Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+].O>CS(C)=O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=[C:3]1[CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1cc2ccccc2o1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(O)c1cccc(OCc2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
2-Bromomethylbenzofuran (5 g, 0.024 mol) and 1-(3-hydroxyphenyl)-1-hexanol (4.7 g,0.024 mol) were dissolved in DMSO (75 ml). To this clear, homogeneous solution was added an aqueous solution of sodium hydroxide (12.5 ml, 2N solution; 0.025 mol NaOH). Immediately after the sodium hydroxide solution was added, the reaction mixture became warm (45°-50° C.). This clear, homogeneous solution was stirred at room temperature for 6 hours, and then poured into water (300 ml). The organics were extracted thoroughly with ethyl acetate (3×50 ml), and the combined organic extract was washed with water, 1N sodium hydroxide solution (to remove excess phenol), water, 0.1N hydrochloric acid solution, water and finally brine. After drying over anhydrous magnesium sulfate, all volatiles were removed from the ethyl acetate extract to leave a clear liquid (7.2 g) which was chromatographed on silica gel using 10% ethyl acetate in hexanes as eluent to obtain the pure compound as a clear, colorless liquid (4.4 g, 56%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[NH:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.O>CN(C=O)C>[CH2:19]([O:18][CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]2[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=[C:29]2[C:28]([F:27])([F:39])[F:38])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)OCC
Temperature: 60 °C

Procedure:
Ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate (371 mg, 1 mmol) was dissolved in DMF (5 ml) and K2CO3 (552 mg, 4 mmol) was added followed by 2-trifluoromethyl benzimidazole (204 mg, 1.1 mmol). The reaction mixture was heated to 60° C. for 17 hrs. After the completion of the reaction, water was added and the product was extracted with Et2O. The product was purified by column chromatography on silica gel using ethyl acetate and hexanes as solvent (333 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH2:27][CH2:28]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N2CCN(c3ccccn3)CC2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 1-(2-pyridyl)piperazine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([CH:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C#N)=[CH:5][CH:4]=1.CC(C)([O-:21])C.[K+].OO>C(#N)C>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C(C#N)c2cccnc2)nn1
Agent: OO
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)c2cccnc2)nn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
(6-Methoxypyridazin-3-yl)pyridin-3-ylacetonitrile (7.7 g, 0.034 mol) were dissolved in acetonitrile (200 ml) at 23° C. under a nitrogen atmosphere, and potassium tert-butoxide (4.16 g, 0.037 mol) was added. The suspension was stirred at 23° C. for 30 minutes, cooled to −4° C., and hydrogen peroxide (30% solution, 11.34 ml, 0.11 mol) was slowly added dropwise. The reaction mixture was stirred at 0° C. for a further 30 minutes and subsequently at room temperature for 2 hours. Conventional work-up gave 3.46 g (48% yield) of (6-methoxypyridazin-3-yl)pyrdin-3-ylmethanone;
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:28][C:29](=[NH:31])[CH3:30]>CN(C=O)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1([C:12]2[O:14][N:31]=[C:29]([CH3:30])[N:28]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (1.01 g, 5.00 mmol) in 2 mL of DMF was added carbonyldiimidazole (0.812 g, 5.01 mmol). This reaction mixture was stirred at room temperature for 6 h. N-Hydroxy-acetamidine (0.374 g, 5.05 mmol) was added. This reaction mixture was stirred at room temperature for 2 h then heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration, washed with acetonitrile and water and air-dried to give 1.05 g of [1-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a white solid, m/z 240 [M+1]+.
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC=C(Cl)C=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2cccc(Cl)c2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Yield: 27 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(3-chlorophenyl)-N-hydroxyacetamide and 2{[4-(2-butynyloxy)phenyl]sulfinyl}-2-(3-chlorophenyl) N-hydroxyacetamide (210 mg, 0.56 mmol), and following the procedure as outlined in Example 75, 60 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl)-2-(3-chlorophenyl)-N-hydroxyacetamide was isolated as a white powder. mp: 50° C.; Yield: 27%; MS: 394.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ1.84 (t, J=2.22 Hz, 3H), 4.86 (d, J=2.31 Hz, 2H), 5.06 (s, 1H), 7.12 (d, J=8.97 Hz, 2H), 7.19-7.39 (band, 2H), 7.48 (m, 4H), 9.33 (d, J=1.2 Hz, 1H), 10.9 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[SH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[N:6]=[CH:7][C:2]([S:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Reactant: CCOC(=O)CS
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in N,N-dimethylformamide (1 mL) were added ethyl sulfanylacetate (98 μL) and tetrakistriphenylphosphinepalladium(0) (230 mg), and the mixture was stirred using a microwave synthesis apparatus at 120° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 54%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 555 (MH+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]([OH:38])(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:38])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: CN(C(=O)c1ccccc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with benzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-benzoyl-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 470 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=O.[Cl:10][C:11]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][N:23]1[CH2:24][CH2:25][O:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]3[C:11]([Cl:10])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: COC(=O)C(C)(C)C=O
Reactant: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(C)(C)CN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester (WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7 mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture was stirred overnight at RT, and subsequently treated with 5% aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionic acid methyl ester (1.12 g) as a clear colourless oil. The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows: To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester (10.00 g; 75.7 mmol) in CH2Cl2 (200 mL) was added pyridinium chloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. The reaction mixture was allowed to slowly warm to RT and stirred overnight. Subsequently, the mixture was diluted with CH2Cl2, filtered over kieselguhr, and concentrated in vacuo. The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3) to afford 2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g)
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1N)[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[ClH:22]>O>[CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[Cl:22])[CH3:2]
Reactant: Cl
Reactant: CCc1cc(C)cc(CC)c1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1Cl
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To an initial charge of 65 ml of 36% aqueous HCl are added, in portions, 16.33 g [0.1 mol] of 2,6-diethyl-4-methylaniline. The resulting thick suspension is stirred at 50° C. for 5 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 65° C., of 4.18 g [0.025 mol] of FeCl3 in 65 ml of 36% aqueous HCl. The reaction mixture is then stirred at 65° C. for another 1 hour, allowed to cool to room temperature and admixed with 200 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 17.9 g of an oil which, according to GC, contains 93.1% 2,6-diethyl-4-methylchlorobenzene (91% of theory).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:15]C.[Mg].Br[CH2:30]CBr>O1CCCC1>[CH3:30][CH:14]1[CH2:15][C:4]2[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:2][C:3]=2[O:13]1
Reactant: BrCCBr
Reactant: CCC(Oc1ccc(OC(F)(F)F)cc1I)OS(=O)(=O)c1ccc(C)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1Cc2cc(OC(F)(F)F)ccc2O1
Temperature: 25 °C
Yield: 36 %

