1=C32
Reactant: [OH-]
Agent: [Na+]
Product: CN(C)C1CC2=CNC=C3C=C(C(N)=O)OCC1=C32
Temperature: 90 °C
Yield: 62 %

Procedure:
Polyphophoric acid 420 mg was added to compound (48) 31.6 mg under an argon atmosphere and the mixture was heated at 90° C. for 6 h. Ice-water was added to the reaction mixture, which was made alkaline with an aqueous 5 N-sodium hydroxide solution and extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound as colorless crystals, 20.9 mg. Yield 62%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.