Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[Na].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])=[CH:18][CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: NCc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1-c1ccc(CN)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of 2-bromo-4-nitroanisole (5.80 g, 25.0 mmol) and 4-(aminomethyl)phenylboronic acid hydrochloride (4.96 g, 26.6 mmol) was slurried in 1-propanol (50 mL) under nitrogen. Triphenylphosphine (315 mg, 1.20 mmol) and palladium (II) acetate (90 mg, 0.40 mmol) were added, followed by 2.0N sodium carabonate (33 mL, 66 mmol). The mixture was heated at 95° C. (oil bath) under nitrogen for 3 hours, at which time the reaction was judged to be complete by TLC. Water (25 mL) was added and the mixture was stirred open to air for 2 hours at room temperature. The mixture was extracted with ethyl acetate (100 mL, 2×50 mL) and the combined extracts were washed with sodium bicarbonate (25 mL) and brine (25 mL). The solution was dried with sodium sulfate, and concentrated to an oil which was purified by flash chromatography on silica gel (100 g) eluting with 0-4% methanol/0,5% triethylamine/dichloromethane. Pure fractions were combined and concentrated to give 2-(4-aminomethylphenyl)-4-nitroanisole (4.6 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[O:21][CH3:22])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.O1CCCC1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(OC)c1C(O)c1c(OC)cccc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1cccc(OC)c1Cc1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of bis(2,6-dimethoxyphenyl)methanol (4.37 g, 0.014 mol) in acetonitrile (50 mL) and tetrahydrofuran (65 mL) was added p-toluenesulfonic acid monohydrate (2.73 g, 0.014 mol) at 0° C. The resulting solution was warmed to room temperature and stirred for 17 hours, after which water (60 mL) was added and the solvent removed under reduced pressure. The residue was extracted with diethyl ether and the combined extracts dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave bis(2,6-dimethoxyphenyl)methane.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][C:2]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Solvent: CCO
Product: COc1ccc(-c2nc(N)sc2C)cc1
Yield: 77.5 %

Procedure:
A mixture of 2-bromo-1-(4-methoxyphenyl)propan-1-one (10.4 g, 36.1 mmol) and thiourea (2.76 g, 36.2 mmol) in 95% EtOH (70 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (6.16 g) as yellow solids in 78% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 2 H), 7.46-7.44 (m, 2 H), 7.09-7.07 (m, 2 H), 3.81 (s, 3 H), 2.47 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[C:25]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:18]1([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:23][C:25]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[C:2]([CH3:1])=[CH:7][N:6]=3)=[CH:14][CH:13]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Fc1ccc(Br)c2cc[nH]c12
Reactant: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1Nc1ccc(F)c2[nH]ccc12
Yield: 1.7 %

Procedure:
A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Pd2(dba)3 (92 mg, 0.1 mmol). Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HCl salt, 1.5%) as a brown solid.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:17])[CH:8]=1>C(O)(=O)C>[Br:1][C:8]1[C:9]([CH3:17])=[N:10][C:11]2[C:16]([C:7]=1[NH:6][CH2:5][CH2:4][OH:3])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: Cc1cc(NCCO)c2ccccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(NCCO)c1Br

Procedure:
Bromine (15.6 g) was added dropwise to a solution of N-(2-hydroxyetyl)-2-methyl-4-quinolinamine (26 g) in 400 ml of acetic acid. A solid separated which after one hour of stirring was filtered and dissolved in 400 ml of water. The free base was precipitated by adding 20% KOH solution until pH became 10. The solid was filtered and recrystallized from isopropanol. The yield was 14.5 g, mp 154°-155° C.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:19][CH:20]=1
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 4.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-chlorophenyl)methyl](4-isopropylphenyl)amine (1.3 g) as starting materials, N-[(4-chlorophenyl) methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.1 g) was obtained. melting point: 122-123° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[CH3:2])=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1), to give 9.8 g (47 mmol, 71%) of the product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:30][N:31]([C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:20][CH:11]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)=[O:26])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a mixture of 4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid (100 mg) synthesized in Example A94(3), ethyl 3-(methylamino)propanoate (50.8 mg), 1-hydroxybenzotriazole monohydrate (59.3 mg), triethylamine (54 μL) and N,N-dimethylformamide (10 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg) was added, and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (82.5 mg, 64%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.[C:21]([O-])([O-])=[O:22].[Na+].[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:21]=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=C([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c[nH]c2ncc(Br)nc12
Temperature: 80 °C

Procedure:
To a reaction vial, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1 g, 0.00505 mol) was added in TFA (10 ml). Hexamine (1.06 g, 0.00757 mol) was added and reaction mixture was heated to 80° C. in microwave for 15 min. After completion of the reaction, the reaction mixture was poured into aq. Na2CO3 solution. Solid obtained was filtered, dried and purified using column purification by eluting with 3-5% EtOAc in Hexanes to yield 0.450 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(CCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 1.69 g (3.58 mmol) of 4-(5-bromopentyloxy)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, 0.738 g (3.58 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 2.07 g (14.98 mmol) of anhydrous potassium carbonate, and 37.5 mL of 2-butanone was stirred and refluxed for 18.5 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the crude product was purified by flash chromatography on 250 g of silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 1.93 g (90.1%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>O.ClCCCl>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(C2CCCC2)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: c1ccc(Oc2cccc(NCc3cccc(C4CCCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a 1,2-dichloroethane (12 mL) solution of 3-cyclopentylbenzaldehyde (0.69 g, 4.0 mmol; P. L. Ornstein et al., J. Med. Chem. 1998, 41, 358-378) was added 3-phenoxyaniline (0.73 g, 4.0 mmol), NaB(OAc)3H (1.08 g, 5.1 mmol) and acetic acid (0.24 mL, 4.2 mmol). The cloudy solution was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.30 g (22%) of the desired N-(3-phenoxyphenyl)-[[3-cyclopentylphenyl]methyl]amine product as a colorless oil. 1H NMR (CDCl3) δ 1.55 (m, 2H), 1.63 (m, 2H), 1.78 (m, 2H), 2.02 (m, 2H), 2.94 (m, 1H), 4.10 (m, 1H), 4.22 (m, 2H), 6.35 (m, 3H), 7.0-7.2 (m, 10H). The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) and the formation of the benzyl peak (δ 4.22) in the 1H NMR spectrum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]([F:15])([F:14])[CH2:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[ClH:16]>>[ClH:16].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]([F:15])([F:14])[CH2:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCCC(F)(F)P(=O)(CCCN)OCC
Agent: Cl
Product: CCCC(F)(F)P(=O)(O)CCCN
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1.4 g (5.8 mMol) of ethyl 3-aminopropyl(1,1-difluorobutyl)phosphinate and 15 ml of 12M hydrochloric acid is stirred for 8 hours at 80° C. The reaction mixture is evaporated to dryness and the residue is recrystallized from ethanol/ether giving 3-aminopropyl(1,1-difluorobutyl)phosphinic acid hydrochloride, m.p. 149°-151° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[OH-].[Na+]>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)c1ccc(O)cc1
Reaction time: 36 h

Procedure:
It is known that glyoxylic acid in alkaline aqueous medium is little stable and dismutes when hot quantitatively into oxalic and glycolic acids by Cannizzaro's reaction (BOETTINGER, Ber., I880, 13 I931I). For this reason, reactions that involve glyoxylic acid in alkaline aqueous medium are achieved at a temperature lower or equal to the room temperature. Thus, in the process described in French Pat. No. 2,132,364, condensation of glyoxylic acid with phenol in excess dissolved in 10% aqueous sodium hydroxide solution is achieved at 15° to 25° C. in 36 hours. In German Pat. No. 621 567, an alkaline aqueous solution of phenol and glyoxylic acid is held several days at the room temperature to obtain racemic parahydroxymandelic acid. J. GOODMAN et Al. .,Biochem. Biophys. Acta, 1968, 156, 364.67, condense glyoxylic acid with gaiacol in 68 hours at 25° C., and J. KAMLET, U.S. Pat. No. 2,640,083 proceeds in 48 hours at 15°-20° C. to prepare racemic 4-hydroxy 3-methoxy mandelic acid. Recently, Belgian Pat. No. 867 287 has described a process for obtaining an alkaline metal salt of solid monohydrated parahydroxymandelic acid by condensing glyoxylic acid with phenol in excess in alkaline aqueous solution at a temperature slightly higher than room temperature either in 18 hours from 30° to 35° C. (example 1) or 5 hours at 35° C. (example 2), or again 8 hours at 35° C. (example 3).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15](F)[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29]>CS(C)=O>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: CNCCN(C)C
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(N(C)CCN(C)C)c2)s1
Temperature: 120 °C