Procedure:
10 ml solution of (2-iodo-4-trifluoromethoxyphenyloxy)-1-p-toluenesulphonyloxypropane (Description 20; 16 g, 28 mmol) in tetrahydrofuran (50 ml) was added dropwise to a stirred mixture of magnesium turnings (5 g, 208 mmol) in tetrahydrofuran (20 ml). 1,2-Dibromoethane (0.1 ml) was added. The exotermic reaction started. The mixture was warm up to reflux and the rest of (2-iodo-4-trifluoromethoxyphenyloxy)-1-p-toluenesulphonyloxypropane solution was added dropwise. The reaction mixture was heated at reflux for 24 hours, then cooled to room temperature and quenched with 2M aqueous hydrochloric acid. The mixture was extracted with a 1:1 mixture iso-hexane:diethyl ether (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-15%) to give the title compound (2.8 g, 36%).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[O:3].[NH2:16][C:17]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]1.[OH-].[Na+]>CC(C)=O.C(OCC)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:1][C:2]([NH:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)=[O:3])=[CH:5][C:6]=1[C:12]([F:13])([F:14])[F:15])#[N:9]
Reactant: NC1(C(=O)O)CC1
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#Cc1ccc(NC(=O)NC2(C(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (4.56 g, 21.5 mmol) in acetone (12 ml) is added dropwise to 1-aminocyclopropane carboxylic acid (2.02 g, 20 mmol) dissolved in an aqueous solution of sodium hydroxide (12 ml, 0.8 g, 20 mmol). The reaction medium is stirred for 1 hour at ambient temperature then poured into an aqueous solution of sodium hydroxide (1N, 40 ml). The solution obtained is washed with ethyl acetate (30 ml) then acidified by the addition of an aqueous solution of sulphuric acid (2M, 30 ml) and extracted with ethyl acetate (2×50 ml). The organic phase thus obtained is washed with water then with a saturated aqueous solution of sodium chloride, dried over Na2SO4 and filtered. The solvent is evaporated off under reduced pressure. The residue obtained is taken up in ethyl ether in order to produce a white solid, after filtration, with a yield of 50% (3.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN (700 mL) was added CH3I (110 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25° C. overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:23]=3[F:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1cccc(F)c1F
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2cccc(F)c2F)nc1C(F)(F)F
Yield: 24.8 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) was added 2,3-difluoroaniline (Aldrich) (113 mg) and the mixture was stirred at reflux for 47 hours using a Radleys Greenhouse Parallel Synthesiser. The dioxan was removed using a nitrogen blow down unit. The residue was taken up into methanol (0.5 ml) and dimethylsulfoxide (0.5 ml) and purified using a mass directed auto-preparative system to give the title compound (16 mg)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.Br[CH2:34]C=C(C)C>>[CH3:6][C:7]([CH3:34])=[CH:2][CH2:1][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1F
Reactant: CC(C)=CCBr
Product: CC(C)=CCn1ncc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(F)cc2)c1=O
Yield: 30 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 1-bromo-3-methyl-2-butene in place of 4-fluorobenzyl bromide, to provide the title compound (yield: 50 mg, 30%). mp 134-136° C. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J=7.5 Hz, 2H), 5.48 (t, J=6 Hz, 1H), 6.96 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.85 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 414 (M+H)+. Anal. calc. for C21H20FN3O3S: C, 61; H, 4.87; N, 10.16. Found: C, 60.98; H, 4.66; N, 9.95.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].C(P(O)(=O)O)CC.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCCP(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.7 %

Procedure:
To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid in 50 mL of chloroform were added 370 μL (4.34 mmol) of isopropylamine, 4 mL of anhydrous propanephosphonic acid (25 wt % solution in ethyl acetate) and 1.4 mL (10 mmol) of triethylamin, and the mixture was stirred for 6 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41][CH3:42])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[C:30]3[NH:32][N:33]=[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([S:41]([CH3:42])=[O:9])[N:36]=4)[C:29]3=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (428 mg, 2.4 mmol) was added slowly to a solution of 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (from Example 12 supra) (550 mg, 1.2 mmol) in a mixture of dichloromethane and methanol (100 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. (Yield 180 mg, 31.5%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>>[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Product: Cc1c(NCc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 2,4-difluorobenzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1CC[CH2:25][CH2:24]1>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:24](=[O:23])[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 0.15 ml of acetic anhydride and 0.24 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction solution was filtered with silica gel and NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (459 mg, 100% yield).