Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([CH2:11][CH2:12][CH2:13][S:14]([OH:17])(=O)=[O:15])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CN(C)C=O>[ClH:3].[N:5]1([CH2:11][CH2:12][CH2:13][S:14]([Cl:3])(=[O:17])=[O:15])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=S(=O)(O)CCCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=S(=O)(Cl)CCCN1CCOCC1

Procedure:
Thionyl chloride (10 ml) was added to 4-morpholinepropane sulfonic acid (4.4 g) followed by dimethylformamide (0.2 ml). The mixture was heated at reflux under nitrogen for 5 h. The thionyl chloride was removed in vacuo and the residue triturated with acetonitrile and filtered to give a white solid. This was dried at 80° C. in vacuo to give the title compound as a white solid (2.7 g). Found: C,31.9; H,5.9; N,5.1. C7H14CINO3S.HCl requires C,31.8; H,5.7; N,5.3%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:21]Br.Cl>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:21])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-acetyl-4-hydroxybenzoate (240 g, 1236 mmol) in DCM (2 L) was added pyridine (0.400 L, 4944 mmol) followed by a dropwise addition of dibromine (0.070 L, 1360 mmol) at 0° C. The reaction mixture was stirred at RT for 2 hrs then cooled to 5° C. and HCl 4N (0.927 L, 3708 mmol) was added dropwise. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a brown solid which was stirred in ether/petroleum ether (1:1, 1 L) for 1 hr. The solid was collected by filtration and dried to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (270 g, 80%) as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([CH2:24]Cl)[N:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CS(C)=O>[N:31]([CH2:24][C:22]1[N:23]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:26])[C:11]2[N:27]([CH3:30])[C:28](=[O:29])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)[S:20][CH:21]=1)=[N+:32]=[N-:33]
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CCl)cs4)ccc3n(C)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN=[N+]=[N-])cs4)ccc3n(C)c21
Temperature: 45 °C

Procedure:
400 mg (0.8 mmol) of compound A, 3-(4-bromophenyl)-6-(4-chloromethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 10 ml of DMSO. 160 mg (2.4 mmol) of NaN3 are added. The mixture is heated at 45° C. overnight. The mixture is allowed to return to ambient temperature. The reaction medium is poured into water, and the precipitate is filtered off and washed with water. The product is taken up in ethanol and evaporated to dryness.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH3:21])[CH2:15]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(C)C)(C)C>O1CCCC1>[CH2:20]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:1]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[O:2])[CH2:15]1)[CH3:21]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN1CCCC(N)C1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCN1CCCC(NC(=O)N2CCN(c3ccccc3)CC2)C1
Yield: 65.3 %

Procedure:
This compound was prepared according to the procedure of Example 5. A mixture of 5.7 g (0.035 mole) of 1,1'-carbonyldiimidazole, 4.4 g (0.034 mole) of 3-amino-1-ethylpiperidine and 4.9 g (0.030 mole) of 1-phenylpiperazine in a total of 200 ml of tetrahydrofuran gave 6.2 g (65%) of white solid, m.p. 100°-103° C. (diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([CH2:16][CH2:17][CH3:18])[CH:13]=[CH:14][N:15]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:11]2[N:12]([CH2:16][CH2:17][CH3:18])[CH:13]=[CH:14][N:15]=2)=[N:20]\[OH:21])=[CH:4][CH:3]=1.[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:11]2[N:12]([CH2:16][CH2:17][CH3:18])[CH:13]=[CH:14][N:15]=2)=[N:20]/[OH:21])=[CH:4][CH:3]=1
Reactant: CCCn1ccnc1C(=O)Cc1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1ccnc1/C(Cc1ccc(N)cc1)=N/O
Product: CCCn1ccnc1/C(Cc1ccc(N)cc1)=N\O

