Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:9]([S:11]([CH3:10])(=[O:13])=[O:12])[S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N(c1cc(Br)cnc1Cl)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridin-3-amine (3.04 g, 14.7 mmol) of pyridine (20 mL) in 150-mL round-bottom flask, methanesulfonyl chloride (2.83 ml, 36.6 mmol) was added dropwise at 0° C. The ice bath was removed and the light brown solution was stirred at RT for overnight. Water (100 mL) was added and the precipitate was formed. The mixture was stirred at RT to break up lumps. The cream color solid was collected via filtration and washed with water several times then air dried to afford N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (5.16 g, 96.9% yield) as a cream colored powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.65 (s, 6H), 8.69 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.3 Hz, 1H). m/z (ESI, positive ion): 362.8 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Na].Cl[C:7]1[N:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:8]=1>O>[CH:2]([O:4][C:7]1[N:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[N:10]=[C:9]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:8]=1)([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Agent: [Na]
Solvent: O
Product: COc1cc(Nc2nc(OC(C)C)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 66 %

Procedure:
To 2-propanol (321 mg, 5.34 mmol) was added metallic sodium (9 mg, 0.39 mmol). The resulting alcoholate-solution was treated with (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (100 mg, 0.27 mmol) and the resulting mixture refluxed for 3 hours. Water was added and the product extracted with ethyl acetate. The crude material was purified by chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent to give the title compound as a colorless solid (71 mg, 67%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: COCC1CCCN1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COCC1CCCN1c1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
The mixture of 2-(methoxymethyl)-1-(3-nitrophenyl)pyrrolidine (200 mg, 0.85 mmol), Pd/C (50 mg, 10%) in 50 mL of MeOH was stirred at room temperature for 18 hours under H2 atmosphere. Pd/C was filtrated off and the filtrate was concentrated under reduce pressure to give crude 3-(2-(methoxymethyl)pyrrolidin-1-yl)aniline (170 mg) as an oil. LC-MS: 207 [M+H]+, tR=1.15 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Crude 5-bromopyridine-3-sulfonyl chloride from step 1 above was dissolved in THF (14 L, 8 vol) and then transferred to a 20 L RB flask equipped with mechanical stirrer under inert atmosphere. The solution was cooled to 0-5° C. and tert-butyl amine (1.95 Kg, 26.66 moles) was added at 0-5° C. Upon completion of addition, the reaction mixture was warmed to ambient temperature where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The solvent was evaporated under vacuum to give a thick residue. The residue was dissolved in ethyl acetate (18 L, 12 vol). The organic layer was separated, washed with water (9 L, 5 vol) and then concentrated under vacuum to yield a residue. Hexanes (9 L, 5 vol) were added to the residue and the product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.5 Kg, 54.28% overall yield). 1H NMR (DMSO-D6, 400 MHz, δ ppm); 8.99 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 8.29 (t, J=2 Hz, 1H). [M++1]=293.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
A solution of 2.0 g (11 3 mmoles) of N-benzyl-3-hydroxypyrrolidine in 10 ml of dry THF was added dropwise at room temperature to a stirred slurry of 0.53 g (12.4 mmoles) of 56% NaH in 10 ml of dry THF, under nitrogen atmosphere. After 2 h the solution was cooled to 0° C. and 1.8 g (12.4 mmoles) of methyl iodide were added.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[C:13]([OH:15])=O.[N:31]1([C:37]2[N:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O.C(Cl)CCl.CN(C=O)C>[N:31]1([C:37]2[N:42]=[CH:41][C:40]([CH2:43][NH:44][C:13](=[O:15])/[C:12](=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)/[CH2:11][CH2:10][CH2:9][Cl:8])=[CH:39][CH:38]=2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: NCc1ccc(N2CCOCC2)nc1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)NCc2ccc(N3CCOCC3)nc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To an ethanol (50 mL) solution of 2-[6-(morpholin-4-yl)pyridine-3-yl]methylisoindoindol-1,3-dione (3.8 g) obtained above, hydrazine monohydrate (2.95 mL) was added, and heat-refluxing of the reaction solution was carried out for 2 hours. The reaction solution was allowed to be cooled to room temperature, diethyl ether (100 mL) was added to the reaction solution, and the reaction solution was agitated for 30 minutes at room temperature. C-[6-(morpholin-4-yl)pyridine-3-yl]methylamine (3.0 g) was obtained by filtering off insoluble solids in the reaction solution and condensing the obtained filtrate under reduced pressure. To a DMF (30 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (0.20 g) obtained in Example 418 and C-[6-(morpholin-4-yl)pyridine-3-yl]methylamine (0.30 g), HOBT (0.181 g), IPEA (0.388 mL) and EDC (0.257 g) were added at room temperature, and the reaction solution was agitated at room temperature for 12 hours. The reaction solution was added to water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: from heptane-ethyl acetate system to methanol-ethyl acetate system) and 0.21 g of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid [6-(morpholin-4-yl)pyridine-3-yl]methyl amide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN1CC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc2C1=O
Temperature: 0 °C
Yield: 83.8 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-morpholino-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (451 mg, 1.29 mmol) in THF (7.0 mL) in an ice bath was added 1.00 M potassium t-butoxide in THF (1.42 mL, 1.42 mmol) and the resulting solution was stirred in the ice bath for 30 minutes. Methyl bromoacetate (184 uL, 1.94 mmol) was added and the solution was stirred for 1 hour in the ice bath. The reaction was quenched with saturated NH4Cl (10 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→40/60) to give 455 mg (84% yield) of the title compound as a light yellow oil. LC/MS (FA) ES+ 421. 1H NMR (400 MHz, CDCl3) δ: 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 5.38 (s, 1H), 4.09 (d, 1H, J=17.2 Hz), 4.06-4.01 (m, 1H), 3.99 (d, 1H, J=17.2 Hz), 3.63-3.61 (m, 4H), 3.57-3.53 (m, 2H), 3.52 (s, 3H), 2.99-2.97 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32]I)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:31][CH2:32][O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(CCI)CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(CCCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1

