Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[O-:28][CH2:29][CH3:30].[Na+].C(O)C>C(OCC)(=O)CC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2([OH:25])[C:29](=[O:28])[C:30]3[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH:7]2[C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:22][CH:21]=1
Reactant: CC[O-]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cn1ccnc1/C=N/c1cccc2c1COC2=O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(O)(c1ccc(F)cc1)C(c1nccn1C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a mixture of (E)-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one (590 mg, 2.4 mmol) and 4-fluorobenzaldehyde (300 mg, 2.4 mmol) in ethyl propionate (20 mL) was added a solution of sodium ethoxide in ethanol [sodium (220 mg, 9.6 mmol) in ethanol (10 mL)]. After the addition, the mixture was stirred at room temperature overnight. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by flash chromatography to give the title compound (100 mg, yield 10%). LC-MS (ESI) m/z: 410 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:21]1[C:26]([C:27]#[N:28])=[C:25]([CH3:29])[N:24]=[C:23]([S:30][CH3:31])[N:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:29][C:25]1[C:26]([C:27]#[N:28])=[C:21]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:22]=[C:23]([S:30][CH3:31])[N:24]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
(S)-1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (77 mg, 0.384 mmol) and Et3N (0.059 mL, 0.423 mmol) in DMF (2 mL) were combined to give a yellow solution. The reaction mixture was stirred overnight at room temperature. The product was purified by LC/MS using a 15-40% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to afford the title compound as a white solid (109 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.26 (s, 3 H), 1.50-1.65 (m, 3H), 2.40 (s, 3 H), 2.81-2.91 (m, 2 H), 3.07-3.20 (m, 2 H), 3.74-3.79 (m, 4 H), 3.82 (s, 3H), 5.88-6.00 (m, 1 H), 6.58-6.69 (m, 1 H), 7.76-8.07 (m, 1 H), 7.74-7.78 (m, 1 H), 7.85 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H25N2OS, 424.5; found 424.5.
Reaction SMILES: Br[CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C-:14]#[N:15].[Na+].O.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1(C)C=CC=CC=1>[C:14]([CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1)#[N:15]
Reactant: [C-]#N
Reactant: O=C1C2=C(C=CC1Br)CCCCC2
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1C=CC2=C(CCCCC2)C1=O
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2-cyanobenzocycloheptan-1-one (compound Ia) was prepared by dissolving 2-bromobenzocycloheptan-1-one (30.2 g, 0.126 mol) in toluene (150 mL) in a 500 mL round bottom flask equipped with a condenser. NaCN (18.6g, 0.38 mol), water (50 g), and dibenzo-18-crown-6 (0.5 g) were added to the flask. The reaction mixture was stirred vigorously at 90° C. under a static blanket of nitrogen for 15 hours. The reaction mixture was cooled and washed three times with water (70 mL×2+100 mL). The toluene solution was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was distilled under vacuum to give a yellow liquid (21.1 g, b.p. 158-162° C. at 17 mm Hg). The purity of the liquid was 96% by GC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH:12]=O)=O>C(O)C>[CH3:12][C:10]1[N:1]=[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]2=[N:8][CH:9]=1
Reactant: Nc1cccnc1N
Reactant: CC(=O)C=O
Solvent: CCO
Product: Cc1cnc2cccnc2n1
Yield: 60.5 %

