Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:25]([O:27][CH3:28])=[O:26])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]([O:14]CC3C=CC=CC=3)=[CH:9][CH:10]=2)[O:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1([C:25]([O:27][CH3:28])=[O:26])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Agent: [Pd]
Solvent: CO
Product: CCCc1c(O)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
920 mg (2.41 mmole) of the compound from Example 38 was dissolved in 50 ml methanol and 92 mg 5% palladium on carbon added. The suspension was hydrogenated at room temperature and 2 psi for 2.5 hours. Removal of the catalyst by filtration and removal of methanol by rotary evaporation gave 640 mg (91%) of the title compound as a light orange oil, which began to crystallize on standing, homogeneous by thin layer chromatography in 20% ethyl acetate-hexane.
Reaction SMILES: [I-:1].[C:2]([O:6][C:7]([NH:9][C@@H:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:14]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16](=O)[C@H:11]12)=[O:8])([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.P(Cl)(Cl)Cl>O>[I-:1].[C:2]([O:6][C:7]([NH:9][C@@H:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:26])=[C:14]([CH2:18][N+:19]3[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2S(=O)C1
Agent: [I-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate 1-oxide iodide (20 g) and N,N-dimethylformamide (100 ml) was stirred at -35° C. Phosphorus trichloride (7.8 g) was added thereto and stirred for 10 minutes at the same temperature. The reaction mixture was added to water (600 ml). The precipitates were collected by filtration and washed with water to give benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (15.4 g).
Reaction SMILES: [Li+].[Cl-].FC(F)(F)S(O[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=1)(=O)=O.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:25]([F:36])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 85 °C
Yield: 52.4 %

Procedure:
Pd(PPh3)4 (87 mg, 0.0075 mmol), LiCl (190 mg, 4.5 mmol), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (0.50 g 1.5 mmol), 4-(trifluoromethoxy)phenylboronic acid (0.43 g, 2.1 mmol) and aq Na2CO3 (2 mL, 2N solution) were mixed in 5.2 mL DME and heated at 85° C. for 3 h followed by cooling to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM (10 mL), aq Na2CO3 (10 mL, 2N solution) and conc NH4OH (0.6 mL). The layers were separated and the aqueous layer extracted with DCM (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification by column chromatography (SiO2, Heptane/Ethylacetate/DCM 5:1:1) gave tert-butyl 4-[4-(trifluoromethoxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (0.27 g, 52%). The product and 5% Pd/C (30 mg) was mixed in MeOH (3 mL) and stirred under H2 (1 atm) for 24 h. The mixture was filtered through Celite and concentrated to give tert-butyl 4-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate (0.23 g, 86%). The crude product was dissolved in a mixture of TFA (2 mL) and DCM (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (0.14 g, 58%, three steps 26%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[S:16]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[O:15][C:21]([C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)=[N:23][N:24]=1
Reactant: NNC(=O)c1ccsc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccsc2)o1
Yield: 38 %

Procedure:
As described for example 121, 5-methyl-3-phenylisoxazole-4-carboxylic acid (357 mg, 1.76 mmol) using thiophene-3-carboxylic acid hydrazide instead of thiophene-2-carboxylic acid hydrazide was converted to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 207 mg, 38%) which was obtained as a yellow semisolid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15]([OH:16])=[N:14][N:13]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.C(OCC)C>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:15]([OH:16])=[N:14][N:13]([C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(O)cc3)nc(O)c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
7-Chloro-1-hydroxy-3-(4-methoxyphenyl)-3,4,5,10-tetrahydropyridazino[4,5-b]-quinoline-4,10-dione (0.800 g, 2.16 mM) was stirred in methanesulfonic acid (16 mL) to give an amber solution. This solution was heated to 160° C. for 6 hours and cooled to room temperature. Addition of ethyl ether (250 mL) gave a tan precipitate which was stirred for 1 hour. The solid was collected and washed with methanol/ether to give the title compound (0.661 g, 77%) as a tan powder, mp 393°-395° C.; MS(CI): 356 (M+H). Analysis for C17H10CNl3O4 ·0.2CH3SO3H·1.3 H2O: Calculated: C, 51.86; H, 3.39; N, 10.55; Found: C, 51.76; H, 3.02; N, 10.37; NMR: 13.30 (s, 1H, exchangeable), 12.5 (v br s, 1H, exchangeable), 10.8 (br s, 1H, exchangeable), 8.29 (d, J=8.76 Hz, 1H,), 8.23 (br s, 1H), 7.61 (br d, J=8.76 Hz, 1H,), 7.45 (d, J=8.81 Hz, 2H), 6.88 (d, J=8.81 Hz, 2H), 2.32 (s, 0.5H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Yield: 72 %

Procedure:
A suspension of 4-bromo-2-(methylsulphonyl)benzoic acid (5.00 g; 17.9 mmol) in MeOH (100 ml) was treated with conc. sulphuric acid and the resulting mixture was heated at reflux for 5 days. The mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc then washed with water, twice with NaHCO3 (sat) then with brine, dried on MgSO4, filtered and concentrated to give the title compound as a yellow solid (4.00 g, 72%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[N:8][C:7]([S:11][CH3:12])=[CH:6][N:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[Br:3][C:4]1[C:9](=[O:10])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([S:11][CH3:12])=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1cnc(Br)c(O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cnc(Br)c(=O)n1CC(=O)OC(C)(C)C

Procedure:
SODIUM HYDRIDE (40 MG OF A 60% DISPERSION IN MINERAL OILS, 1.0 MMOL) WAS ADDED TO A STIRRED SOLUTION OF 2-BROMO-3-HYDROXY-5-METHYLTHIOPYRAZINE (100 MG, 0.45 MMOL) IN DRY THF (10 ML) UNDER ARGON. T-BUTYL BROMOACTATE (202 MICROL, 1.5 MMOL) WAS ADDED AND THE REACTION WAS STIRRED FOR 16 H. THE VOLATILES WERE EVAPORATED IN VACUO AND THE RESIDUE WAS PARTITIONED BETWEEN WATER AND METHYLENE CHLORIDE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE CRUDE PRODUCT WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (30% ETHYL ACETATE/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: CN(C)CCCN=C=NCC.[CH:12]([NH:15][C:16]1[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH3:13].[N:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[C:24]=S>O1CCCC1.C(OCC)(=O)C>[CH:12]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]=[C:24]1[NH:23][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Nc1ccccc1N
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2nc3ccccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 206 mg, 1.34 mmol) is added to a solution of N1-isopropylbenzene-1,2-diamine (100 mg, 0.67 mmol) and methyl 4-isothiocyanatobenzoate (138 mg, 0.67 mmol) in tetrahydrofuran. The reaction may be heated to reflux for a time period (for example 2 hours) and cooled to room temperature. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any method, including Biotage column chromatography to give methyl 4-(1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (122 mg)
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:21].[K+].[K+].CC#N.O>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: c1cc2c(cc1OCC1CCCCC1)CCCCC2
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCCc2cc(OCC3CCCCC3)ccc21

Procedure:
A mixture of 2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (0.50 g, 1.94 mmol), potassium persulfate (1.57 g, 5.82 mmol), copper(II) sulfate pentahydrate (0.48 g, 1.94 mmol) and CH3CN/H2O (1:1, 13 mL) were heated at reflux for 45 min. After cooling the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate, concentrated, and chomatographed over silica gel (20% EtOAc/hexane) to a white solid (0.46 g, 87%). MS [M+H]+ 273, m.p. 86-88° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C[O-].[Na+].CO.[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OC)(OC)OC>[CH:16]1([CH:22]=[CH:1][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(C=CC1CCCCC1)c1cccc(O)c1
Reaction time: 0.67 h