Procedure:
To a solution of 3.1 g (5 mmol) of ethyl 8-[N-(p-chlorophenylsulfonyl)-N-(t-butoxycarbonyl)amino]-4-(2-iodoethyl)octanoate in 10 ml dimethylformamide at 0° C. under an inert atmosphere is added a solution of 0.62 g (6.5 mmol) 3-hydroxypyridine and 0.73 g potassium-t-butoxide in 20 ml dimethylformamide, dropwise. After 24 hours at room temperature the reaction is evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is washed with cold 5% Na2CO3 solution and brine, dried and evaporated to yield ethyl 8-[N-(p-chlorophenylsulfonyl)-N-(t-butoxycarbonyl)-amino]-4-[2-(3-pyridyloxy)-ethyl]-octanoate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=[C:7]([CH:15]2[CH2:17][CH2:16]2)[N:6]=1)=[O:4].[OH-].[K+].Cl.[Cl-].[K+]>CO.O>[CH:15]1([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(C2CC2)nc1C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2CC2)nc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 6-cyclopropyl-pyridine-2,3-dicarboxylic acid dimethyl ester (D81, 12.6 g, 53.62 mmol) in methanol (90 ml) and water (30 ml) was added potassium hydroxide (9.02 g, 160.86 mmol) at 0˜5° C. After heated to 60° C. for 2 hours, the mixture was acidified with 1N HCl until pH=5 and then concentrated to give D82 (21.34 g, containing KCl) as a grey solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Br[C:23]1[N:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:19]([NH2:21])=[O:20])=[N:28][CH:27]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(Nc2sc(-c3ccc(N4CCOCC4)nc3)nc2C(N)=O)nc1

Procedure:
The title compound was prepared as described in Example 22, Step 3 using 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide (Example 22, Step 2) (70 mg, 0.23 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (for preparation, see WO 2004/050024 A2Example 120 Step A) (50 mg, 0.23 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), X-PHOS (55 mg, 0.12 mmol), potassium carbonate (35 mg, 0.25 mmol), and tert-amyl alcohol (1.2 mL) as starting materials. 1H NMR (500 MHz, d6-DMSO): δ 11.19 (s, 1H), 8.67 (d, 1H), 8.40 (s, 1H), 8.08 (dd, 1H), 7.80 (dd, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.12 (d, 1H), 6.93 (d, 1H), 5.13 (s, 1H), 3.70 (m, 4H), 3.53 (m, 4H), 1.43 (s, 6H). LRMS (APCI) calc'd for C21H25N6O3S [M+H]+ 441.2, found 441.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[F:24][C:25](I)([F:27])[F:26].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[O:18])[C:10]=1[C:25]([F:27])([F:26])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)I
Reactant: Cn1c(NC(=O)OC(C)(C)C)cc(=O)n(C)c1=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(NC(=O)OC(C)(C)C)c(C(F)(F)F)c(=O)n(C)c1=O
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
0.26 g (1.0 mmol) of 6-tert-butoxycarbonylamino-1,3-dimethyluracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 6-tert-butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil (19F-NMR yield: 95%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 6-tert-Butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil was obtained as a white solid (0.30 g, yield: 93%) by column chromatography.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(OC)(C)C>O1CCCC1.CC(C)=O.CCCCCCC>[Si:1]([O:8][CH2:9][CH2:10][NH:11][S:26]([CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:28])=[O:27])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanamine (11.7 g, 66.6 mmol) and triethylamine (11.2 mL, 79.9 mmol) in tetrahydrofuran (222 mL) at 0° C. was slowly added phenylmethanesulfonyl chloride (12.7 g, 66.6 mmol) portion wise and the reaction was stirred at room temperature for 16 hours. MTBE was then added and the Et3N.HCl salt was removed by filtration. The filtrate was then concentrated and purified by silica gel column chromatography (0-30% Acetone in heptane, 216 nM) to N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-phenylmethanesulfonamide (17.8 g, 81% yield). LCMS (ESI), m/z, 330. [M+H]+.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN1CCN(C)C1=O>C1COCC1>[CH2:8]([C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: c1cc[cH-]c1
Reactant: CCCCCCCCBr
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CCCCCCCCC1=CC=CC1
Temperature: -78 °C

