Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH2:18][Cl:19]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCl)OC1CCCCC1

Procedure:
A solution of 3.0 g of cyclohexanol and 2.4 ml of pyridine in 30 ml of methylene chloride is cooled to -78° C. and, with stirring, 2.4 ml of chloromethyl chloroformate is added dropwise to the solution. After completion of addition, a cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 4.5 g of colorless oil, which is crystallized from ligroine giving the title compound as colorless crystals melting at 36°-37° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:24][CH:23]=2)[N:20]=1)(=O)=O>CS(C)=O>[CH:3]1([N:2]([CH3:1])[C:15]2[C:16]3[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])=[CH:24][CH:23]=3)[N:20]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Reactant: CNC1CCCCC1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(C)C4CCCCC4)n2)CN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
N-Methylcyclohexanamine (9.67 mg, 0.09 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (40 mg, 0.09 mmol, Example 9a) in DMSO (1 mL) and the reaction was stirred at 80° C. for 2 h. Solvent was allowed to cool down, filtered and the product purified on preparative HPLC to give N4-cyclohexyl-N4,6-dimethyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (22.00 mg, 59.7%). MS (ESI+)/(ESI−) m/z 432/430
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:42][CH:41]=5)[CH2:35][CH2:34]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:11].[H-].[Na+].I[CH3:55].O>CN(C=O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([N:13]([CH3:55])[C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]([F:50])([F:49])[F:51])=[CH:44][CH:45]=5)[CH2:37][CH2:38]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 2,4,6-trimethyl-N-[6-(1-methyl-2-{4-[4-(2,2,2-trifluoroethoxy)benzyl]piperazine-1-carbonyl}-1H-indol-6-yloxy)pyridin-3-yl]benzenesulfonamide (0.38 g, 0.53 mmol) in DMF (4 mL) was added 60% sodium hydride in oil (0.025 g, 0.63 mmol) under ice cooling and stirred for 10 minutes. Then to the mixture was added iodomethane (0.036 mL, 0.58 mmol) at 0° C. and the mixture was stirred for 2 hours. Water (8 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (AcOEt to AcOEt:MeOH=95:5) to give 0.28 g of the title compound as a colorless amorphous powder.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=O.O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1>[CH3:1][S:2][CH2:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCC(=O)CS(C)=O
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)CSC
Temperature: 25 °C
Yield: 60 %

Procedure:
A stirred mixture of 1-methylsulphinylheptadecan-2-one (10 g), water (100 ml), sodium metabisulphate (50 g) and dioxan (50 ml) was heated on a steam bath for 18 hours. The mixture was cooled to room temperature and extracted with diethyl ether (2×100 ml). The ether extract was dried over magnesium sulphate and was evaporated to give 1-methylthioheptadecan-2-one (5.7 g) as a white solid, m.p. 38°-40° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[F:15])[CH2:5][C:4](=[O:16])[CH2:3]1.[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1.[OH-].[K+]>C(O)C>[F:15][C:9]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:22][CH:17]=[C:18]([CH3:19])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccccc1
Reactant: NC1CC(=O)CC(c2cc(F)ccc2F)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1F)C2
Reaction time: 5 h

Procedure:
A mixture of 1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g), 3-oxobutylaldehyde dimethyl acetal (5.5 g), toluene (120 ml) and ethanol (70 ml) was stirred at 115° C. with adding potassium hydroxide powder (0.77 g). The mixture was combined with potassium hydroxide powder (0.16 g) after 30 minutes and with potassium hydroxide powder (0.16 g) and 3-oxobutylaldehyde dimethyl acetal (0.44 g) after 1 hour and further with potassium hydroxide powder (0.16 g) after 1 hour and 30 minutes, and then stirred at the same temperature for 5 hours. After cooling, the solvent was distilled off under reduced pressure and ethyl acetate was added. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to a silica gel column (ethyl acetate-hexane), and the resultant crystal was recrystallized from ethyl acetate-hexane to obtain 7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26].[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:27]1([NH:24][C:25]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) (Example 11b) in chloroform (2 mL) was added isocyanatobenzene (0.030 mL, 0.276 mmol) The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide (54 mg, 0.147 mmol, 80% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.32-7.38 (m, 2H), 7.20-7.31 (m, 4H), 7.10-7.17 (m, 1H), 7.05-7.10 (m, 2H), 6.98-7.05 (m, 1H), 4.20 (d, J=12.63 Hz, 2H), 2.79-3.01 (m, 2H), 2.65 (d, J=6.57 Hz, 2H), 2.28-2.45 (m, 1H), 1.95 (ddd, J=3.16, 5.94, 9.35 Hz, 1H), 1.70-1.90 (m, 3H), 1.14-1.31 (m, 2H), 1.10 (dt, J=4.86, 9.47 Hz, 1H), 1.03 (dt, 1H); LC-MS Rt=0.56 min; MS (ESI): 350.