Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1[NH:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].Cl>[N+]([O-])([O-])=O.[Ag+].CC#N.O>[CH3:8][CH:7]([CH3:9])[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:5]
Reactant: COc1ccccc1NC(c1ccccc1)C(C)C
Agent: [Ag+]
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)C(N)c1ccccc1
Temperature: 60 °C
Yield: 32.2 %

Procedure:
To 2-methoxy-N-(2-methyl-1-phenylpropyl)aniline (1.36 g, 5.34 mmol, 1.00 equiv) in 2:1 v/v MeCN/H2O (76 mL) was added AgNO3 (0.271 g, 1.60 mmol, 0.300 equiv) and the reaction mixture was heated to 60° C. Ammonium persulfate (8.58 g, 37.6 mmol, 7.04 equiv) was added in three portions over 15 min and the reaction mixture was heated at 60° C. for 1 h. An aqueous solution of HCl (10 mL, 2 N in H2O) was added. The reaction mixture was filtered through a celite pad, eluting with H2O. The aqueous layer was washed with Et2O (3×30 mL) and the combined organic layers were washed with HCl (2×30 mL, 0.5 N in H2O). The combined aqueous layers were basified with 2.5 M NaOH and the aqueous layer was extracted with Et2O (4×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Kugelrohr distillation (50 mTorr, 60° C.) to give 2-methyl-1-phenylpropan-1-amine as a colorless oil (0.257 g, 32% yield).
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[SH:8].CS(O[CH:14]1[CH2:17][N:16]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1)(=O)=O>C1COCC1>[CH:18]([N:16]1[CH2:17][CH:14]([S:8][C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[CH2:15]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Sc1cccs1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(C(c2ccccc2)N2CC(Sc3cccs3)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Potassium hydroxide (141 mg, 2.52 mmol) and thiophene-2-thiol (292 mg, 238 μL) were added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (400 mg, 1.26 mmol) solubilized in THF (7 mL). The reaction mixture was stirred a first time under microwave irradiations (100 W) at 80° C. for 30 minutes. Potassium hydroxide (141 mg, 2.52 mmol) and thiophene-2-thiol (292 mg, 238 μL) were added and the reaction mixture was stirred for a second time under microwave irradiations (100 W) at 80° C. for 30 minutes. After concentration to dryness, the residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (1:0 to 9:1) as eluent. The title product was obtained as a yellow solid (160 mg, 37%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[Cl:31])[N:20]2[N:32]=[CH:33][C:34]([C:35]#[N:36])=[C:19]12)=[O:17]>>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=1[C:21]1[N:20]2[N:32]=[CH:33][C:34]([C:35]#[N:36])=[C:19]2[N:18]([C:16](=[O:17])[CH2:15][N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH2:23][CH:22]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cc(Cl)ccc1Cl
Product: N#Cc1cnn2c1N(C(=O)CN1CCC(Cc3ccccc3)CC1)CC=C2c1cc(Cl)ccc1Cl

