Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:10](N1C(=O)C2C(=CC=CC=2)C1=O)(=[S:12])[CH3:11]>C(O)C.N1C=CC=CC=1.[Pd]>[C:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[S:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OCCN
Reactant: CC(=S)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=S)NCCOC(C)(C)C
Reaction time: 23 h

Procedure:
Dissolve (2-tert-butoxyethyl)dicarbamic acid benzyl ester (387.8 mg, 1.01 mmol) and 5% Pd/C (0.212 g) in absolute ethanol and expose it to 60 psi of H2 for 18 hours. Filter the reaction mixture over a pad of celite. Acidify the filtrate with 5N HCl and concentrate in vacuo to obtain 139.4 mg of a crude residue containing the HCl salt of 2-tert-butoxyethylamine. Dissolve this crude material (139.4 mg, 0.852 mmol) in 10 mL pyridine at 25° C. To this add 2-thioacetylisoindole-1,3-dione (180.53 mg, 0.88 mmol) and allow to stir for 23 hours. Concentrate the reaction mixture in vacuo and dissolve the residue in methylene chloride and wash it with 1N HCl (1×). Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 266.9 mg of crude product. Triturate this crude material in diethyl ether and remove the solids by filtration. Concentrate the filtrate in vacuo to afford 176.2 mg of a crude solid. Purify via Biotage chromatography to afford 74.1 mg of N-(2-tert-butoxyethyl)thioacetamide. Dissolve this thioacetamide (74.1 mg, 0.423 mmol) in 20 mL methylene chloride and add methyl trifluoromethanesulfonate (76.3 mg, 0.465 mmol). Allow the reaction mixture to stir for an additional 21 hours. Decant the diethyl ether from the oil and triturate the oil with diethyl ether (3×). Remove any excess diethyl ether from the oily residue in vacuo to obtain 60.3 mg of crude triflic acid salt of N-(2-tert-butoxyethyl)thioacetimidic acid methyl ester as an oil. Dissolve this crude product (60.3 mg, 0.62.5 mmol) in 10 mL pyridine and add N-(R)-(6-amino-2(R)-hydroxyindan-1-yl)-4-bromobenzamide (62.5 mg, 0.180 mmol). Allow the reaction to stir at 25° C. for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 31.4 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc) to afford 6.6 mg of the titled product (8% yield). MS (ES): m/z 488.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[NH:12][C:13](=[O:27])[CH:14]([NH:16]C(=O)OCC3C=CC=CC=3)[N:15]=2)=[CH:5][CH:4]=1.Br.CCOCC>C(O)(=O)C>[NH2:16][CH:14]1[C:13](=[O:27])[NH:12][C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15]1
Reactant: COc1ccc(C2=NC(NC(=O)OCc3ccccc3)C(=O)Nc3ccccc32)cc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(C2=NC(N)C(=O)Nc3ccccc32)cc1
Temperature: 70 °C
Yield: 89.8 %

Procedure:
Intermediate 6B (1000 mg, 2.407 mmol) was treated with 33% HBr in acetic acid (5 mL) to give a suspension. The reaction mixture was then heated to 70° C. for 3 hrs with stirring. The reaction mixture was then poured into ether (100 mL). The resulting solid was filtered and then partitioned between DCM (100 mL)/saturated NaHCO3 (100 mL). The aqueous phase was back extracted with DCM (3×100 mL). The combined organic phases were dried with MgSO4, filtered and concentrated to provided Intermediate 6C (0.608 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 10.61 (br. s., 1H), 7.62-7.53 (m, 1H), 7.44 (d, J=8.8 Hz, 2H), 7.34-7.23 (m, 2H), 7.23-7.17 (m, 1H), 6.99 (d, J=9.0 Hz, 2H), 4.20 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]2[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=2[N:10]=1.OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Temperature: 25 °C
Yield: 67 %

Procedure:
2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500 mg, 1.63 mmol) obtained in step 3 was dissolved in methanol, H2SO4 (0.43 ml, 8.15 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (393 mg, 1.23 mmol) in a yield of 67%.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:16]3[C:21]([N:22]=2)=[CH:20][N:19]=[CH:18][N:17]=3)[CH2:9][CH2:8]1>O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:15]2[C:14]([NH:13][CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]3)=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:29][CH:28]=1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3cncnc32)cc1