Procedure:
A mixture of 3-hydroxyacetophenone on Wang resin (6.0 g, 5.52 mmol) was swelled in trimethyl orthoformate (60 mL) for 10 min. 25% NaOMe in MeOH (2.4 g, 11.0 mmol) was added and the mixture was stirred for 40 min. Cyclohexanecarboxaldehyde (1.9 g, 16.56 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 6.62 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O.C(O)C.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)c(N)c1
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g; 43.1 mmol), ethanol (100 ml), acetic acid (100 ml) and iron powder (9.63 g; 172 mmol) was heated at 100° C. for 2 h. The mixture was cooled to room temperature and diluted with water (300 ml). The suspension was neutralized with solid potassium carbonate. The mixture was filtered on a plug of celite and extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure to afford 2-bromo-5-methoxyaniline, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:31])[C:22]([O:24][CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][O:27]1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:6][C:5]1[CH:18]=[CH:19][C:2]([O:1][CH:21]([CH3:31])[C:22]([O:24][CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][O:27]3)=[O:23])=[CH:3][CH:4]=1)[CH:16]=[N:15]2
Reactant: Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Reactant: CC(Br)C(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)OCC1CCCO1
Yield: 85 %

Procedure:
To a 500 milliliter roundbottom flask were added 0.055 mole of 2-(4-hydroxyphenoxy)-6-chloroquinoxaline, 0.055 mole of 2-tetrahydrofuranylmethyl 2-bromopropanoate, 0.110 mole of anhydrous potassium carbonate, and 250 milliliters of acetonitrile. The mixture was refluxed for 5.5 hours and the solvent removed. The residue was filtered through a column of alumina with dichloromethane. Solvent removal and recrystallization from boiling hexane resulted in an 85% yield of 2-tetrahydrofuranylmethyl 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propanoate. The material melted over a range of 52-55° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:11][C:10]=1[F:30])C1C=CC=CC=1>C1COCC1.[Pd].[H][H]>[CH2:28]([CH:25]1[CH2:24][CH2:23][CH:22]([CH:19]2[CH2:20][CH2:21][CH:16]([C:12]3[CH:11]=[C:10]([F:30])[C:9]([NH2:8])=[C:14]([F:15])[CH:13]=3)[CH2:17][CH2:18]2)[CH2:27][CH2:26]1)[CH3:29]
Reactant: CCC1CCC(C2CCC(c3cc(F)c(N(Cc4ccccc4)Cc4ccccc4)c(F)c3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC1CCC(C2CCC(c3cc(F)c(N)c(F)c3)CC2)CC1

Procedure:
40.8 g of dibenzyl[4-(4′-ethylbicyclohexyl-4-yl)-2,6-difluorophenyl]-amine are hydrogenated using 10 g of Pd/C/H2 (5%) in 400 ml of THF. Conventional work-up gives 4-(4′-ethylbicyclohexyl-4-yl)-2,6-difluorophenylamine.
Reaction SMILES: F[B-](F)(F)F.C[O+](C)C.[F:10][C:11]([F:52])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@@:30]3([NH:34][C:33](=O)[CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([BH3-])#N.[Na+].Cl.C([O-])(O)=O.[Na+]>ClCCl.CO>[F:52][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@@:30]3([NH:34][CH2:33][CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1
Reactant: COC(=O)C1CC(=O)N[C@@]12CCN(C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H](c1ccc(F)cc1C)C2
Agent: C[O+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCN[C@@]12CCN(C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H](c1ccc(F)cc1C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A solution of trimethyloxonium tetrafluoroborate (33.5 mg, 0.226 mmol) and methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-4-carboxylate (Intermediate 40, 70 mg, 0.113 mmol) in Dichloromethane (DCM) (3 ml) was stirred at rt overnight. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated. The residue obtained was dissolved in Methanol (3 ml) and to the solution, cooled to 0° C., was added sodium cyanoborohydride (28.5 mg, 0.454 mmol). A solution of 1.25M HCl in MeOH was added maintaining the pH around 3-4 and the reaction was left stirring at rt for 2 hrs. To the solution NaHCO3 saturated solution and DCM were added and the aqueous layer was extracted with DCM. Organic layers were combined and filtered through a phase separator tube and concentrated. The crude was purified by SP4 (12M cartridge, eluting from 90%:10% to 50%:50% Cy:EtOAc). Relevant fractions were collected obtaining the title compound (12 mg, 0.020 mmol, 17.54% yield) as a single diasteroisomer. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (s, 1H) 7.68 (s, 2H) 7.13 (dd, 1H) 6.89 (dd, 1H) 6.76 (t, 1H) 5.20-5.40 (m, 1H) 4.43 (dd, 1H) 3.61 (s, 3H) 3.11-3.19 (m, 1H) 3.01-3.10 (m, 1H) 2.89-2.97 (m, 1H) 2.80-2.88 (m, 1H) 2.71 (s, 3H) 2.45-2.55 (m, 1H) 2.32 (s, 3H) 1.85-2.05 (m, 2H) 1.61-1.71 (m, 1H) 1.53-1.60 (m, 2H) 1.46 (d, 3H) 1.38-1.50 (m, 1H); Despite some signals' overlapping (H10 eq and H6 eq), causing missing information, stereochemistry could be assigned on the basis of the following noe data:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N)C[C@@H]1C)CCC3
Temperature: 25 °C
Yield: 104.2 %

