Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17](F)[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25].CC#N>O1CCCC1>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2ccccc2=O)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a suspension of NaH (315 mg, 1.4 eq) in 50 ml of tetrahydrofuran, a solution of 2-hydroxypyridine (801 mg, 1.5 eq) in 5 ml of tetrahydrofuran is added drop-wise. The mixture is stirred at room temperature for 30 min before addition of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.61 mmol) in 10 ml of tetrahydrofuran. The resulting mixture is stirred at room temperature for 16 hours. The solvent is removed in vacuo and the crude oil is solubilised in ethyl acetate. The organic phase is washed with sat NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo to afford a crude yellow oil. The crude product is purified by flash-chromatography (ethyl acetate/hexane (0:100 to 100:0)) to obtain 2-nitro-5-(2-oxo-2H-pyridin-1-yl)-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (1.3 g, 68% yield) (ES-MS: m/z 328 [M+H+CH3CN]+, Rt 4.67 min.).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 54-68, 4-morpholinecarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 377.2295.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[N:6]([CH3:8])[N:7]=1)[CH3:2].[CH:10]1(C(=O)CC#N)CC[CH2:11]1>>[CH:1]1([C:3]2[CH:4]=[C:5]([NH2:9])[N:6]([CH3:8])[N:7]=2)[CH2:11][CH2:10][CH2:2]1
Reactant: N#CCC(=O)C1CCC1
Reactant: CCc1cc(N)n(C)n1
Product: Cn1nc(C2CCC2)cc1N

Procedure:
This is synthesized in an analogous manner to 5-ethyl-2-methyl-2H-pyrazol-3-ylamine except using 3-cyclobutyl-3-oxopropionitrile instead of 3-oxo-pentanenitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)O1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:38][CH2:37][CH2:36][S:35]3(=[O:40])=[O:39])=[CH:32][CH:33]=2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc(N3CCCS3(=O)=O)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Product: Nc1ncc(-c2ccc(N3CCCS3(=O)=O)cc2)cc1OCc1c(F)ccc(F)c1Cl

Procedure:
3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine was prepared following procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]isothiazolidine 1,1-dioxide.
Reaction SMILES: O[C@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:17][CH:16]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C)C=O>[C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:37][C@@H:2]([N:42]5[C:41](=[O:43])[C:40]6=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]6[C:38]5=[O:48])[CH2:3][C@H:4]4[CH2:13]3)=[O:36])=[CH:20][CH:19]=2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@H](N4C(=O)c5ccccc5C4=O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a solution of (2R,3aS)-2-hydroxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (1.2 g) prepared in Example 3, phthalimide (0.54 g) and triphenyl phosphine (0.96 g) in anhydrous N,N-dimethylformamide (10 ml), there was gradually dropwise added, under ice-cooling, a solution of diisopropyl azodicarboxylate (0.74 g) in anhydrous N,N-dimethylformamide (4 ml). After stirring the reaction solution at room temperature for 2 hours, it was poured into ice water and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with hexane/ethyl acetate (1/1) to give 1.1 g (yield 73.0%) of the title compound as amorphous powder.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=CC(S(O[N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[N:29]2)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:1]([O:9][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[N:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(=O)(On1nnc2ccccc21)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(On1nnc2ccccc21)c1ccccc1
Yield: 81.6 %

Procedure:
Benzoic acid (2.44 g) is dissolved in chloroform (30 ml), and thereto are added triethylamine (2.80 ml) under ice-cooling and further 1-(p-chlorobenzenesulfonyloxy)-1,2,3-benzotriazole (6.2 g) at room temperature, and the mixture is stirred for 2 hours. After the reaction, chloroform is distilled off, and to the resulting residue are added water and ethyl acetate. The ethyl acetate layer is washed with water, an aqueous sodium hydrogen sulfate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give yellow crystals of 1-benzoyloxy-1,2,3-benzotriazole (3.9 g). The product is recrystallized from isopropanol to give faint yellow crystals of the product, melting point: 75°-78.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccn(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[I:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1]
Reactant: Cc1cc2ccncc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c2cnccc2c1I
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-Methyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.76 mmol) was dissolved in CHCl3 (5 mL), N-iodosuccinimide (179 mg, 0.79 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with 1 M aq sodium thiosulphate (5 mL) and the CHCl3 was removed in vacuo. The reaction mixture was partitioned between sat aq NaHCO3 (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organic fractions were washed with sat aq NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a cream solid (179 mg, 92%). LCMS (ES+): 258.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:10]([C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]2[C:19]=1[CH2:18][S:17][CH2:16]2)=[O:11].[OH-].[Na+].C>C(Cl)Cl.C(#N)C>[C:2]1([NH:1][C:10]([C:12]2[CH:13]=[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:15]3[C:19]=2[CH2:18][S:17][CH2:16]3)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cc(-c2cccnc2)n2c1CSC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Nc1ccccc1)c1cc(-c2cccnc2)n2c1CSC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
A solution of aniline (11.2 g) in methylene chloride (50 cc) is added over 15 minutes at a temperature of about 24° C. and 29° C. to a suspension of 7-chloroformyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (12 g) in methylene chloride (200 cc). The suspension obtained is stirred at a temperature of about 20° C. for 16 hours. Methylene chloride (300 cc) and distilled water (200 cc) are then added to the suspension. The insoluble material is separated off by filtration, washed 3 times with methylene chloride (75 cc in total) and 3 times with distilled water (75 cc in total). The mother-liquors from filtration and washing are combined; the organic phase is separated off, washed twice with distilled water (400 cc in total), once with a 2 N aqueous solution of sodium hydroxide (200 cc), then twice with distilled water (400 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g) and filtered. A crude solution (625 cc) of product in methylene chloride is thus obtained. The insoluble material obtained earlier is taken up with a 5 N aqueous solution of sodium hydroxide (200 cc). The oil obtained is extracted 3 times with methylene chloride (750 cc in total). The organic extracts are combined, washed 3 times with distilled water (450 cc in total), dried over anhydrous magnesium sulphate, treated with decolourising charcoal (0.5 g) and filtered. The methylene chloride solution obtained is combined with the methylene chloride solution obtained earlier (625 cc) and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. A crude product (15.4 g) is thus obtained. This product is dissolved in boiling acetonitrile (210 cc). The solution obtained is treated with decolourising charcoal (0.5 g) and filtered hot. The filtrate is cooled at a temperature of about 4° C. for 2 hours. The crystals which have appeared are separated off by filtration, washed 3 times with acetonitrile (30 cc in total) cooled to a temperature of about 4° C. and 3 times with isopropyl ether (75 cc in total) and are then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-phenyl-5-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (7.4 g) is thus obtained in the form of cream crystals melting at 188° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:21]([Mg]Br)#[CH:22]>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2C=O)cc1
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2c(Cl)cccc12
Yield: 93.8 %

Procedure:
In a similar manner as described in Example 46 from 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.11 g, 17.8 mmol) and ethynylmagnesium bromide (89 mL, 0.5 M in tetrahydrofuran, 44.6 mmol) at 0° C. was obtained 1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (5.22 g, 94%) as an off-white solid. 1H NMR (CDCl3): δ 8.02 (d, 1 H), 7.73 (d, 2 H), 7.18 (t, 1 H), 7.02 (d, 2 H), 6.97 (d, 1 H), 5.79 (m, 1 H), 3.87 (s, 3 H), 2.68 (m, 1 H), 2.25 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:40]4[CH2:39][CH2:38][CH:37]([N:31]([CH3:30])[CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)[CH2:42][CH2:41]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(C1CCNCC1)C1CCOC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4CCOC4)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (72 g, 0.19 mmol), methylpiperidin-4-yl(tetrahydrofuran-3-yl)amine (42 mg, 0.23 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 390 as a cream solid (55 mg, 53%). LCMS (Method G): RT 4.96 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.23 (m, 2 H); 4.34 (m, 4 H); 3.96 (m, 1 H); 3.91-3.69 (m, 12 H); 3.45-3.26 (m, 3 H); 2.97 (d, J=11.3 Hz, 2 H); 2.51 (m, 1 H); 2.26 (s, 3 H); 2.16 (t, J=11.3 Hz, 2 H); 2.03 (m, 1 H); 1.89 (m, 2 H); 1.76 (s, 2 H); 1.66 (m, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([N:15]3[CH2:25][CH2:24][C:18]4[N:19]=[C:20]([NH2:23])[N:21]=[CH:22][C:17]=4[CH2:16]3)=[C:13]([CH3:26])[CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][C:13]=3[CH3:26])[CH2:25][CH2:24][C:18]=2[N:19]=1
Reactant: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Reaction time: 0.5 h

Procedure:
A solution of 6-{2-[(4-methoxybenzyl)oxy]-4-methylpyridin-3-yl}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (3.92 g, 10.39 mmol) in dichloromethane (150 ml) was treated with trifluoroacetic acid (5.71 ml, 76.89 mmol) at room temperature. After stirring for 30 minutes, the solvent and excess acid was removed in vacuo and the residue was treated with ethyl acetate. Washing with sat'd NaHCO3(aq.) gave a yellow, amorphous precipitate. The solid was collected, washed with water, EtOAc, and dried in vacuo at 50° C. to give (1.65 g, 62%). HPLC analysis showed the compound has a purity of 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Cl:27]N1C(=O)CCC1=O.Cl>O1CCCC1.O>[Cl:27][C:6]([CH2:5][C:4]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:3]=1[O:2][CH3:1])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C(Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cl)(Cc1cc(OC)c(OC)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
In 70 ml of anhydrous tetrahydrofuran is dissolved 6.5 g of diethyl 2,4,5-trimethoxybenzylmalonate and, then, 760 mg of 60% oily sodium hydride is added. The mixture is stirred at room temperature for 15 minutes, after which time 2.54 g of N-chlorosuccinimide is added. The mixture is further stirred at room temperature for 30 minutes. The reaction mixture is poured into a mixture of 300 ml water and 10 ml 6N-HCl and, then, extracted with ether. The ethereal layer is washed with water, dried (over MgSO4) and distilled to remove the ether, whereupon 6.5 g (91.5%) of diethyl α-chloro-α-(2,4,5-trimethoxybenzyl)malonate is obtained as crystals melting at 84°-85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:3]1.C(O)(=O)C>Cl.O.[OH-].[Na+]>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:3]1
Reactant: CC1(C)CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCCC(NC(=O)Nc2cnc3[nH]ccc3n2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.3 %

Procedure:
1-(3,3-Dimethyl-cyclohexyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.095 g, 0.227 mmol) was dissolved in 1M HCl in acetic acid (2 mL, 2.04 mmol) and the resulting yellow solution stirred at 50° C. for 1.5 hours. The reaction mixture was diluted with 2 mL of H2O and basified with 3M NaOH. Light yellow precipitate forms. The solvent was evaporated. The yellow solid was taken up in MeOH:H2O:Et3N 8:1:1 and stirred at RT for 1 hour. The mixture was absorbed onto SiO2 and purified by SiO2 chromatography (12 g SiO2, DCM/magic (DCM:MeOH:NH4OH 60:10:1) 0-35% magic) to give 0.023 g of 1-(3,3-dimethyl-cyclohexyl)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid (35% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]2[OH:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13][CH:12]2[OH:17])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=COCc1ccccc1
Reactant: C=CCOc1ccc(C2CCNCC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1

Procedure:
Analogously to Example 10f, 29.45 g of 4-(4-allyloxyphenyl)piperidin-3-ol and 26.8 g of benzyl formate are reacted. The title compound is obtained as a white solid. Rt=4.62.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCCN(C)C)cc3)ncn2)c1
Yield: 13 %

Procedure:
Using an analogous reaction procedure to that described in Example 23, 4-(4'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine (0.6 g) was reacted with 3-dimethylaminopropyl chloride. The product so obtained was chromatographed on silica and precipitated from a mixture of methylene chloride, methanol and hexane to give 4-[4'-(3-dimethylaminopropoxy)anilino]6-(3'-methylanilino)pyrimidine in 13% yield, m.p. 204°-207° C.;
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH2:17]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([NH:7][CH3:6])[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[C:10]2[CH:16]=[N:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(F)ccc1-c1c(NC(=O)OC(C)(C)C)cnc2c1cnn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.6 %

Procedure:
To a solution of [1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-carbamic acid tert-butyl ester (2.6 g, 6.01 mmol) in DMF (50 mL) at 0° C. was added NaH (0.462 g, 50% purity, 9.62 mmol). After 20 minutes, iodomethane (1.54 g, 10.8 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (50 mL) and TFA (15 mL) was added. The reaction mixture was heated at 30° C. for 2 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 2.24 g (97%) with high purity (no further purification needed) as a light yellow solid. ES-MS m/e: 347.3 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.Cl.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][NH2:42].C([O-])(=O)C.[K+]>C(O)C.O>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]1[C:11]2[CH:10]=[C:9]3[CH2:8][CH2:7][C@H:6]4[C@H:15]([C@:14]3([CH3:16])[CH2:13][C:12]=2[CH:17]=[N:42]1)[C@H:2]([OH:1])[CH2:3][C@@:4]1([CH3:31])[C@@:22]2([CH2:21][CH2:20][C@H:5]41)[C:26]1([CH2:30][O:29][CH2:28][O:27]1)[O:25][CH2:24][O:23]2
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Reactant: NNc1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@]12Cc3cnn(-c4ccc(F)cc4F)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2
Temperature: 90 °C
Yield: 59.7 %

Procedure:
(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde (Steroids 2003, (68), 177-191) (400 mg, 0.92 mmol) was dissolved in ethanol (10 ml) and water (1 ml). (2,4-difluorophenyl)hydrazine hydrochloride (167 mg, 0.92 mmol) and potassium acetate (160 mg, 1.63 mmol)) were added and the mixture was heated under microwave irradiation at 90° C. for 20 minutes. The mixture was partitioned between EtOAc (10 ml) and water (10 ml). The organic phase was washed with water (2 times 10 ml) and brine (5 ml) and was dried over Mg2SO4. Filtration followed by evaporation of the solvent gave 297 mg of the crude compound which was used as such without further purification. APCI-MS m/z: 541 [MH+].