Procedure:
To a stirred and cooled (-10° C.) mixture of 5.6 parts of N,N'-methanetetraylbis[cyclohexanamine], 13.9 parts of carbon disulfide and 90 parts of tetrahydrofuran were added portionwise 10 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine. Upon completion, the temperature was allowed to rise to room temperature and the reaction mixture was evaporated, yielding 16 parts of 9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine (compound 181).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: NCc1ccncc1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1(C)CN(CC(=O)NCc2ccncc2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 53 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 4-(aminomethyl)pyridine. The product was isolated as hydrochloride salt in 53% yield.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[CH3:16][CH2:17]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:16][C:17]1[O:15][N:14]=[C:2]([CH:3]2[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:6]2)[N:1]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC(/C(N)=N/O)C1
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc(C2CN(C(=O)OC(C)(C)C)C2)no1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
In a 16 mL vial, tert-butyl 3-[(Z)-amino(hydroxyimino)methyl]azetidine-1-carboxylate (170 mg, 0.74 mmol; which may be prepared as described in Step 3) was dissolved in acetonitrile (7.4 mL) and cooled to 0° C. under nitrogen. DIPEA (387 μL, 2.22 mmol) and acetyl chloride (105 μL, 1.48 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 80° C. overnight, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was taken up in o-xylene (8.4 mL) and heated to 150° C. for 2 h and concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the title compound (97 mg, 55%) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:41])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NCc5ccc(F)cc5)c(F)cc43)c(C)c2C1=O
Yield: 62.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e as starting materials to obtain (Z)-5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 3 (61 mg, yield 62.2%) as a henna solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:26])[CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:20]=2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C1COCCN1
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(O)CN2CCOCC2)c1)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 1 M morpholine in methanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder. 1H NMR (300 MHz, CDCl3): δ 2.20-2.40 (3H, m), 2.50-2.70 (2H, m), 3.60-3.80 (4H, m), 4.66 (1H, m), 6.85-7.00 (2H, m), 7.03-7.19 (3H, m), 7.20-7.30 (1H, m), 7.30-7.40 (1H, m), 7.57 (2H, d, J=8 Hz) and 7.91 (2H, d, J=8 Hz). MS, m/z: Calcd, 474.142. Found, 474.56 (M).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]=[O:8].C(N(CC)CC)C>CCOC(C)=O>[CH3:5][C:6]([CH3:10])([CH3:9])[CH:7]([OH:8])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CC(C)(C)C=O
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.3 %

Procedure:
A mixture of nitromethane (5.87 g, 68.1 mmol), 2,2-dimethyl-propionaldehyde (5.4 g, 88.6 mmol), and triethylamine (689 mg, 6.8 mmol) was stirred at room temperature for two days; then the reaction mixture was diluted with EtOAc, washed with diluted HCl aqueous solution, and saturated NaCl aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to give a clear oil, the title product (7.35 g); The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.52 (dd, 1H, J=2.4 Hz, 12.6 Hz), 4.36 (dd, 1H, J=10.0 Hz, 12.6 Hz), 4.01 (m, 1H), 2.42 (d, 1H, J=4.4 Hz), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.O.O.O.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: [H][H]
Reactant: O=C1Nc2ccc3ccccc3c2CCC1(Cl)Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccc3ccccc3c2CCC1Cl
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
A solution of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (6.2 g, 22 mmol) in glacial acetic acid (200 ml) was placed under an atmosphere of nitrogen. Sodium acetate trihydrate (3.8 g, 28 mmol) was added. After 5 minutes palladium on carbon (10%, 0.6 g) was added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature using 450 ml of hydrogen gas. The reaction mixture was filtered through Celite and the solvent was evaporated in vacuo. After reevaporation with toluene (250 ml), the residue was suspended in water (100 ml), stirred for 5 minutes and the solid was isolated by filtration and dried in vacuo to afford 1.7 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1>>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[N:19][C:18]([N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH2:10][CH2:9]4)[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Agent: Cl
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared according to the procedure as described in Example 1, Method B, reacting 1-(piperidin-4-yl)indoline HCl salt and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH2:18][O:19][CH3:20])[CH3:2].[CH3:21]OC(C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH:18]([O:19][CH3:20])[CH3:21])[CH3:2]
Reactant: COC(C)c1occc(=O)c1OCc1ccccc1
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Product: CCn1ccc(=O)c(OCc2ccccc2)c1C(C)OC
Yield: 29.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1 -methoxyethyl)-3-benzyloxy-pyran-4(1H)-one 3.12 g (12 mmol, 1 eq.) yielded the title compound (1.03 g, 29.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([Br:26])=[CH:4][N:3]=1
Reactant: Nc1nccc2scc(-c3ccc(F)c(Cl)c3)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.3 %

