Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:30]([Br:31])=[CH:29][C:5]([CH2:6][C@H:7]([C:26]([OH:28])=O)[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][C:3]=1[Br:32].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([CH3:92])([O:77][C:78]([N:80]1[CH2:85][CH2:84][CH:83]([CH:86]2[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)[CH2:82][CH2:81]1)=[O:79])[CH3:76].C(NCC)C>O1CCCC1>[NH2:1][C:2]1[C:3]([Br:32])=[CH:4][C:5]([CH2:6][C@H:7]([C:26]([N:89]2[CH2:88][CH2:87][CH:86]([CH:83]3[CH2:82][CH2:81][N:80]([C:78]([O:77][C:75]([CH3:92])([CH3:76])[CH3:74])=[O:79])[CH2:85][CH2:84]3)[CH2:91][CH2:90]2)=[O:28])[NH2:8])=[CH:29][C:30]=1[Br:31]
Reactant: Nc1c(Br)cc(C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(C(=O)[C@H](N)Cc3cc(Br)c(N)c(Br)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.60 g (0.01 mol) of 4-amino-3,5-dibromo-N -(9-fluorenylmethoxycarbonyl)-D-phenylalanine, 1.35 g (0.01 mol) HOBt, 3.21 g (0.01 mol) TBTU, 1.29 g (0.01 mol) DIEA, 2.68 g (0.01 mol) 4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine and 150 ml of tetrahydrofuran was stirred for 2 hours at room temperature. After the reaction was complete 20 ml of diethylamine were added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 200 ml of dichloromethane and washed successively with 100 ml of saturated sodium chloride solution and saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The reddish oil remaining after elimination of the solvent was purified by column chromatography on silica gel (30-60 μm) using firstly dichloromethane, then FM4 as eluant. The title compound was obtained in the form of a colourless amorphous substance and in a yield of 4.31 g (73.3% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 gms of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid and 5.6 gms of triethyl amine was added to 25 ml of toluene. 5.1 gms of Pivollyl chloride was added and stirred the reaction mass at room temperature for about 2 hours. 4 ml of Morpholine in 25 ml of toluene was added to the reaction mass at 0° C. Stirred the reaction mass for about 30 minutes at 0-5° C. and 20 ml of water was added. To the reaction mass 30 ml of brine solution was added and organic layer was separated. Dried the separated organic layer over sodium sulfate. Distill off the solvent completely under reduced pressure at 50-55° C. The resulted oily mass was dissolved in 12 ml of toluene and 60 ml of hexane. Cooled the reaction mass and 12 ml of toluene was added. Stirred the reaction mass for about 1-2 hours at 0-5° C., filtered, washed with 5 ml of hexane and dried at 40-45° C. to get 10 gms of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[Cl:16][CH2:17][CH2:18][CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[O:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[ClH:16].[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][N:21]=2)[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#CC1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
To 50 ml of dimethylformamide was added 4.4 g of 4-cyano-4-phenylpiperidine hydrochloride, 6.4 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 10 g of milled potassium carbonate, and 0.01 g of potassium iodide. After stirring at 90° C. for three hrs, the mixture was cooled, filtered, and the filtrate was evaporated to an oil. The oil was stirred with 100 ml of water for ten mins and then extracted with ether. The ether solution was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the solvent was evaporated. The residue was filtered through a silica gel column with tetrahydrofuran. The eluant was evaporated to an oil. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give 2.4 g (29%) of product, mp 235° C. (dec). Recrystallization from ethyl acetate/methanol gave the analytical sample, mp 239° C.
Reaction SMILES: BrCC1C=C(C=CC=1)C[N:7]1[C:11](I)=[C:10](C=O)[CH:9]=[C:8]1[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CO>[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc[nH]1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 2-(trichloroacetyl)pyrrole (1) (10.00 g, 47.1 mmol) in MeOH (20 mL) was added K2CO3 (8.44 g, 61.2 mmol). The resulting mixture was stirred under reflux for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give 2 as a dark brown solid (5.50 g, 93%). 1H NMR (400 MHz, CDCl3) δ 9.49 (brs, 1H), 6.92-6.96 (m, 2H), 6.26 (m, 1H), and 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.05, 123.33, 122.79, 115.56, 110.66, and 51.72.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:17]
Reactant: CSc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A solution of 16.0 g (95 mmol) of 1-methylsulfanyl-4-nitro-benzene in 400 ml of DCM is mixed at room temperature with 24.6 g (100 mmol) of 3-chloroperoxybenzoic acid (about 70%). After 1 hour, the batch is diluted with DCM and washed with saturated NaHCO3 solution. The organic phase is dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 8:2). 7.6 g (41 mmol, corresponding to 43% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C(O)(C)(C)C>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CO
Product: Cc1c(CO)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 91.8 %

