Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:30]([C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:28]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(N2CCOCC2)c1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 89.8 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 3-morpholin-4-yl-benzaldehyde (24.9 mg, 0.130 mmol) were reacted to produce 54 mg (90%) of the title compound. mp: 232-234° C., 1H NMR (300 MHz, DMSO-d6): 12.90 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 6.95 (d, J=8 Hz, 1H), 6.41 (br s, 1H), 6.31 (br s, 1H), 5.17 (t, J=8 Hz, 1H), 3.93 (s, 3H), 3.45 (m, 1H), 3.18 (s, 1H), 2.87 (s, 1H), 2.74 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.89 (s, 1H), 1.38 (d, J=8 Hz, 1H). MS: 509, 511 (M+H), HPLC: 2.43 min (G method).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]([CH3:27])=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[C:25]=2[CH3:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]([CH3:27])=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[C:25]=2[CH3:26])=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc2c(c(C)c1OCCCCSc1ccc(Cl)c(Cl)c1)COC(=O)N2
Reactant: OO
Product: Cc1cc2c(c(C)c1OCCCCS(=O)c1ccc(Cl)c(Cl)c1)COC(=O)N2

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-5,7-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>O>[C:11]([O:10][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC/C=C\CO
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC/C=C\COC(C)=O

Procedure:
Cis-2-nonenol (2.9 g, 0.03 mole), acetic anhydride (3.1 g, 0.045 mole) and pyridine (15 ml) is heated at reflux for 3 hours. The solution is cooled and diluted with water. The organic layer is separated and washed successively with 3% sulfuric acid, and water. The solution is dried over sodium sulfate and distilled under vacuum to yield cis-2-nonenyl acetate, b.p. 58° - 62°C/0.1 mm.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:21][CH:22]=1
Reactant: COc1cc(C=Nc2ccc(SC)cc2)cc(OC)c1OC
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(CNc2ccc(SC)cc2)cc(OC)c1OC
Yield: 94.8 %

Procedure:
From 108e (11.0 g, 35.0 mmol) and NaBH4 (6.6 g, 175 mmol), a similar procedure as described in 109a gave 109e (10.6 g, 94.9%) as an oil: 1H NMR (200 MHz, DMSO-d6) δ7.07 (d, J=8 Hz, 2H), 6.67 (s, 2H), 6.57 (d, J=8 Hz, 2H), 6.23 (t, J=6 Hz, 1H), 4.10, (d, J=6 Hz, 2H), 3.73 (s, 6H), 3.62 (s, 3H), 2.31 (s, 3H). EIMS m/e 319 (M+, 69).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:16]([O-])=O)[N:7]=1)(=[O:3])[CH3:2]>CC(C)=O.[Ni]>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:16])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)OCc1ccc2c(N)cccc2n1

Procedure:
Under hydrogen atmosphere, a solution that consists of 410 mg (1.67 mol) of 2-(acetoxymethyl)-5-nitroquinoline in 61 ml of acetone can be stirred in the presence of 410 mg of Raney nickel for 2 hours at room temperature. It is suctioned off on Celite and rewashed with acetone. After removal of the solvent and subsequent chromatography on silica gel with hexane-ethyl acetate (10-100%), 230 mg (64% of theory) of the product is obtained.
Reaction SMILES: C(O[C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14]Br)C.[CH3:17][O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.NC1C=CC=CC=1>>[CH3:17][O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:14][C:6]3[C:5](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3)[C:4]2=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: Nc1ccccc1
Product: COC(=O)CCc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and 3-(4-amino-phenyl)propionic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-propionic acid methyl ester as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>CO.O1CCCC1.[Pd]>[ClH:25].[C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)(Cc1ccccc1)c1ccc(O)cc1
Reaction time: 6 h

Procedure:
To a solution of 1-phenyl-2-[4-(phenylmethoxy) phenyl)-2-propylamine (3.50 g, 0.011 mol) in methanol (100 mL), tetrahydrofuran (50 mL) and 1N hydrochloric acid (20 mL) was added 5% palladium on carbon (0.8 g) and the mixture was shaken on a Parr apparatus at approximately 40 psi for 6 h. The catalyst was removed by filtration and the solvent removed under vacuum. Crystallization from 2-propanol and ether and vacuum drying at 80° C. for 48 h provided 1.3 g of 1-phenyl-2-(4-hydroxyphenyl)-2-propylamine hydrochloride; mp 160°-161° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[NH:26])[CH:18]=2)[CH:13]=[C:12]([CH2:28][C:29]([OH:31])=[O:30])[C:11]1=[O:32])[CH3:9].[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[NH:26])[CH:18]=2)[CH2:13][CH:12]([CH2:28][C:29]([OH:31])=[O:30])[C:11]1=[O:32])[CH3:9]
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCNC(=N)N)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(CC(=O)O)Cc2ccc(OCCCNC(=N)N)cc21
Reaction time: 72 h
Yield: 14.2 %