Procedure:
A solution of 2-(4-aminophenyl)-1-(1-propylimidazol-2-yl)ethanone (400 mg) and hydroxylamine hydrochloride (149 mg) in ethanol (15 ml) was refluxed for 1 day. The mixture was allowed to be at room temperature, saturated sodium bicarbonate solution was added to the mixture, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate) and recrystallized from hexane-ethyl acetate, to give (1E)-2-(4-aminophenyl)-1-(1-propylimidazol-2-yl)ethanone oxime (220 mg) and (1Z)-2-(4-aminophenyl)-1-(1-propylimidazol-2-yl)ethanone oxime (58 mg) as pale red crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[C:16]3=[O:32])=[CH:11][C:10]=2[CH3:33])=[N:6][CH:7]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)#[CH:35].C(N(CC)CC)C.O>CN1CCCC1=O.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.[Cu](I)I>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([C:35]#[C:34][C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:38][CH:37]=4)=[CH:7][N:6]=3)=[C:10]([CH3:33])[CH:11]=2)[C:16]1=[O:32]
Reactant: COc1ccc(CN2CCCN(c3ccc(Oc4ccc(Br)cn4)c(C)c3)C2=O)cc1OC
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(CN2CCCN(c3ccc(Oc4ccc(C#Cc5ccc(C(F)(F)F)cc5)cn4)c(C)c3)C2=O)cc1OC
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-(5-bromopyridin-2-yloxy)-3-methylphenyl]-3-(3,4-dimethoxybenzyl)tetrahydropyrimidin-2-one (0.3 g, 0.59 mmol) in N-methylpyrrolidone (10 mL) were added bis(triphenylphosphine)palladium dichloride (20 mg, 0.03 mmol), copper iodide (11 mg, 0.059 mmol), 4-ethynyl-α,α,α-trifluorotoluene (0.14 mL, 0.88 mmol) and triethylamine (0.14 mL, 10 mmol) under a nitrogen atmosphere. The resulting solution was stirred for 3 hours at 110 to 120° C. After being left to cool, water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1→1:1), to thereby yield 0.28 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH2:73]([O:75][C:76](=[O:83])[CH2:77][CH2:78][CH2:79]CCBr)C>>[CH3:73][O:75][C:76](=[O:83])[CH2:77][CH2:78][CH2:79][CH2:14][CH2:13][N:12]1[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:31][CH3:32]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)CCCCCn1c(-c2ccc(Cl)cc2OC)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (6-bromo-hexanoic acid ethyl ester (CAS Reg. No. 25542-62-5). Brown solid (67%). MS (Turbo Spray): m/z=437.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH3:42])[CH2:12]1
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: Nc1ncnc2c1n(-c1ccc(Oc3ccccc3)cc1)c(=O)n2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
In mixture of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (76 mg, 0.37 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C., HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm up to rt, and stirred for 2 hrs under N2, and purified directly by preparative-HPLC (RP C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (64) (36 mg, 25.9%) as a light yellow solid. LC-MS (ESI): m/z (M/M+2) 518/520. 1H NMR (400 MHz, DMSO) δ 8.11 (d, J=6.0 Hz, 1H), 7.48-7.36 (m, 4H), 7.23-7.07 (m, 5H), 6.69-6.55 (m, 1H), 6.34 (dd, J=35.9, 15.1 Hz, 1H), 5.89-5.67 (m, 2H), 5.18-4.95 (m, 1H), 4.15-3.42 (m, 4H), 2.97 (dd, J=18.6, 6.2 Hz, 2H), 2.85-2.73 (m, 1H), 2.73-2.58 (m, 1H), 2.33-2.10 (m, 1H), 1.98 (d, J=12.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.63-1.48 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1