Procedure:
The above compound was prepared by the reaction of 4-benzylpiperidine with the compound of Example 9 by the procedure of Example 16, mp 157°-158° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])C.[Li]CCCC.C[C:14]1[CH2:18][CH2:17][CH2:16][N:15]=1.CSC1CCCN=1>C1COCC1>[NH:15]1[CH2:16][CH2:17][CH2:18][C:14]1=[CH:7][C:5]1[CH2:6][CH2:3][CH2:1][N:4]=1
Reactant: CC(C)NC(C)C
Reactant: CC1=NCCC1
Agent: CSC1=NCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C1CCCN1)C1=NCCC1
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (11.1 g, 109.7 mmol) in THF (200 mL) was dropwise added n-BuLi (2.89 M, 37.97 mL, 109.7 mmol) at −78° C. under nitrogen. Once all the n-BuLi was added, the temperature was adjusted to −5° C., and the reaction mixture was stirred for 30 min. Then a solution of 2-methyl-1-pyrroline (5.65 g, 67.9 mmol) in THF (15 mL) was added dropwise to the reaction mixture at −5° C., and then stirred. After 30 min, 2-methylthio-1-pyrroline (6.02 g, 52.3 mmol) was added dropwise over 30 min at −78° C. The reaction mixture was stirred as the temperature was allowed to gradually rise to room temperature, and was continuously stirred at room temperature overnight. THF solvent was removed under reduced pressure, then 50 mL of methanol was added dropwise to the residue. After removing all of the volatile solvent, pentane (2×100 mL) was added to the residue, and the mixture was filtered. Concentration of the filtrate under reduced pressure, followed by vacuum distillation (65° C. at 110 mTorr), delivered 6.29 of product (79%). 1H NMR (CD2Cl2, 500 MHz): δ 7.89 (s, br, 1H), 4.65 (s, 1H), 3.64 (t, 2H, J=7.2 Hz), 2.51 (t, 2H, J=8.0 Hz), 1.85 (m, 2H). 13C NMR (CD2Cl2, 125 MHz): δ 167.0, 81.7, 53.7, 34.8, 23.2.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[O:6][C:5]1=[O:13])(=O)[CH3:2].[OH-].[Na+].O.C(=O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:2]1(/[CH:1]=[C:4]2/[C:5](=[O:13])[O:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]/2)[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCC1CC(C(C)=O)C(=O)O1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC1C/C(=C\c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a mixture of 36.8 g (0.200 mole) of 3-acetyl-5-butyldihydro-2(3H)-furanone in 200 mL of toluene charged to a 500 mL flask fitted with a mechanical stirrer, Dean-Stark trap and an addition funnel was added 8.00 g (0.200 mole) of sodium hydroxide at once. The mixture was vigorously stirred for 10 mins. at room temperature and then heated under reflux for 1 hour while water was removed in the Dean-Stark trap. After the one hour period 23.9 g (0.225 mole) of benzaldehyde was added to the refluxing solution in 4-5 ml aliquats in 1 hour. The reaction was further heated under reflux for an additional 2.5 hours. The reaction mixture was then cooled to room temperature and washed with 3×80 ml of water. The water layer was extracted with 50 ml of toluene and the toluene layers combined. The toluene solution was then washed with 100 ml of saturated sodium chloride and dried over Na2SO4 and concentrated to 35.4 gms of an orange oil under rotoevaporation. 19.0 gms of this oil was subjected to simple straight takeover distillation (0.04 mm Hg: 25°-147° C.) to leave 16 g (64.5% yield) of (E)-3-(phenylmethylene)-5-butyldihydro-2 (3H)-furanone as a viscous liquid. 1HNMR (CDCl3) δ7.5 (m, 6H), 4.56 (pentet, 1H), 3.3 (ddd, 1H), 2.8 (ddd, 1H), 1.9-1.2 (m, 6H), 0.86 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CCCCO>[Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cc1F
Temperature: 155 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide (300 mg, 0.785 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (472 mg, 2.36 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 27% yield).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:17][C@H:16]2[CH3:31])(=[O:14])=[O:13])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C=C(C([O-])=[O:41])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:33][C:2]([F:1])([F:32])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N+:24]([O-:41])=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH2:17][C@H:16]2[CH3:31])(=[O:13])=[O:14])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@@H]1CN(c2ccncc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(c2cc[n+]([O-])cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a flask containing 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol (60 mg, 0.12 mmol) and 1.5 mL of DCM/MeOH (9/1, v/v) was added MMPP (74.6 mg, 0.15 mmol). The resulting slurry was stirred at room temperature over night. Reaction was complete as determined by TLC. This was filtered, washed with DCM. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography to yield 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[1-oxido-3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (13.5 mg, 21.9 yield). HRMS: calcd for C20H21F6N3O4S+H+, 514.12297. found (ESI-FTMS, [M+H]1+), 514.12174.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].CC([O-])(C)C.[Na+]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[C:28]([Cl:34])[CH:27]=[CH:32][C:31]=1[NH:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]23)[CH:10]=1
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(Cl)c1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
An oven dried three-necked round bottom flask was fitted with septa, condenser, and a stopper. The flask was charged with tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (134 mg, 0.36 mmol), 1-bromo-2,4-dichlorobenzene (70 mg, 0.31 mmol), NaOtBu (60 mg, 0.62 mmol), and anhydrous toluene (5 mL). The solution was purged with argon at 80° C. for 25 min then cooled to room temperature. While maintaining a blanket of argon, Pd2(dba)3 (3.4 mg, 3.7 μmol), and BINAP (7 mg, 11.2 μmol) were added quickly. The resulting mixture was heated to 80° C. for 20 hours under argon while monitoring the consumption of starting material by TLC (50% ethyl acetate/hexanes). After cooling to room temperature, the dark solution was diluted with ethyl ether (10 mL) and filtered through a pad of silica, washing with ether and ethyl acetate. The resulting solution was concentrated and chromatographed (Combiflash, 95:5 to 75:25 hexanes/ethyl acetate gradient) yielding the title compound (78 mg, 48%) as a tan solid. 1H NMR(CDCl3, 300 MHz) δ 1.41 (s, 9H), 1.79-1.97 (m, 2H), 2.85-3.18 (m, 6H), 3.46-3.61 (m, 4H), 3.68 (s, 2H), 5.84 (s, 1H), 6.71 (d, 1H, J=1.9 Hz), 6.79 (d, 1H, J=1.8 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=2.3, 8.8 Hz), 7.29 (d, 1H, J=2.3 Hz) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl.[Cl:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:15]2[CH2:16][CH2:17][CH:13]([CH2:12][CH2:11][Cl:10])[CH2:14]2)=[CH:7][CH:6]=1
Reactant: ClCCC1CCNC1
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCC1CCN(c2ccc(Cl)nn2)C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 8.9 parts of 3,6-dichloropyridazine, 8.6 parts of 3-(2-chloroethyl)pyrrolidine hydrochloride, 21,2 parts of sodium carbonate and 235 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 12.2 parts (99.1%) of 3-chloro-6-[3-(2-chloroethyl)-1-pyrrolidinyl]pyridazine as a residue (int. 94).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([CH:18]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[O:19]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O[Li].O>CC(O)C.C(Cl)Cl.O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH2:22][CH:18]1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:17]
Reactant: CCOC(=O)C1(NC(=O)C2Cc3ccccc3O2)Cc2ccccc2C1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)C1Cc2ccccc2O1
Reaction time: 19 h
Yield: 95.7 %