Procedure:
cis-4-Benzyloxycarbonylamino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 2) (500 mg), 10% palladium on carbon (150 mg), and a mixture of ethanol-cyclohexene (1:1, 50 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 5% methanol/ethyl acetate afforded the title compound (350 mg). MS m/z 258 (M+-16); 1H NMR (CDCl3) δ1.1 (d, 3H), 1.3 (t, 3H), 2.1 (m, 2H), 2.4 (m, 1H), 4.2 (m, 2H), 4.5 (m, 1H), 3.8 (dd, 1H), 7.2 (s, 2H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([Cl:23])[CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[C:22]([N:21]=1)=[C:13]1[C:14]([C:4]3[C:3]([S:9](=[O:11])(=[O:10])[NH:12]1)=[CH:2][CH:7]=[C:6]([Cl:8])[CH:5]=3)=[CH:15][CH:16]=2
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3ccc(Cl)nc23)-c2cc(Cl)ccc21
Yield: 42.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(2-chloro-quinolin-8-yl)-benzenesulfonamide (Intermediate 287) (0.1 g, 0.27 mmol), t-butyl nitrite (0.05 ml, 0.41 mmol) and AcOH:THF (1 ml: 2 ml), gave the title compound (0.04 g, 45%) after purification by column chromatography with DCM/MeOH (90:10) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)[N:7]=2)[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1>O1CCOCC1>[F:30][C:29]([F:32])([F:31])[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([N:6]3[CH:5]=[C:4]4[C:8]([CH:9]=[CH:10][C:2]([NH:1][C:41]([NH:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)=[O:42])=[CH:3]4)=[N:7]3)[CH2:16][CH2:15]2)=[CH:23][CH:22]=1)([OH:33])[C:25]([F:26])([F:27])[F:28]
Reactant: Nc1ccc2nn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2c1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc2nn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2c1
Yield: 11.1 %

Procedure:
2-(4-((4-(5-Amino-2H-indazol-2-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.212 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.318 mmol, 0.068 g) were combined and stirred in dioxane (2 mL) at 100° C. in a Reactivial. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (14 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16](O)=[O:17])=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>ClCCl>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16]([N:42]([O:43][CH3:44])[CH3:41])=[O:17])=[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2.83 h

Procedure:
To a solution of (E)-3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid (2.0 g, 6.0 mmol) in dichloromethane (25 ml) at −5° C. is added triethylamine (0.668 g, 6.6 mmol).and pivaloyl chloride (0.725 g, 6.0 mmol). After stirring at 0° C. for 170 min, N,O-dimethyl-hydroxylamine hydrochloride (0.59 g, 6.0 mmol) and triethylamine (1.22 g, 12.0 mmol) are added. After stirring in an ice bath for 90 min, and at room temperature for 30 min, more N,O-dimethylhydroxylamine hydrochloride (0.177 g, 1.8 mmol) is added and the reaction is stirred at room temperature for 17 h. After quenching with 0.2M citrate buffer pH5 (25 ml), the organic phase is separated and washed with 0.2M citrate buffer pH5 (25 ml), 0.2M phosphate buffer pH7 (25 ml) and water (25 ml). The water phases are extracted with dichloromethane (2×20 ml). Combined organic phases are dried over magnesium sulphate, evaporated, and the crude product chromatographed on silica gel (hexane/ethyl acetate 2:1) to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-N-methoxy-N-methyl-acrylamide (7). MS (ES): [M+H]+ 377, Mp. 155-156° C.