Procedure:
1-fluoro-4-nitrobenzene (3.0 g 21.26 mmol), piperidin-4-ol (2.26 g, 22.32 mmol), K2CO3 (4.4 g, 31.89 mmol) was mixed in 20 mL DMF, reacted at 80° C. for 2.5 hours. Then the mixture was extracted by EA and brine, washed by brine and then water, dried over Na2SO4, concentrated. The crude product was used directly in the next step without further purification.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[O:44]1[C:48]2[C:49]([NH2:53])=[CH:50][CH:51]=[CH:52][C:47]=2[CH2:46][CH2:45]1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:53][C:49]3[C:48]4[O:44][CH2:45][CH2:46][C:47]=4[CH:52]=[CH:51][CH:50]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1cccc2c1OCC2
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cccc4c3OCC4)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 2,3-dihydro-benzofuran-7-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH3+:10])=[CH:5][CH:4]=1.[OH-].[Na+].[C:13](Cl)(=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.O.[Cl-].[Na+].O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: [NH3+]Cc1ccc(Br)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
In a 500 mL flask, (4-bromophenyl)methanaminium chloride (10.0 g, 44.9 mmol) and sodium hydroxide (4.00 g, 100 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL). The flask was placed in an ice water bath and benzyl carbonochloridate (7.06 mL, 49.4 mmol) was added dropwise. The reaction was allowed to stir for 3 h. The reaction was then poured into brine solution and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (14.1 g, 97%): 1H NMR (400 MHz, DMSO-d6) δ 7.88 (t, J=6.1 Hz, 1H), 7.58-7.46 (m, 2H), 7.46-7.27 (m, 5H), 7.23 (d, J=8.2 Hz, 2H), 5.06 (s, 2H), 4.19 (d, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 156.34, 139.19, 137.05, 131.10, 129.22, 128.32, 127.78, 127.73, 119.79, 65.44, 43.22; ESIMS m/z 320 ([M+H]+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a stirred solution of isopropylamine (130 mg, 2.2 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.65 mL of a 2M solution in toluene, 1.3 mmol). After 1 h, a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (170 mg, 0.55 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. overnight. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 6% methanol in dichloromethane then heptane:ethyl acetate=100:0 to 1:4) gave the title compound (30 mg, 16%) as a white solid. MS: m/e=336.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH2:8]([C:4]1[C:3]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[C:2]([C:24]2[CH:23]=[N:22][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:26][CH:25]=2)[CH:7]=[CH:6][N:5]=1)[CH3:9]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1nccc(-c2ccc(C(F)(F)F)nc2)c1C#Cc1ccc(N)nc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 150 mg (0.58 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 167 mg (0.87 mmoL) 2-trifluoromethyl-pyrid-5-yl boronic acid, 4.5 mg (0.03 mmol) Pd(PPh3)4 and 154 mg (1.11 mmol) K2CO3 in a mixture of 6.0 mL DME and 1.5 mL water. The reaction mixture is stirred twice under microwave irradiation at 150° C. for 120 min. The reaction mixture is concentrated in vaccuo and the crude product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 15 mg (7%).
Reaction SMILES: I[CH2:2][CH3:3].[NH:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:3]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 56.6 %

Procedure:
Iodoethane (1.34 g) was added to a mixture of benzyl (S)-pyrrolidine-2-carboxylate (1.0 g) and potassium carbonate (1.77 g) in dry DMF (7 mL) and the resultant mixture was stirred at room temperature for 3 days. The mixture was diluted with water, extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 10-20% to give benzyl (S)—N-ethylpyrrolidine-2-carboxylate (0.643 g) as a pale straw coloured oil.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[C:29]([CH3:30])=[C:28]([CH:31]=O)[C:27]([CH3:33])=[N:26]4)=[CH:21][C:20]=3[CH3:34])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.Cl.[NH2:40][OH:41].N1C=CC=CC=1>O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[C:5]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[C:29]([CH3:30])=[C:28]([CH:31]=[N:40][OH:41])[C:27]([CH3:33])=[N:26]3)=[CH:21][C:20]=2[CH3:34])[CH2:2][CH2:3]1
Reactant: NO
Reactant: Cc1cc(-n2nc(C)c(C=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(-n2nc(C)c(C=NO)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Yield: 79.7 %

Procedure:
At room temperature, a mixture of 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-4-formyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 51) 1.7 g, chloroform 20 ml, hydroxylamine hydrochloride salt 0.3 g and pyridine 0.9 g was stirred for twelve hours. To the resulting mixture was added water 20 ml, and the mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and then was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3,5-dimethyl-1H-pyrazole-4-carbaldehyde oxime 1.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2.CO.[Cl-].[NH4+]>C1COCC1.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 5-chloro-4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (2.00 g, 6.48 mmol) in THF (50 mL)/MeOH (80 mL) was added zinc dust (2.12 g, 32.4 mmol) followed by ammonium chloride (1.73 g, 32.4 mmol). After stirring at rt for 8 h, the reaction mixture was filtered through Celite® with MeOH and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (2×100 mL) then brine (1×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50 % EtOAc/hexanes) to give the title compound (1.51 g, 84%) as a pale yellow solid. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.69 (d, 1H, J=2.8 Hz), 7.09 (t, 1H, J=8.4 Hz), 6.79 (d, 1H, J=2.8 Hz), 6.58 (dd, 1H, J=11.6, 2.6 Hz), 6.51 (d, 1H, J=8.7 Hz), 3.92 (br s, 2H); MS(ESI+) m/z 279.2 (M+H)+.