Procedure:
A stirred mixture of 1-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 73) (0.05 g, 0.14 mmol) and N,N,N′-Trimethylethylenediamine (0.25 ml, 2.1 mmol) in dry DMSO (0.5 ml) is heated under argon at 120° C. for 2 hours. The solvent is in vacuo removed and the product is purified by chromatography on silica eluting with ethanol-triethylamine (98:1) to give the titled compound. MH+: 440.1051
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:11]2[CH2:13][CH2:12]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C2CC2)ccc1N
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
Combine 2-amino-5-bromo-benzonitrile (1.76 g, 8.95 mmol), cyclopropyl boronic acid (1.0 g, 11.64 mmol), tricyclohexylphosphine (0.251 g, 0.89 mmol) and potassium phosphate (6.65 g, 31.26 mmol) in a mixture of toluene (40 ml) and water (2 ml) and stir the mixture for 10 minutes. Add palladium acetate (0.101 g, 0.45 mmol) and heat the mixture to 100° C. After 3 hours add more tricyclohexylphosphine (0.251 g, 0.89 mmol) and palladium acetate (0.101 g, 0.45 mmol). After an additional 3 hours at 100° C., add 20 ml of water and extract the mixture three times with 50 ml of ethyl acetate. Combine the organic layers, dry over sodium sulfate and concentrate. Purify the residue using flash chromatography and eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.988 g of the title compound (6.24 mmol, 70% yield) as a clear yellow oil: Mass spectrum (m/e): 159(M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47]2[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=2)[CH2:43][CH2:42]1)=[O:40].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:53]([C:50]1[CH:51]=[CH:52][C:47]([CH:44]3[CH2:45][CH2:46][N:41]([C:39](=[O:40])[C:38]([F:58])([F:37])[F:57])[CH2:42][CH2:43]3)=[CH:48][CH:49]=1)(=[O:54])=[O:55])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 77.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethy)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.51 mmol), 4-[1-(2,2,2-trifluoroacetyl)-4-pipendinyl]benzenesulfonyl chloride (preparation 20) (157 mg, 0.48 mmol) and triethylamine (155 mg, 1.53 mmol) in tetrahydrofuran (25 ml). This gave the title compound as a solid (300 mg). MS: 811 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:21][CH2:20]1>>[CH3:13][CH:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH2:28][O:27][C:26]3=[O:35])[CH2:23][CH2:24]2)=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)NS(=O)(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from the product of step (i) (0.14 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.1 g) using the method of example 115 step (ii). Yield 0.037 g.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=O)[CH2:19][CH2:18]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO>[NH2:31][CH:20]1[C:21]2[C:17](=[CH:16][C:15]([C:12]3[N:10]4[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]4=[N:14][CH:13]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:19]1
Reactant: [BH3-]C#N
Reactant: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCC4=O)n2n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCC4N)n2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A mixture of 5-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-indan-1-one (50 mg, 0.16 mmol), ammonium acetate (500 mg), and methanol (5 mL) was maintained at RT for 5 min, then treated with sodium cyanoborohydride (500 mg). The resulting mixture was heated to 50° C. and maintained 16 h, then cooled to RT and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford [3-(1-amino-indan-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-butyl-amine (26 mg, 52%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.22 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.54-7.66 (m, 2H), 6.72 (d, J=9.6 Hz, 1H), 4.77-4.83 (m, 1H), 3.38 (t, J=7.2 Hz, 2H), 3.18-3.30 (m, 1H), 3.01-3.13 (m, 1H), 2.59-2.73 (m, 1H), 2.06-2.22 (m, 1H), 1.72 (quin, J=7.4 Hz, 2H), 1.43-1.57 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); LCMS (ESI) m/e 322.3 [(M+H)+, calcd for C19H24N5 322.2].