Procedure:
2,3-Diaminopyridine (2.0 g) and a 40% aqueous pyruvic aldehyde solution (3.30 g) were refluxed in ethanol for 20 minutes. The reaction solution was concentrated, and the residue was recrystallized from 2-propanol, collected by filtration, and dried to give 3-methylpyrido[2,3-b]pyrazine (1.61 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5](Cl)=[O:6])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH3:15][C:12]([C:16]1[CH:21]=[C:20]([C:5](=[O:6])[C:3]([O:2][CH3:1])=[O:4])[CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A dichloromethane (50 mL) solution of 13.6 g (106.5 mmol, 1.1 equiv.) of methyloxalylchloride is added over 15 minutes to a 0° C. stirred slurry of 14.2 g (106.5 mmol, 1.1 equiv.) of AlCl3 in 100 mL of dichloromethane under nitrogen atmosphere. The reaction is stirred at 0° C. for 5 minutes and treated with a dichloromethane (50 mL) solution of 20.0 g (96.9 mmol) of 2,6-di-t-butylphenol over 30 minutes. The reaction is stirred for 3 hours and poured onto 700 mL of ice water and the layers separated. The aqueous layer is extracted with diethyl ether (3×200 mL). The combined organic layers are washed with aqueous 1N HCl (200 mL), water (4×200 mL) and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give a yellow solid. Recrystallizing from n-pentane gives a first crop of 8.40 g (mp 85°-86° C.) and a second crop of 4.45 g (mp 82.5°-84° C.). The total yield is 12.85 g (28.33 g theor., 45%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[CH:13]=[N:14][N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16]=2[C:17]([OH:19])=O)[CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:12]3[CH:13]=[N:14][N:15]([CH:20]4[CH2:21][CH2:22]4)[C:16]=3[C:17]2=[O:19])[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2cnn(C3CC3)c2C(=O)O)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: Cn1cc(N2C(=O)c3c(cnn3C3CC3)C2c2ccc(Cl)cc2)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-1H-pyrazole-5-carboxylic acid (Step 35.2). tR: 4.30 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 415/417 [M+H]+ (LC-MS 2); Rf=0.33 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.10 (m, 2H) 1.17-1.30 (m, 2H) 3.42 (s, 3H) 3.83-3.94 (m, 1H) 6.11 (s, 1H) 7.21-7.29 (m, 2H) 7.32-7.38 (m, 2H) 7.41 (s, 1H) 7.88 (d, J=2.4 Hz, 1H) 7.92 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=O.[Cl:19][C:20]1[N:21]=[N:22][C:23]([NH:26][NH2:27])=[CH:24][CH:25]=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:26]([C:23]2[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[N:27]=1)=[O:18]
Reactant: COC(=O)C(=O)CC(=O)c1ccc(N(C)C)cc1
Reactant: NNc1ccc(Cl)nn1
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)n(-c2ccc(Cl)nn2)n1

Procedure:
The above-obtained 4-(4-dimethylaminophenyl)-2,4-dioxobutanoic acid methyl ester (742 mg) and 3-chloro-6-hydrazinopyridazine (473 mg) in methanol (30 mL) was refluxed under heat for 18 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give 1-(6-chloro-3-pyridazinyl)-5-(4-dimethylaminophenyl)pyrazole-3-carboxylic acid methyl ester as a solid (679 mg, 63%).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](O)[CH2:11][OH:12].P(=O)(O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[O:9]1[CH2:10][CH2:11][O:12][CH:1]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: OCCO
Reactant: O=Cc1ccccc1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: Oc1ccccc1C1OCCO1

Procedure:
A mixture of 244 parts of salicylaldehyde, 125 parts of ethyleneglycol, 1 part of zinc chloride, 1 part by volume of concentrated phosphoric acid and 500 parts by volume of benzene was boiled in a circulating distillation apparatus until water was no longer being eliminated. The solution of the product was filtered and evaporated. The residue was distilled under a high vacuum. The product boiled at 88° to 91°C under 0.04 mm Hg pressure and melted at 67° to 70°C.
Reaction SMILES: C12(COC3C(Cl)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.[N:49]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]OC[CH2:50]1.N1(S(N)(=O)=O)CCC1>>[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:58][S:55]([N:49]4[CH2:54][CH2:53][CH2:50]4)(=[O:57])=[O:56])=[O:42])=[CH:38][C:37]=3[C:45]([F:47])([F:48])[F:46])[CH2:25][CH:26]3[CH2:32][CH:30]([CH2:29][CH:28]([CH2:27]3)[CH2:33]1)[CH2:31]2
Reactant: O=C(O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1

Procedure:
Following the procedure as described in Example 98 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid and morpholine-4-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.05 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.26-8.22 (m, 2H), 7.38-7.35 (m, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.76 (s, 2H), 2.20-2.09 (m, 2H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 471.3 (M−1); MS (ES+) m/z 473.2 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:15](O)(=O)(=O)=O.II.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:15][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)CCc1ccccc1-2
Temperature: 0 °C