Procedure:
39.0 g (0.2 mol) of methyl 2-methyl-3-nitrobenzoate was dissolved in 600 ml of tert-butanol, and 19.0 g of sodium borohydride was added thereto. Under refluxing, 150 ml of methanol was dropwise added thereto over a period of 1 hour. The refluxing was continued further for 1 hour to complete the reaction. The reaction mixture was left to cool, and then water was added thereto. The solvent was distilled off under reduced pressure. To the residue, water and chloroform were added, and the organic layer was separated and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 30.7 g of 2-methyl-3-nitrobenzyl alcohol.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36])[O:10]C1(C)C)=O)(C)(C)C.Cl.COC(=O)[C@H](C)CN>>[NH2:8][C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[C@@H:11]([OH:10])[CH2:33][C@@H:34]([CH:35]([CH3:36])[CH3:37])[C:38]([OH:40])=[O:39]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: COC(=O)[C@H](C)CN
Agent: Cl
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously to Example 124b) from 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124c) and 3-amino-2(R)-methylpropionic acid methyl ester hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1ccccc1O)c1ccccc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)c1ccccc1OC(=O)C(C)(C)C

Procedure:
2 g (0.01 mole) of 2,2'-dihydroxybenzophenone was dissolved in 30 mls of dry pyridine and 3 g (0.03 mole) of pivaloyl chloride added and contents warmed for 3 hrs. at 50° C. Solvent was removed by rotary evaporator and H2O added and crystals filtered. Recrystallized from ethanol, 3.2 g (83%) yield, M.P.~106°-108° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.[Fe]>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: [Cu]I
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(C)n(-c3ccccc3)c12
Temperature: 100 °C
Yield: 41.4 %

Procedure:
A reaction tube containing 2-Bromo-3-nitrotoluene (108 mg, 0.5 mmol), N-phenylacetamide (81 mg, 0.6 mmol) and trans-1,2-cyclohexanodiamine (6 μL, 0.05 mmol), potassium phosphate (212 mg, 1 mmol), copper(I) iodide (9.5 mg, 0.05 mmol) in dry toluene (3 mL) was purged with dry argon for 3 min. Then the mixture was heated at 100° C. for 18 h. After cooling, the reaction was hydrolyzed with 3 mL of water and filtered through a Varian cartridge Chem Elut 12198007, rinsing with ethyl acetate. The crude mixture was dissolved in 10 mL of glacial acetic acid and refluxed for 30 min in the presence of iron powder (279 mg, 5 mmol). The acid was removed under reduced pressure and the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained crude was purified by preparative HPLC, affording the title compound as a pale yellow solid (46 mg, 41%). mp 107-109° C. NMR (DMSO) δ 1.83 (s, 3 H), 2.34 (s, 3 H), 7.02 (d, J=7.8 Hz, 1 H), 7.22 (t, J=7.8 Hz, 1 H), 7.53 (d, J=7.8 Hz, 1 H), 7.55-7.63 (m, 5 H); 13C NMR δ 13.3, 17.1, 114.8, 121.7, 123.0, 125.5, 128.6, 129.4, 129.9, 136.0, 144.5, 151.2, 157.2. HRMS (FAB): cal. for C15H15N2 [M+H+]: 223.1235; found: 223.1231.
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6]1)(=[O:4])=[O:3].[NH:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][S:2]([CH:5]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:19])=[CH:20][CH:21]=2)(=[O:12])=[O:11])[CH2:6]1)(=[O:3])=[O:4]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)C1
Product: CS(=O)(=O)C1CCN(S(=O)(=O)c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)C1
Yield: 49.7 %

Procedure:
The title compound is prepared from 4-(3-methanesulfonyl-pyrrolidine-1-sulfonyl)-benzoic acid (230 mg, 0.69 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (CAS 51207-66-0)(88 mg, 0.57 mmol) in a manner substantially similar to Procedure G to provide 133 mg (50%) of the title compound. MS (ES+) 470.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([N:30]1[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31]1)=[O:29])[C@H:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])=[CH:18][CH:17]=1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([N:30]1[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31]1)=[O:29])[C@H:10]([CH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH2:18][CH2:17]1)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)[C@@H](c1ccc(N2CCCC2=O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H](C1CCC(N2CCCC2=O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1