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[C:16]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOc1ccc(C(=O)n2c(C)cc3c(C=CC(=O)O)cccc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C(=O)n2c(C)cc3c(CCC(=O)O)cccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of 3-(1-(4-butoxybenzoyl)-2-methylindol-4-yl)acrylic acid (300 mg; prepared in Example 4) in methanol-ethyl acetate (5 ml+5 ml) was added palladium on activated carbon (100 mg) at room temperature. The inside of the vessel was replaced with hydrogen and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite (trademark). The filtrate and washing with chloroform were combined, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give the title compound (25 mg) having the following physical data.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([NH:21][CH2:22][CH2:23][CH2:24]Br)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 4-hydroxy-naphthalene-1-carbaldehyde (15.2 g, 58.1 mmol) in DMF (50 mL) at r.t. was added N-Boc 3-bromo-propylamine (15.2 g, 63.9 mmol), followed by potassium carbonate (12 g, 87.2 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted by CH2Cl2. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from EtOAc/hexane to afford [3-(4-formyl-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (13.8 g, 72%) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([CH3:23])[CH3:22]>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(C)c1ccccc1N
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Yield: 8 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (305 mg, 1 mmol) and 2-isopropylaniline (1 ml) in 25 ml acetonitrile was refluxed overnight. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on a prep-TLC (methylene chloride: ethyl acetate 1:1) yielding 30 mg (8%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)[CH:22]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:25]1[C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][C:23]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1noc(-c2cc(Cl)ccc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc(Cl)ccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (11 mg, 0.043 mmol) and 4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (10 mg, 0.045 mmol) in DMF (5.0 mL) is added Oxone (27 mg, 0.044 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (10 mg, 50%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.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>[CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(N)=O)nc4)cc3c21
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 112.1.1, 34 mg, 0.075 mmol), 5-bromo-pyridine-2-carboxylic acid amide (Combi-Blocks, San Diego, USA, 20 mg, 0.099 mmol), and PdCl2(PPh3)2 (3.5 mg, 0.005 mmol) in DMF (0.9 ml) and 1 M aqueous K2CO3 (0.187 ml) was stirred under argon at 105° C. for 2.5 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 97:3 to 55:45). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.44 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.75-8.69 (m, 1H), 8.24-8.19 (m, 1H), 8.18-8.07 (m, 2H), 8.07-7.98 (m, 3H), 7.75-7.67 (m, 1H), 7.61-7.56 (m, 1H), 4.61-4.48 (m, 1H), 3.58 (s, 3H), 1.97 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H))
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1.[Li]CCCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CSc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
1-Bromo-3-methylsulfanyl-benzene (5.0 g, 24.6 mmol) was dissolved in dry THF (40 ml) and cooled to −78° C. under a stream of Argon (g). n-BuLi (12.8 ml, 2.5 M in hexane, 31.9 mmol) was added dropwise via syringe and the reaction mixture was stirred for an additional 30 min at −78° C., then the temperature was increased to 0° C. for 5 min and then decreased to −78° C. 1-tert-Butoxycarbonyl-4-piperidone (5.4 g, 27.06 mmol) dissolved in dry THF (30 ml) was added via syringe. The reaction mixture was allowed to reach room temperature and then stirred for 1 hour, and finally quenched with saturated ammonium chloride solution (30 ml). The mixture was extracted several times with EtOAc and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The oily residue was chromatho-graphed on a silica column using CH2Cl2:MeOH (19:1 (v/v)) as eluent, yielded 4-hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (6 g, 76%). MS m/z (relative intensity, 70 eV) 323.1 (M+, 6), 223.0 (11), 178.0 (7), 152 (3), 57.0 (bp), 56 (30).