Procedure:
To the solution of 4-amino-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (240 mg, 0.86 mmol) in 10 ml of THF cooled at 0° C. was added NBS (153 mg, 0.86 mmol) and the reaction mixture was stirred for 1 hour at 0° C. The resultant mixture was poured into 10% Na2SO3 and ethyl acetate, the organic phase was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (333 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.97 (s, 1H), 7.73 (dd, J=2.1, 7.2 Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J=8.8 Hz, 1H), 7.48 (ddd, J=2.2, 4.7, 8.4 Hz, 1H), 5.66 (s, 2H). MS: m/z 357, 359, 361 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[O:1]([C:8]1[N:13]=[C:12]2[N:14]=[C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[NH:15][C:11]2=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)nc1N
Reactant: COc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3nc(Oc4ccccc4)ccc3[nH]2)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
6-Phenoxy-2,3-pyridine diamine (Compound of Reference Example 115) (0.2 g) and 3-methoxybenzoic acid (0.08 g) were dissolved in phosphorus oxychloride (5 ml) and the solution was stirred at 140° C. for 4 hours. The reaction mixture was poured onto ice, neutralized with 8 N sodium hydroxide solution and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 5-phenoxy-2-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine (0.04 g, 23%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: C1CNCCN1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 111.2 %

Procedure:
A mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.0 g, 4.0 mmol), piperazine (860 mg, 10 mmol) and lithium perchlorate (625 mg, 6 mmol) in acetonitrile (15 ml) was heated under reflux for 48 h. The solvent was removed under reduced pressure, the residue was treated with crushed ice and extracted with ethylacetate (3×30 ml). The combined organic extract was washed with water, brine, dried (Na2SO4) and concentrated to give the title compound as thick viscous gum (1.5 g, 78%). The title compound was also prepared by hydrolysis of 2R,3R-2-(2,4-difluorophenyl)-3-(4-ethoxycarbonylpiperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 1 with 2M sodium hydroxide solution.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:15]=[N:16][N:17]([CH3:19])[N:18]=3)=[CH:12][N:11]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29]C(OCC)=O)=[O:28])=[CH:23][CH:22]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])C.[Na+].[Na+].[Cl-]>C(O)C>[CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:15]=[N:16][N:17]([CH3:19])[N:18]=3)=[CH:12][N:11]=[C:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:35])(=[NH:29])=[O:28])=[CH:25][CH:26]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nnn(C)n3)c(NC3CCCCC3)n2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nnc(-c2cnc(Nc3ccc(S(C)(=N)=O)cc3)nc2NC2CCCCC2)n1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
117 mg (0.23 mmol) (RS)—S-(4-{[4-(cyclohexylamino)-5-(2-methyl-2H-tetrazol-5-yl)pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide) (Ex. 3.1) in 1.7 ml ethanol are treated with 0.4 mL (0.61 mmol) of a freshly prepared 1.53 molar sodium ethanolate solution and stirred for 7 hours at 60° C. The mixture is diluted with 2 mL ethanol and then treated with a further 1.0 ml (1.53 mmol) of the 1.53 molar sodium ethanolate solution. After 24 hours at 60° C., the mixture is heated to 70° C. and stirred for a further 20 hours. The mixture is treated with saturated NaCl solution and extracted with THF. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is chromatographically (DCM/EtOH 95:5) purified. 76 mg (0.18 mmol, corresponding to 76% of theor.) of the product is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.P([S-])(OCC)(OCC)=[S:12].O>Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([NH2:8])=[S:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(N)=S)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67 %

Procedure:
4-Methylthiobenzonitrile (12 g) was dissolved in a solution (130 mL) of 4N hydrogen chloride in ethyl acetate. To this solution was added O,O-diethyl dithiophosphate (15 mL) and the mixture was stirred at room temperature for 22 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate. The insoluble material was filtered off and the filtrate was washed with saturated brine, dried and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (10 g, yield 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:5][CH:4]=1.[CH3:16]OC1C=CC(C(C)CCCO)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)CCCO)cc1
Reactant: COc1ccc(CCCC(N)CN)cc1
Product: COc1ccc(C(C)CCC(N)CN)cc1

Procedure:
This compound is prepared analogously to Intermediate I by replacing 4-(4-methoxyphenyl)-1-butanol with 4-(4-methoxyphenyl)-1-pentanol.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>CS(C)=O>[O:21]=[C:15]1[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18][CH2:17][NH:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 249.5 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (Chem-Impex International, Wood Dale, Ill.; 168 mg, 0.840 mmol) in DMSO (0.5 mL) was stirred under argon at 100° C. for 19 h, then at 130° C. for 5 h, then at 150° C. for 17 h. The mixture was cooled to 25° C. and partitioned between DCM (30 mL) and water (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (193.5 mg) as a brown solid (used without further purification in the subsequent transformation): m/z (ESI, +ve) 462.4 (M+H)+.