Procedure:
A solution of [1-ethyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]-acetic acid trifluoroacetate (400 mg, 0.87 mmol) in 20 ml of methyl alcohol and 0.4 g of 10% Pd/C was hydrogenated under 50 psi of hydrogen for 3 days. The reaction mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo to a residue which was dissolved in 10 ml of hot acetic acid and hydrogenated over 0.4 g of 10% Pd/C for 3 days. The reaction mixture was filtered through diatomaceous earth and the filter cake washed with hot methyl alcohol. The combined filtrates were evaporated in vacuo to a residue of oil and solid. The residue was purified by chromatography on a reverse phase column to afford 57 mg of the title compound as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:17](=[O:25])[C:16]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=1[CH3:34]>C(OCC)(=O)C>[CH2:12]([O:11][C:9]([O:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:17](=[O:25])[C:16]=1[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32])=[O:10])[CH3:13]
Reactant: Cc1cc(C)c(-c2c(O)cc(C(C)(C)C)oc2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C(C)(C)C)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
2.0 g (20 mmol) of triethylamine and subsequently 2.2 g (20 mmol) of ethyl chloroformate in 20 ml of ethyl acetate are added dropwise at 0° C. to 5.7 g (20 mmol) of 4-hydroxy-6-tert.-butyl-3-(2,4,6-trimethylphenyl)pyrone in 50 ml of ethyl acetate. The mixture is stirred for 20 hours at 20° C. and filtered, the organic phase is washed with semi-concentrated sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35-70 μm) using toluene/acetone (20:1 parts by volume). 6.0 g of 4-ethoxycarbonyloxy-6-tert.-butyl-3-(2,4,6-trimethylphenyl)pyrone are obtained (yield: 84% of theory). M.p.=92°-94° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C(Cl)Cl>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5cc[nH]c(=O)c5n(C5CCCC5)c4n3)nn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2c3cnc(Nc4ccc(N5CCNCC5)nn4)nc3n(C3CCCC3)c12