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:22][C:23]4[C:28]([N:29]=3)=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl.[OH-].[Na+]>O1CCOCC1>[N:29]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[O:22][C:21]=1[N:18]1[CH2:17][CH2:16][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:20][CH2:19]1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (R)-1-[4-(4-oxazolo[5,4-b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 9, Step B, 11.0 g, 27.6 mmol) in dioxane (11.5 mL) was added concentrated hydrochloric acid (23 mL, 276 mmol). This mixture was stirred at room temperature overnight, neutralized with 6 N aqueous sodium hydroxide, and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (3.5% methanollchloroform) to give 8.4 g (93%) of the title compound as a white solid. mp: 153-156° C.; 1H NMR (CDCl3, 300 MHz) δ 8.25 (d, 1H), 7.95 (dd, 1H), 7.58 (dd, 1H), 7.15 (dd, 1H), 6.45 (d, 1H), 4.72 (q, 1H), 4.25 (br s, 1H), 3.85-3.82 (c, 8H), 1.51 (d, 3H); MS (Cl/NH3) 327 (MH+); [α]D+16.1 (c, 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3,4-dichloroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:18]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][Cl:17])[CH:7]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:18][C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)=[O:21]
Reactant: COC(=O)C(=Cc1ccc(OC)c(OCCCl)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OCCCl)c(OC)cc2[nH]1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 16 (6.81 g, 21.8 mmol) in toluene (200 mL) was heated at reflux for 4 h. After cooling to room temperature the reaction mixture was concentrated in vacuo. The formed precipitate was isolated by filtration and dried in vacuo to give 17 (4.48 g, 72%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ=3.82, 3.84 (2×s, 6 H, OMe, CO2Me), 3.93 (t, J=5.3 Hz, 2 H, 2′-H2), 4.21 (t, J=5.3 Hz, 2 H, 1′-H2), 6.92 (s, 1 H, 7-H), 7.02 (d, J=1.5 Hz, 1 H, 3-H), 7.15 (s, 1 H, 4-H), 11.62 (sbr, 1 H, NH) ppm. —13C NMR (50.3 MHz, DMSO-d6): δ=42.9 (C-2′), 51.3 (CO2Me), 55.5 (OMe), 69.4 (C-1′), 94.8 (C-7), 105.6 (C-4), 107.9 (C-3), 119.7 (C-3a), 125.4 (C-2), 133.2 (C-7a), 144.1 (C-5), 149.8 (C-6), 161.4 (C═O) ppm. −MS (70 eV, EI): m/z (%)=283 (100) [M]+, 220 (50) [M-CH2)2Cl]+. —C13H14ClNO4 (283.71): calcd. C, 55.04; H, 4.97; found C, 54.86; H, 5.06.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][N:14]=[C:13]3[CH:20]=[CH:21][S:22][C:12]=23)[CH2:6][C@H:5]1[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)#[N:2]>[Pd].CO>[NH2:17][C:16]1[C:11]([NH:10][C@@H:7]2[CH2:6][C@@H:5]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:4]([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]2)=[C:12]2[S:22][CH:21]=[CH:20][C:13]2=[N:14][CH:15]=1
Reactant: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of benzyl {(1R,2R,5S)-2-(cyanomethyl)-5-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}carbamate (28 mg, 0.060 mmol) and 10% palladium on carbon (7.0 mg) in methanol (0.44 mL) was stirred under an atmosphere of H2 (balloon) for 3 h. The mixture was filtered and concentrated to give 26 mg of the desired product. LCMS calculated for C23H26N5O2S (M+H)+: m/z=436.2. Found: 436.0.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]([NH2:23])=[S:22])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][CH:26]=O>CN(C=O)C>[CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]3[S:22][CH:25]=[CH:26][N:23]=3)=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=S)Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: c1ccc(Oc2cnc(Nc3nccs3)c(OC3CCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
(3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea (0.29 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred 3 h at 100° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-ter.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A21”) is obtained after reversed phase chromatography (water/acetonitrile+0.1% TFA) as yellow solid in a yield of 47%; 138.2-139.7°; HPLC (method C): 2.00 min; LC-MS (method A): 2.00 min, 354.1 (M+H+);