Procedure:
THF in a volume of 100 ml was added to 50 ml (100 mmol) of a 2 M THF solution of sodium cyclopentadienide, and the mixture was cooled to −78° C. A THF solution of 19.3 g (100 mmol) of 1-bromooctane was added thereto dropwise. Further, 11.4 g (100 mmol) of 1,3-dimethyl-2-imidazolidinone was added dropwise. The mixture was stirred at −78° C. The mixture was further stirred at room temperature for 24 hours and was cooled to 0° C. The reaction was terminated by adding 1N hydrochloric acid, and hexane was added to the reaction liquid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, was filtered, and was concentrated under reduced pressure. The concentrate was purified by distillation under reduced pressure to give 6.7 g (37.5 mmol) of target n-octylcyclopentadiene. The compound was identified by GC-MS. GC-MS: 178 (MS).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH:14]([N:13]([CH3:17])[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]4=[O:28])[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1)([CH3:15])[CH3:18]
Reactant: Cc1ccc[nH]c1=O
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, except for substituting the product of Example 52A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.89 (d, J=1.84 Hz, 1H) 7.42 (dd, J=8.75, 1.99 Hz, 1H) 7.23-7.34 (m, 2H) 6.18 (t, J=6.75 Hz, 1H) 3.52-3.63 (m, 1H) 3.12-3.27 (m, 1H) 2.90-3.03 (m, 1H) 2.55-2.73 (m, 2H) 2.25-2.44 (m, 2H) 2.20 (s, 3H) 2.13 (s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:35][NH2:36]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:25])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:36][N:35]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-phenyl-2-morpholinecarboxamide (340 mg, 0.61 mmol) and hydrazine monohydrate (0.39 mL, 12.54 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. in a sealed tube for 18 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by flash chromatography (60 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (243 mg) as a pale yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.24 (d, J=6.6 Hz, 3H), 2.86 (d, J=4.0 Hz, 3H), 2.97-3.15 (m, 1H), 3.83 (d, J=11.1 Hz, 1H), 3.94 (d, J=11.1 Hz, 1H), 4.16 (dd, J=11.2, 2.9 Hz, 1H), 4.33-4.88 (bs, 2H), 5.39 (s, 2H), 6.56-6.73 (m, 2H), 7.10 (t, J=7.3 Hz, 1H), 7.34 (t, J=7.9 Hz, 2H), 7.63 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.3 Hz, 3H), 8.01 (s, 1H), 9.88 (s, 1H), 11.51 (s, 1H).
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: CC(=O)O
Solvent: 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: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].O.O[N:16]1[C:20]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(O)C.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[CH3:20][NH:16][C:11](=[O:13])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
(2-Nitrophenyl)acetic acid (10.0 g, 55.21 mmol) was dissolved in N,N-dimethylformamide (15 ml) and dichloromethane (50 ml). 1-Hydroxybenzotriazole hydrate (7.46 g, 55.21 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10.58 g, 55.21 mmol) was added. The solution was stirred for 15 min at 0° C. A 8.0 M solution of methylamine in ethanol (10.3 ml, 82.81 mmol) and ethyldiisopropylamine (9.55 ml, 55.21 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (180 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 8.01 g of N-methyl-2-(2-nitrophenyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH2:13][CH2:14][CH:10]([OH:9])[CH2:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OC1CCN(c2cccc(Br)n2)C1
Temperature: 70 °C
Reaction time: 11 h
Yield: 100.9 %

Procedure:
A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated under stirring under nitrogen atmosphere in an oil bath at 70° C. for 11 hours. The reaction mixture was separated with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silicagel column chromatography with 10–30% ethyl acetate/hexane, to give 5.9 g of 2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine.