Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=C)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.O.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]=[O:24])[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O
Reaction time: 60 h

Procedure:
1.00 g (3.25 mmol) of the compound from Example 214A and 217 mg of OsEnCat 40 (micro-encapsulated osmium tetroxide, 0.3 mmol/g, 65 μmol) are placed in 20 ml dioxan and 9 ml water and slowly treated with 2.09 g (9.8 mmol) of sodium periodate at RT. This is allowed to react with vigorous stirring (1-4 days) until HPLC testing of the mixture shows adequate conversion. For the workup, the osmium catalyst is removed by filtration, then washed with dioxan and the total filtrate freed from the organic solvents on the rotary evaporator. The aqueous residue is diluted with more water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent removed on the rotary evaporator. The oily residue is dried under high vacuum. 948 mg (purity ca. 84%, 79% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:21]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 70.3 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[2-(dimethylamino)ethoxy]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (50 mg, 0.13 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.20 mmol) followed by formation of the dihydrochloride salt to afford the desired product (40 mg, 54%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.35 (br s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H), 7.76 (dd, J=8.8, 2.7 Hz, 1H), 7.35 (br s, 1H), 7.10 (br s, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.74-4.68 (m, 2H), 3.66-3.60 (m, 2H), 3.02 (s, 6H), 2.84 (s, 3H); ESI MS m/z 496 [M+H]+; HPLC 98.3% (AUC), tR=9.47 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)N1CCNCC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of 1-isopropylpiperazine (61.5 mmol) and 9.2 ml of DBU (61.5 mmol) is stirred overnight at 100° C. The reaction mixture is returned to ambient temperature and the solution is diluted with water and extracted with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue is chromatographed on an SiO2 column, eluting with a mixture of CH2Cl2/MeOH 98/2 and then 96/4, to yield the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc(Br)cc1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (3.0 g, 17 mmol), 4-bromobenzaldehyde (3.1 g, 17 mmol) and piperidine (8.4 mL, 85 mmol) in ethanol (113 mL) was heated at 90° C. for overnight. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel to give 2.4 g (41%) of 3-(4-bromo-benzylidene)-4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as a yellow orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1>[C:20]([NH:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1)(=[O:22])[CH3:21]
Reactant: CCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CCCc1nc(NC(C)=O)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2 g (7.2 mmol) of 2-amino-5-(4-nitrobenzyl)-4-propylthiazole in 2.5 ml of acetic anhydride, in the presence of 88 mg of 4-dimethylaminopyridine (0.72 mmol), are heated at 80° C. for 1 hour. As the reaction mixture is cooled, the formation of a precipitate is observed. This is filtered off and washed with ether to give 1.6 g of the derivative 2-acetamido-5-(4-nitrobenzyl)-4-propylthiazole, which is pale yellow solid melting at 170° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[N:13]/[OH:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=1.Cl([Na])=O>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([C:28]([F:29])([F:30])[F:31])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:27])([F:26])[F:25])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: O/N=C/c1ccc(Br)c2ccccc12
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(Br)c4ccccc34)=NO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (100 mL), (E)-N-[(4-bromonaphthalen-1-yl)methylidene]hydroxylamine (4.5 g, 17.99 mmol, 1.00 equiv), 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.9 g, 17.84 mmol, 1.00 equiv), chlorosylsodium (30 mL). The resulting solution was stirred overnight at room temperature. The aqueous layer was extracted with 3×20 mL of dichloromethane and the organic layers combined and washed with 3×40 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and washed with ethyl acetate/petroleum ether (1/10-1/5). This resulted in 7.1 g (75%) of 3-(4-bromonaphthalen-1-yl)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a off-white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CN(C)C=O.O>[C:23]1([NH:22][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccccn1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of carbonyldiimidazole (8.10 g) in dry dimethylformamide (100 mL) under N2 atmosphere, was added the picolinic acid (15.0 g) portionwise, then stirred for 30 minutes. Aniline (10.93 mL) was added rapidly dropwise, then stirred for 18 hours at room temperature. The reaction mixture was poured into water (400 mL), basified with 2.5N NaOH (25 mL) and stirred for 30 minutes while solid precipitated. The solid was collected by vacuum filtration, washed with water, and dried in vacuo. This tan solid was recrystallized from ether/hexane (1/1) to afford 7.69 g (32.3%) of an off-white solid, m. p. 75°-77° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:12])[C:9](Cl)=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].Cl>CCOCC.C(Cl)Cl>[S:7]1[C:9](=[O:10])[C:8](=[O:12])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]1=2
Reactant: Sc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Sc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of benzenthiol (1 ml, 9.7 mmol) in Et2O (30 ml) at 0° C. oxalyl chloride (0.94 ml, 10.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hour, then, the solvent was evaporated under reduced pressure. The crude was dissolved in CH2Cl2 (40 ml) and a solution of AlCl3 (4.75 g, 35 mmol) in CH2Cl2 (32 ml) was added dropwise at 0° C. The mixture was stirred for 16 hours at room temperature, then, ice and 1M HCl were added until a clear mixture was obtained. After 1 hour, the phases were separated and the aqueous layer was extracted with CH2Cl2 (3×30 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated, affording 18 (1.2 g, 78%) as orange solid that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CCOP(=O)(Cc1cccc(C#N)n1)OCC
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Yield: 22.5 %

Procedure:
Diethyl (6-cyano-2-pyridyl)methylphosphonate (1.4 g, 5.8 mmol) and methyl thiosalicylate (1.9 g, 11.6 mmol) were dissolved in toluene (8 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 13 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (10:1, v/v) were collected, concentrated and recrystallized from diisopropyl ether-ethanol to give the titled compound (510 mg, 22%) as pale yellow crystals.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)COS(C)(=O)=O)[CH2:6]2.O.[CH2:27](O)[CH3:28]>>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:20]=[CH:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:28][CH:27]=1)[CH2:6]2
Reactant: CCO
Reactant: Cc1ccc2c(c1)CN(C(COS(C)(=O)=O)c1ccccc1)C2=O
Agent: [Na]
Solvent: O
Product: Cc1ccc2c(c1)CN(CC=Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under argon sodium metal (0.58 g, 24.37 mmol) was slowly added to anhydrous ethanol. After all the sodium was reacted methanesulfonic acid 2-(5-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl ester (5.61 g, 16.25 mmol) dissolved in ethanol was added to the reaction mixture and the solution was stirred for 6 h at room temp. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was used in the next step without further purification. Yield 3.64 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10]3[N:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:27]1[CH2:31]OC[CH2:28]1>>[CH:28]1([C:8]2([OH:17])[C:7]3[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:12][CH2:11][C:10]3[N:13]=[CH:14][CH:15]=[CH:16][C:9]2=3)[CH2:27][CH2:31]1
Reactant: COc1ccc2c(c1)C(=O)c1cccnc1CO2
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(O)(C1CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one (5.0 g) in THF (50 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (25 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give 5-cyclopropyl-5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-ol (5.0 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (3.65 g, 24 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (5.00 g, 24 mmol), HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6] (11.0 g, 29 mmol) in anhydrous DMF (30 mL) is added DIPEA (8.30 mL, 50 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (400 g silica gel, gradient elution: 10-80% EtOAc in heptane) to give a pure product (3) as white solid (5.5 g, 67%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[N:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[C:7]=[O:8]>C(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:7](=[O:8])[NH:6][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CNCCO
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N(C)CCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.1 %

Procedure:
To an ice-cooled solution of N-methylethanolamine (0.600 g, 7.99 mmol) in DCM (80 mL) was added methyl 4-isocyanatobenzoate (1.56 g, 8.79 mmol). After 20 minutes the coolant was removed and the reaction mixture was stirred for 2 hours. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0 to 100% ethyl acetate/iso-hexane to afford the title compound (2.26 g, 112%).
Reaction SMILES: Cl.C([O:9][C:10]([C:12]1([C:15](=[O:47])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:19][C:18]=2[F:46])[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1.[OH-].[Na+]>O.C(OCC)(=O)C>[F:46][C:18]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)=[O:32])[CH:25]=2)[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C:12]1([C:10]([OH:11])=[O:9])[CH2:14][CH2:13]1)=[O:47]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester hydrochloride (2 g) was dissolved in water (20 ml) and ethyl acetate (20 ml), and a 2N aqueous solution of sodium hydroxide (4 ml) was added, and the layers were separated. The organic layer was washed with water and concentrated. Addition of tetrahydrofuran and subsequent concentration was repeated three times. The residue was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (1.6 ml), and palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.2 MPa) for 5 hours. Tetrahydrofuran (4 ml) and methanol (6 ml) were added to the reaction mixture, which was filtered. The residue was washed with 90% aqueous methanol (3 ml). Tetrahydrofuran (12 ml) and the seed crystals obtained in (Method 1) were added to the filtrate, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (32 ml) was added, and the mixture was stirred for 14 hours. The crystals were filtered and dried to give the title compound (1.2 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][O:33]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:9]([O:10]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:8]2[F:53])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:9]([OH:10])[C@@H:8]2[F:53])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: F[C@H]1[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
Compound 4 (0.10 g, 0.12 mmol) was dissolved in 10% CF3COOH in CHCl3 (10 mL) and stirred at room temperature in a stoppered flask for 60 min. The reaction mixture was evaporated to dryness in vacuo, the oily residue was purified by flash chromatography (EtOAc/hexane 5:1, 2 cm×15 cm), appropriate fractions pooled, solvent removed in vacuo and the white residue crystallized from MeOH/H2O to give 25 mg (60%) of compound 6 as white crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C:17](OCC)=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>>[NH2:24][CH2:23][CH2:22][NH:25][C:17](=[O:18])[CH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN
Reactant: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Product: NCCNC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Yield: 80 %

Procedure:
A mixture of 1.6 g (5.7 mmol) of ethyl (2-phenylindol-3-yl)acetate and 15 ml of ethylenediamine was heated at reflux overnight. The excess diamine and the formed water were removed by distillation at 90° C. in vacuo, and the crude product was chromatographed with dichloromethane/ethanol 1:1 to afford 1.35 g (80%) of N-(2-aminoethyl)-(2-phenylindol-3-yl)acetamide as a yellow crystalline solid. The amide and 20 ml of HMDS were heated at reflux under argon overnight. The crystals formed upon cooling were collected by filtration, dissolved in ethanol, and traces of HMS were stripped off along with ethanol. The title imidazoline was purified by chromatography with dichloromethane/ethanol 7:3, dissolved in ethanol and treated with ethanolic HCl to form a hydrochloride salt which was recrystallized from EtOH/EtOAc to yield 0.45 g (31%) of colorless crystals along with 0.32 g of the product salt from the mother liquid (54% overall yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:21][CH:22]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2CCCc3ccccc32)cc1
Yield: 61 %

Procedure:
To a solution of 1-(4-methoxycarbonylbenzoyl)-1,2,3,4-tetrahydroquinoline (22.7 g) in methanol (300 ml) is added 5% aqueous sodium hydroxide solution (150 ml) and the mixture is refluxed for 2 hours. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted hydrochloric acid, extracted with diethyl ether, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting crystal is collected by filtration to give 1-(4-carboxybenzoyl)-1,2,3,4-tetrahydroquinoline (13.2 g) as white powder, m.p. 181-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18](Br)([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(C)Br
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Product: CC(C)N1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and iso-propylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 306 (M+, 30), 291 (bp), 206 (25), 193 (15), 179 (20).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][C:15]2=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][C:15]2=[O:18])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a solution of 4-(2-methoxycarbonyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 12.0 mmol) in anhydrous THF (75 mL) was slowly added a solution of methyl magnesium bromide in diethyl ether (3 M, 6 mL, 18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h, then allowed to warm to RT and stirring was continued for 72 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and an aqueous solution of ammonium chloride. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (598 mg, 20%). To a solution of 4-(2-oxo-azetidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (595 mg, 2.34 mmol) in DCM (6 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (325 mg, 90%).