Procedure:
A 50 mL flask containing the 2-[(2,3-dihydrobenzofuran-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (0.447 g, 1.39 mmol) is charged with 1,4-dioxane (5 mL) and MeOH (5 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2.5 mL) is added followed by the LiOH hydrate (133 mg, 3.17 mmol). After 19 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜12 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 0.43 g of white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C@H:27](Cl)[CH3:28]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:27]([C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[Cl:20])[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccncc1Cl
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2ccncc2Cl)nc2nc(N)sc12
Yield: 8 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (860 mg, 2.87 mmol) and 3-chloro-4-[(1R)-1-chloroethyl]pyridine from the previous step. Purification by flash chromatography yielded the title compound (105 mg, 8% yield) as a diastereomeric mixture.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:28][C:29]([F:33])([F:32])[CH2:30][OH:31].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C(Cl)Cl>[N:21]1[C:22]2[C:27](=[N:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[CH:3]=[C:2]([O:31][CH2:30][C:29]([F:33])([F:32])[F:28])[CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)=[N:19][CH:20]=1
Reactant: OCC(F)(F)F
Reactant: Ic1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Product: FC(F)(F)COc1ccnc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c1
Reaction time: 72 h
Yield: 26.1 %

Procedure:
To a solution of N-(2-{4-[(4-iodopyridin-2-yl)oxy]phenyl}ethyl)pteridin-4-amine (300 mg, 0.64 mmol) and 2,2,2-trifluoroethanol (5 mL, 1.27 mmol) in a 45 mL Parr Bomb was added Cs2CO3 (412 mg, 1.27 mmol), 1,10-phenanthroline (22 mg, 0.127 mmol), and Cut (12 mg, 0.064 mmol). The reaction was held at 110° C. for 72 h, diluted with CH2Cl2, and washed with H2O. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to afford pteridin-4-yl-(2-{4-[4-(2,2,2-trifluoroethoxy)-pyridin-2-yloxy]-phenyl}-ethyl)-amine (74 mg, 26%) as a yellow solid: mp 166° C.; EIMS m/z 442 ([M]+).
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]([NH2:29])=[O:28])[CH2:22]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>C(O)(C)C.[Pd]>[CH3:8][NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([C:26]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:27]([NH2:29])=[O:28])[CH2:22]2)=[CH:16][CH:17]=1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCc2ccc(CCNCCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: CC(C)O
Product: CNCCc1ccc(CCCN2CC[C@@H](C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 2.5 h
Yield: 9 %

Procedure:
A stirred solution of the intermediate from Step E (0.8 g, 1.46 mmol) in isopropanol (100 mL) was flushed with nitrogen gas and then palladium (80 mg; 10 wt. % (dry basis) on activated carbon) was added. The reaction flask was then placed under vacuum and then flushed with hydrogen gas (3 cycles). The reaction mixture was then stirred for 2.5 hours and then was flushed with nitrogen gas, filtered and the solvent removed under reduced pressure. To the residue was added a 1:1 mixture of acetic acid/water (1.0 mL) and this mixture was then chromatographed on reverse-phase silica gel (gradient elution, 10-50% ACN/water) to provide 60 mg of the title compound (6% yield) as a bis(trifluoroacetate) salt. MS m/z: [M+H+] calc'd for C30H37N3O 456.3. Found 456.3. Retention time=3.04 min (10-70% ACN: H2O, reverse phase HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1>[Pt]>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1
Reactant: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Product: COc1cc(C)c(Cl)cc1N

Procedure:
4-Chloro-5-methyl-2-aminoanisole was prepared by the same method as described in Step 2 of Preparation 2c except using 4-chloro-5-methyl-2-nitroanisole (20 g) and 10%Pt(S)/C (2 g). Workup gave crude 4-chloro-5-methyl-2-aminoanisole, V (16 g, 94%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ6.69 (s, 1 H), 6.60 (s, 1 H), 3.81 (s, 3 H), 2.25 (s, 3 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][CH:10]=1.[Br:18]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:18][C:8]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
t-Butyl 2-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (6.70 g, 26.8 mmol) synthesized in Example (1f) was dissolved in tetrahydrofuran (100 mL) and cooled to 0° C. With stirring under nitrogen atmosphere, N-bromosuccinimide (4.79 g, 26.9 mmol) was divided into 5 parts to be added every 10 minutes, followed by further stirring at 0° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-16%) to afford the desired compound (7.55 g, yield 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[O:6][CH2:17][CH3:18]
Reactant: NC(=O)c1cccc(Cl)c1F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1cccc(Cl)c1F

Procedure:
starting from 3-chloro-2-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 3-chloro-2-fluorobenzimidate as an oil; mass spectrum: 200 (10), 173 (25), 166 (15), 157 (100), 156 (73);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12]
Reactant: NCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30.5 mmol (6.42 g) of 2-naphthylsulphonyl chloride and 15 ml of 4M aqueous sodium hydroxide are added in succession to a solution of 15.2 mmol (2 g) of 6-aminocaproic acid in 15 ml of 4M aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours. The solution is then rendered acidic to pH=2 with concentrated hydrochloric acid, and extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated, and the resulting residue is recrystallised from hexane to yield the expected compound.
Reaction SMILES: C(O)C.[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([O:18]CC)=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5].[OH-].[Na+]>O>[C:4]([CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:5]
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC1CCCc2c(C(=O)O)cccc21
Temperature: 50 °C

Procedure:
In 90 ml. of ethanol is dissolved 9.6 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and a solution of 2.5 g. of sodium hydroxide in 90 ml. of water is added. The mixture is stirred under heating at 50°C for 3 hours, after which the ethanol is distilled off. Then, following the addition of 2N hydrochloric acid, the residue is extracted with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the crystalline residue is recrystallized from benzene. The described procedure gives 1-cyano-1,2,3,4-tetrahydro-5-naphthoic acid, melting point: 177°-179°C.