Procedure:
25.0 g (0.139 mol) of 9,10-dihydrophenanthrene, 6.30 g (27.6 mmol) of periodic acid and 17.0 g (67.0 mmol) of iodine are heated at 70° C. for 1 h in a solution of 4 ml of conc. sulfuric acid and 28 ml of water in 140 ml of glacial acetic acid. The solution is subsequently added to ice-water and extracted three times with ethyl acetate. The combined org. phases are washed with sat. sodium hydrogencarbonate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is distilled in a bulb tube at 170° C. and 0.3 mbar, giving 2-iodo-9,10-dihydrophenanthrene as yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:4](OCC)=O.[NH2:17][C:18]([NH2:20])=[S:19].[O-]CC.[Na+]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([C:3]2[C:2](=[O:1])[NH:17][C:18](=[S:19])[NH:20][CH:4]=2)[CH3:10])[CH:12]=1
Reactant: CCOC(=O)C(CO)C(C)c1cccnc1
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Product: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O

Procedure:
Treatment of ethyl 2-(hydroxymethyl)-3-(3-pyridyl)-butyrate with thiourea and sodium ethoxide, followed by acidification gave 5-(1-(3-pyridyl)ethyl)-2-thiouracil m.p. 225°-228°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[CH3:25])=[N:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:25])=[N:4][N:3]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate (1.20 g, 3.31 mmol) was dissolved in dry dichloromethane (40 mL). Trifluoroacetic acid (8 mL) was added dropwise and allowed to stir at RT for 2 hours. The reaction was added to saturated NaHCO3 (200 mL) and the aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow solid. MS (M+H)+=263.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([O:30]C)[C:24]=4[N:23]=[C:22]3[CH2:32][O:33]C)[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=4[N:23]=[C:22]3[CH2:32][OH:33])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14]
Reactant: COCc1nc2c(OC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C/C(C#N)=C1/c2ccc(Cn3c(CO)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
[step 4] (E)-2-(3-fluoro-8-{[4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.0 g, 2.1 mmol) obtained in step 3 was dissolved in dichloromethane (11 mL), boron tribromide (21.0 mL, 21.0 mmol, 1.0 mol/L dichloromethane solution) was added at 0° C., and the mixture was stirred at room temperature for 2 hr. To the mixture was added 2 mol/L aqueous sodium hydroxide solution, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-90/10 v/v) to give (E)-2-(3-fluoro-8-{[4-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (0.7 g, 75%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:13]=2)=[CH:5][C:4]=1[C:27]1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[N:28]=1>O1CCOCC1>[NH:31]1[C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[N:28]=[C:27]1[C:4]1[C:3]([NH2:2])=[N:8][CH:7]=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:13]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5[nH]4)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5 ml of 4M HCl in dioxane are added to 41.8 mg (0.091 mmol) of tert-butyl 4-{4-[6-amino-5-(1H-benzimidazol-2-yl)pyridin-3-yl]pyrazol-1-yl}piperidine-1-carboxylate, and the mixture is stirred at room temperature for 14 h. The reaction mixture is evaporated to dryness, and water is added. The aqueous phase is adjusted to pH>10 using 2N NaOH and extracted 3× with ethyl acetate. The organic phases are dried using sodium sulfate, filtered and evaporated. The residue is lyophilised, giving 3-(1H-benzimidazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-ylamine as free base; HPLC-MS [M+H]+ 360.2;
Reaction SMILES: C([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:29](C4CCCCO4)[N:30]=[C:31]([CH3:32])[C:17]=23)[C@@H:10]([CH3:39])[CH2:9]1)C1C=CC=CC=1>CO>[CH3:39][C@H:10]1[CH2:9][NH:8][C@H:13]([CH3:14])[CH2:12][N:11]1[CH2:15][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)[N:19]=[C:18]2[NH:29][N:30]=[C:31]([CH3:32])[C:17]=12
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c12
Solvent: CO
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3C[C@@H](C)NC[C@@H]3C)c12
Reaction time: 15 h

Procedure:
585 mg 4-[4-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-ylmethyl)-3-methyl-1-(tetra-hydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol were dissolved in 10 ml methanol and 5 ml of THF and purged with argon. 50 mg Palladium (10% on charcoal) were added and the mixture was hydrogenated at r.t. for 15 h. The catalyst was filtered off and the solvents were evaporated. The residue was taken up in ethyl acetate and 1N aqueous hydrochloric acid. The phases were separated and the aqueous phase was washed with dichloromethane. To the aqueous phase was then added 1 ml concentrated aqueous hydrochloric acid and the reaction was left standing overnight. After freeze-drying 390 mg (90%) of the title compound were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:17]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)=[N:16][C:13]=4[O:14][CH2:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[N:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:17]([C:26]5[CH:27]=[CH:28][C:29]([C:32]6([NH2:36])[CH2:35][CH2:34][CH2:33]6)=[CH:30][CH:31]=5)=[N:16][C:13]=4[O:14][CH2:15][C:10]3=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 40.8 %

Procedure:
Tert-butyl (1-(4-(1,8-diphenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (5 mg, 40% yield). LCMS (Method D) RT=0.846 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.91-7.86 (2H, dd), 7.83-7.76 (3H, m), 7.59-7.54 (2H, d), 7.53-7.48 (2H, d), 7.42 (1H, s), 7.37-7.28 (3H, m), 7.09-7.03 (2H, dd), 5.86 (2H, s), 2.91-2.81 (2H, m), 2.74-2.63 (2H, m), 2.40-2.29 (1H, m), 2.13-2.02 (1H, m).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.N1C=CC=CC=1.S(Cl)([Cl:25])=O.C([O:30][CH2:31]C)(=O)C>C1(C)C=CC=CC=1>[N:1]1([C:31]([Cl:25])=[O:30])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: O=S(Cl)Cl
Reactant: C1CCCNCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCCCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of azepane (2 g, 20.2 mmol) in 30 mL of anhydrous toluene was added DIEA (3.5 mL, 20.0 mmol) and pyridine (1.63 mL, 20.2 mmol). The mixture was cooled to −10° C. under nitrogen. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 min, and then a solution of thionyl chloride (1.74 mL, 24.0 mmol) in 10 mL of toluene was added at −10° C. Upon completion of addition, the reaction mixture was stirred for 1 hr while the temperature was kept under 10° C. The reaction mixture was then diluted with ethyl acetate, washed with cold 0.5 N HCl solution and brine, dried over Na2SO4, and concentrated to give the title compound (2.76 g, 85%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=[CH2:11])[C:7]=1[CH2:8][OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:12][C:3]1[C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([CH2:8][OH:9])[C:6]([CH:10]=[CH2:11])=[CH:5][N:4]=1
Reactant: C=Cc1cnc(C)c(O)c1CO
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CO
Reaction time: 8 h

Procedure:
To a mixture of 0.1 mole 3-hydroxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. of acetone and 25 gm. potassium carbonate is added 0.11 mole of benzyl chloride. The reaction mixture is stirred overnight, filtered, and the acetone removed in vacuo to yield 2-methyl-3-benzyloxy-4-hydroxymethyl-5-vinylpyridine.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>CS(C)=O.O>[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[CH2:4][O:19]2)=[CH:16][CH:15]=1
Reactant: Cn1ccnc1-c1ccc(C=O)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccnc1-c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a suspension of 0.045 g (1.1 mmol) of sodium hydride in DMSO (2 mL) was added a 0.225 g (1.10 mmol) of trimethylsulfonium iodide as a solution in DMSO (2 mL). The mixture was allowed to stir at room temperature for 10 min then a solution of 0.100 g (0.537 mmol) of the above aldehyde in DMSO (1 mL) was added dropwise. The mixture was stirred at room temperature for 4 h then diluted with H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.056 g (52.1%) of 1-methyl-2-(4-oxiranyl-phenyl)-1H-imidazole as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][CH:3]=1>N.CO.[Ni]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][NH2:12])[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2cccc(C#N)c12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1c[nH]c2cccc(CN)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 232 (200 mg, 1.28 mmol) in 7 N NH3 in MeOH (10 mL) was added Raney nickel (20 mg) and the solution was stirred under hydrogen (1 atm.) at RT overnight. The dark mixture was filtered and the filtrate was concentrated under reduced pressure to afford 200 mg (91%) (3-methyl-1H-indol-4-yl)methanamine (234) as white solid: MS (ESI) m/z=144.3 [M−16]+.