Procedure:
To a solution of the material prepared in Step A (0.46 g, 0.91 mmol) in 100 mL of acetic acid was placed solid platinum (IV) oxide (200 mg). The mixture was placed under 3 atm hydrogen for 24 h at ambient temperature. The mixture was then filtered through Celite, and concentrated in vacuo. Purification by reverse phase liquid chromatography (25%-65% acetonitrile in water gradient) afforded the title compound as a mixture of cis and trans 1,4-disubstituted cyclohexyl diastereomers. These diastereomers were separated by chiral HPLC (Chiracel OD column, 5% ethanol in hexanes) affording each pure diastereomer: The faster eluting diastereomer: LC/MS 514.4 (M+1); the slower eluting diastereomer: LC/MS 414.4 (M+1-Boc).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].N#N.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
Add 4-chlorosulfonyl-benzoyl chloride (103 g (0.433 mol) and anhydrous THF (1.2 L) to a 5-L 3-neck round bottom equipped with overhead stirrer, dropping funnel, N2 line, and temperature probe and cool to −78° C. Add to the stirring solution dropwise over 4 h a solution of 4-fluorobenzylamine (52 g, 0.416 mol), triethylamine (42 g, 0.415 mol), and 4-DMAP (5.3 g, 0.043 mol) in dry THF (1.2 L). Slowly bring to room temperature the resulting mixture and stir overnight. Filter the solids, back-wash with THF, and concentrate the filtrate to a solid. Partion the solid between 1N HCl (1 L) and ethyl acetate (2×1 L). Combine the organics, dry over magnesium sulfate, filter, and concentrate to a solid. Suspend the solid in methyl t-butyl ether (1 L), stir at room temperature for 2 h, filter, and back-wash with ethyl ether (500 mL). Dry the resulting white powder (20 mm Hg, 40° C.) to give 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride as a white solid (108.5 g, 80%): 1HNMR (DMSO-d6) δ 9.07 (t, J=5.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 4.44 (d, J=5.9 Hz, 2H); MS (ESI) m/z 326 (m−H); HPLC, 93.6%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN.C(Cl)Cl>C(Cl)Cl.C(O)C>[CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
A solution of Example 24F (0.48 g, 0.98 mmol) in CH2Cl2/ethanol (1:1, v/v, 12 mL) was treated with hydrazine hydrate (0.476 mL, 9.79 mmol). The reaction was stirred at 25° C. for 5 hours and was concentrated under reduced pressure on a rotary evaporator to provide a residual oil. The concentrate was treated with CH2Cl2 (15 mL) and a white suspension formed. The suspension was filtered and the filtrate was concentrated on a rotary evaporator to provide 0.32 g of a pale yellow oil. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 98:1:1 to 97:2:1 CH2Cl2/CH3OH/NH4OH to provide 0.09 g (25%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46 (d, J=3.68 Hz, 1H) 7.38 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.68, 0.74 Hz, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 4.17-4.29 (m, 1H) 1.35 (d, J=6.62 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (APCI) m/z 362 (M+H)+.
Reaction SMILES: [I-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][I:1])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: [I-]
Reactant: CC(C)(C)c1ccc(COS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
1.65 g (11 mmol) of sodium iodide were added to a solution of 2.00 g (6.96 mmol) of 2-t-butyl-5-(methanesulfonyloxymethyl)-1-nitrobenzene [prepared as described in step (i) above] in 40 ml of acetone, and the mixture was stirred at 50° C. for 20 minutes. At the end of this time, the reaction mixture was cooled to room temperature, and filtered. The precipitate was washed with ethyl acetate, and the combined filtrate and washings were concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate, and the resulting solution was washed with water, with an aqueous solution of sodium thiosulfate, and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give 2.18 g (yield 98%) of the title compound as crystals, melting at 98°-99° C. (after recrystallization from a mixture of methylene chloride, diethyl ether and hexane).
Reaction SMILES: [NH2:1][N:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]1=[NH2+:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:23][CH2:24][C:25](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:23][CH2:24][C:25]1[N:9]=[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[N:2]2[N:1]=1
Reactant: COC(=O)CCl
Reactant: Cc1cccc(=[NH2+])n1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc2nc(CCl)nn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A suspension of 1-amino-6-methylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (520 mg, crude product from the previous step, 1.61 mmol), methyl 2-chloroacetate (700 mg, 7.80 mmol) and potassium carbonate (444 mg, 3.22 mmol) in EtOH (10 m L) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography (eluting with EtOAc in PE, a gradient from 17% to 30% v/v) to give the title compound (290 mg, yield 84%). ESI MS: m/z 182, 184 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:26][S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: FC(F)(F)c1cnc(NCC2(c3ccccc3)CCCCC2)c(Cl)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C2(CNc3ncc(C(F)(F)F)cc3Cl)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
185 mg of (3-Chloro-5-trifluoromethyl-pyridin-2-yl)-(1-phenyl-cyclohexylmethyl)-amine were dissolved in 15 ml of methylenchloride and 0.14 ml of chlorosulfonic acid were added. The reaction mixture was stirred at room temperature for 4 days and than poured on ice water (20 ml). The organic layer was separated, washed twice with 50 ml of brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 194 mg g of the crude product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:19])=[O:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2ccccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0° C. was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 4-hydroxynaphthoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[N:36]=[N:37][NH:38][N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[N:38]=[N:39][C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:36]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nnc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-2H-tetrazole.