Procedure:
Compound 162 was treated with 1:1 TFA/DCM (2 mL) at room temperature for an hour. The solvent was evaporated. The residue was re-dissolved in 4 mL methanol and purified on a C-18 reverse phase column (150×30 mm, 4 micro) using Mass directed preparative HPLC and gradient elution of acetonitrile in water containing 0.1% TFA to provide the title compound 161 as a TFA salt. LCMS retention time (minutes): 0.793. LCMS-ESI (POS), M/Z, M+1: 432.2
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([SiH:12]([CH3:14])[CH3:13])[C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3].[BH4-].[Na+]>CCO>[CH2:1]([C:4]1[CH:5]=[C:6]([SiH:12]([CH3:14])[CH3:13])[C:7]([CH2:10][OH:11])=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(C=O)c([SiH](C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCc1cnc(CO)c([SiH](C)C)c1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 5-allyldimethylsilyl-2-pyridinecarboxaldehyde (8 Scheme 27, 3.1 g, 15 mmol) in EtOH (80 mL) was added sodium borohydride (1.1 g, 30 mmol) portion-wise for 10 min at room temperature. After further stirring for 30 min, excess sodium borohydride was quenched by slow addition of acetone (5 mL) to the reaction mixture. The solvent was evaporated and the residue was extracted with ethyl acetate/brine. The organic layer was dried (Na2SO4) and concentrated to afford an oil (2.7 g, 87%); 1H NMR (300 MHz, CDCl3) δ 0.27 (s, 6 H), 1.72 (dt, J=6.75, 1.05 Hz, 2 H), 4.74 (s, 2 H), 4.80 (dd, J=3.00, 1.20 Hz, 1 H), 4.48 (d, J=1.20 Hz, 1 H), 5.36 (bs, OH, 1 H), 5.69 (ddt, J=14.70, 9.30, 7.80 Hz, 1 H), 7.33 (d, J=7.80 Hz, 1 H), 7.76 (d, J=7.80 Hz, 1 H), 8.54 (s, 1 H), 13C NMR (75 MHz, CDCl3) −3.4 (2C), 23.5, 64.6 114.3, 120.6, 131.9, 133.9, 142.6, 153.0, 160.8. HRMS (EI) calcd for C11H17NOSi 207.1079, found 206.0999.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][N:31]4C(=O)C5C(=CC=CC=5)C4=O)[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:31][CH2:30][CH2:29][N:24]([S:25]([CH3:28])(=[O:26])=[O:27])[C:12]1[C:13]([CH:21]2[CH2:22][CH2:23]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of Compound (6) (92 mg, 0.14 mmol) and hydrazine hydrate (0.15 mL) in ethanol (7 mL) was stirred at RT for 16 h. The resulting suspension was filtered and the filtrate was concentrated to give a crude oil which then was partitioned between EtOAc (5 mL) and water (2 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×3 mL). The combined organic phase was dried (MgSO4) and the solvent was removed in vacuo to give 6-[(2-aminoethyl)(methylsulfonyl)amino]-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (7) (68 mg, 93%). ESI-MS m/z calculated for [M+H]+: 506.08/508.09; found: 505.88/507.89.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:9]=1[O:17][CH3:18])[C:4]([OH:6])=[O:5])#[N:2].[BH4-].[Na+]>CCO>[C:1]([CH:3]([CH2:7][C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:9]=1[O:17][CH3:18])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: COc1ccc(Br)c(C=C(C#N)C(=O)O)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Br)c(CC(C#N)C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of α-cyano-6-bromo-2,3-dimethoxycinnamic acid (41.7 g, 0.13 mole), and absolute EtOH (1 L) was stirred under N2 at 0° as NaBH4 (42 g. 1.11 mole) was added portionwise. The reaction mixture was stirred at room temperature for 0.5 hr., and at reflux for 0.75 hr. After cooling to room temperature, EtOH was removed (in-vacuo). Water was added to the residue, followed by 10% HCl until acidic. The solution was extracted with CH2Cl2. The combined organic layers were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 39.25 g cream colored solid; mp 120°-2°; M+ 313.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([Cl:21])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(Cl)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
35.5 g (0.143 mol) of bis(4-fluorophenyl)acetic acid were stirred at the reflux temperature in 150 ml of thionyl chloride for 4.5 hours and the excess thionyl chloride was evaporated off in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[CH3:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=1.COC(=O)C(=CC1C=CC(F)=CC=1)CC(O)=O>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][N:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[CH3:17]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1C
Reactant: CCS(=O)(=O)c1ccc(Br)nc1
Agent: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)c(C)c3ccc(F)cc23)nc1
Yield: 74.5 %

Procedure:
Starting with (6-fluoro-4-hydroxy-1-methyl-naphthalen-2-yl)acetic acid methyl ester (18 mg, 0.073 mmol) and 2-bromo-5-ethanesulfonyl-pyridine (27 mg, 0.109 mmol), using a method analogous to the one described for the methyl ester of example 1-1, [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-1-methyl-naphthalen-2-yl]-acetic acid methyl ester (22.7 mg, 75%) was obtained as a light yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C1C[O:23][CH2:22]C1>>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]
Reactant: Brc1cccnc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=Cc1ccncc1Br
Temperature: -60 °C
Yield: 76 %

Procedure:
A solution of di-isopropylamine (3.44 g, 34.1 mmol) was cooled to -78° C. and treated with n-butyl lithium 1.6M, 34.1 mmol). A solution of 3-bromopyridine (4.71 g, 30 mmol) in THF (5 ml) was added dropwise trying to keep the temperature below -70° C. The reaction was very exothermic, a solid precipitated and THF (2 ml) was added to improve stirring. The temperature rose to -45° C., after cooling to -60° C. and added remaining pyridine. DMF (2.49 g) in THF (15 ml) was added and the reaction stirred at -65° C. for 30 minutes. Water was added to quench the reaction and the reaction allowed to warm to ambient temperature. The reaction was partitioned between ethyl acetate/water and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated and the residue was subjected to chromatography (eluting with diethyl ether/hexane) to give 3-bromo-4-pyridinecarbaldehyde (1.4 g, 76%).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:33]=[CH:32][C:8]2[O:9][C:10]3[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=3[CH2:12][N:13]([C:14](=[O:27])[CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]=2[CH:6]=1>C(O)C>[NH2:16][CH2:15][C:14]([N:13]1[CH2:12][C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[O:9][C:8]2[CH:32]=[CH:33][C:5]([Cl:4])=[CH:6][C:7]1=2)=[O:27]
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
Hydrazine monohydrate (1.25 mL) and 8-chloro-10,11-dihydro-10[(1,3-dihydro-1,3-dioxo-2H -isoindol-2-yl)acetyl]-dibenz[b,f][1,4]-oxazepine (5.00 grams) were refluxed in absolute ethanol (125 mL) for 4 hours. The resulting mixture was filtered hot, and the collected solid was rinsed twice with ethanol, and then with hot methylene chloride. The filtrate and rinses were combined, evaporated in vacuo, and purified by flash chromatography through silica gel 60 (300 mL) using 95:5:0.5 chloroform:methanol:ammonium hydroxide. Trituration of the purified product with ethyl ether/hexane yielded the title compound as a white solid. Yield: 2.91 grams (84%). Mp: 108°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([NH2:20])=[C:15]([NH2:21])[CH:14]=1>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:20][C:16]2[CH:17]=[C:18]([F:19])[C:13]([F:12])=[CH:14][C:15]=2[N:21]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cc(F)c(F)cc1N
Solvent: C1CCOC1
Product: Cl
Product: Fc1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2cc1F
Temperature: 70 °C

Procedure:
2,6-Dichlorophenyl isothiocyanate (0.3 g) and 4,5-difluoro-1,2-phenylenediamine (0.21 g) were stirred at RT for 4 h in THF (15 ml) and then concentrated and dried in a high vacuum. The foamy residue was dissolved in ethanol and heated to 70° C. with stirring. Methyl iodide (0.73 ml) was then added dropwise.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[NH:24]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:25]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)(4-trifluoromethyl-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.5 %

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.293 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.84 g) in acetonitrile (50 ml) were treated under ice cooling and an argon atmosphere with N-methyl-morpholine (3.034 g) and the mixture was stirred for 2 h at 0° C. Then 4-isopropyl-phenylamine (1.42 g) in acetonitrile was added dropwise and the reaction mixture was stirred at RT for 48 h. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off. The residue was then triturated with AcOEt/diethyl ether/heptane to give the desired 4-(4-isopropyl-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.68 g) as white solid. MS (ESI): 347.28 (MH+)
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:17][CH:16]=1)C1C=CC=CC=1.CO[CH:30](OC)[CH2:31][NH2:32]>C(O)C>[NH:32]1[CH:31]=[CH:30][N:26]=[C:25]1[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=1
Reactant: COC(CN)OC
Reactant: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: CCO
Product: NCCCCc1ccc(OCCCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.2 %

Procedure:
Compound 2 (0.156 g, 0.425 mmol) was dissolved in anhydrous ethanol (10 mL). To the solution was bubbled anhydrous HCl gas for 3 min. The reaction vessel was sealed and the mixture was stirred at room temperature for 48 h, and then concentrated to dryness under vacuum. The resulting residue was dissolved in anhydrous methanol (5 mL). To the newly formed solution was added 2,2-dimethoxyethylamine (0.097 mL, 0.891 mmol) in one portion. After stirring at room temperature overnight, temperature was raised to reflux which was maintained for another 3 h before the mixture was cooled to ambient temperature. Solvent was removed under vacuum and the residue was treated with 1.2 N HCl aqueous solution at 80° C. for 2 hours. The mixture was then cooled to ambient temperature again and neutralized to pH˜9 with powder K2CO3. Water was completely removed under vacuum and the residue was dissolved in methanol. The methanol solution was loaded onto silica gel, and the product was eluted with a mixture of concentrated ammonium hydroxide/MeOH/CH2Cl2 (1.8:18:81.2, v/v), affording the product 21 (27 mg, 23% overall yield) as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 1.60 (m, 4H), 2.14 (m, 2H), 2.56 (t, 2H), 2.76 (t, 2H), 2.86 (t, 2H), 3.94 (t, 2H), 6.79 (d, 2H), 6.91 (s, 2H), 7.08 (d, 2H). m/z (APCI): 274 [C16H23N3O+H]+.