Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4].[Bi:12]>O>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][C:8]=1[OH:9])[OH:4].[Bi:12]
Reactant: O=C(O)c1c(O)cccc1O
Agent: [Bi]
Solvent: O
Product: O=C([O-])c1c(O)cccc1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A first process consists in reacting γ-resorcylic acid with a bismuth compound; the said acid is dispersed in water and the temperature of the mixture is raised to a temperature of between approximately 40° C. and approximately 60° C., preferably approximately 50° C., and then the bismuth compound is added and the temperature is raised, with stirring, to a temperature of between approximately 70° C. and approximately 90° C., preferably approximately 80° C., allowing the reaction to continue, advantageously for between 2 and 15 hours, preferably approximately 5 hours. The suspension is filtered off, washed and dried; the product obtained corresponds to a γ-resorcylate containing one atom of bismuth per molecule of acid.
Reaction SMILES: CN(C)C([C:5]1[CH:18]=[CH:17][C:8]2[CH:9]=[C:10](CCCCN)[O:11][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:11]1[C:7]2[CH:6]=[CH:5][CH:18]=[CH:17][C:8]=2[CH:9]=[CH:10]1
Reactant: CN(C)C(=O)c1ccc2cc(CCCCN)oc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2occc2c1
Reaction time: 2 h

Procedure:
N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide (13.0 g., 0.05 mole) in tetrahydrofuran (60 ml.) is added dropwise with stirring to lithium aluminum hydride (3.0 g., 0.08 mole) in tetrahydrofuran (60 ml.) at 25°-30° C. The mixture is stirred for 2 hours at 25°-30° C. and then is treated successively with 3 g. of water, 3 g. of 15% sodium hydroxide solution and 9 g. of water. The solid precipitate is removed by filtration. The tetrahydrofuran solution is evaporated at reduced pressure to provide 2-(4-aminobutyl)-6-dimethylaminomethyl)benzofuran.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([OH:25])=O)=[C:10]([CH2:12][C:13]3[C:21]4[C:16](=[C:17]([CH3:22])[CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].Cl.[OH:32][C@@H:33]1[CH2:37][O:36][NH:35][CH2:34]1>>[OH:32][CH:33]1[CH2:37][O:36][N:35]([C:23]([C:9]2[C:6]3[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]=3[S:11][C:10]=2[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([CH3:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:25])[CH2:34]1
Reactant: Cc1cccc2c(Cc3sc4c(c3C(=O)O)c(=O)n(C)c(=O)n4CC(C)C)c[nH]c12
Reactant: O[C@H]1CNOC1
Agent: Cl
Product: Cc1cccc2c(Cc3sc4c(c3C(=O)N3CC(O)CO3)c(=O)n(C)c(=O)n4CC(C)C)c[nH]c12

Procedure:
Prepared using the procedure described in example 1 part g) from the product of step b) and (S)-4-hydroxyisoxazolidine hydrochloride [Example 1 part b] to give the title compound after purification by flash silica chromatography eluting with 0-3% methanol in ethyl acetate and recrystallisation from ethyl acetate:isohexane (9:1). MS (APCI) 497.1 [M+H] δ 1HDMSO 0.81-0.84 (6H,m), 2-2.1 (1H, m), 2.44 (3H, s), 3.2 (3H, s), 3.5-3.9 (6H, 3m), 4.1-4.2 (2H, m), 4.7-4.8 (1H,2m), 5.5 (1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H, m), 10.95 (1H, bs)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C@H:15]2[CH2:17][C@@H:16]2[C:18](=[O:31])[NH:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][C:26]([Cl:30])=[CH:25]3)([CH3:14])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:30][C:26]1[CH:27]=[N:28][C:29]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[NH:19][C:18]([C@H:16]1[CH2:17][C@@H:15]1[C@:12]1([CH3:14])[C:11]([F:32])([F:33])[CH2:10][O:9][C:8]([NH2:7])=[N:13]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)([C@H]2C[C@@H]2C(=O)Nc2cccc3cc(Cl)cnc23)C(F)(F)CO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1([C@H]2C[C@@H]2C(=O)Nc2cccc3cc(Cl)cnc23)N=C(N)OCC1(F)F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of {(R)-4-[(1S,2S)-rel-2-(3-chloro-quinolin-8-ylcarbamoyl)-cyclopropyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester (4.7 mg, 9.5 μmol) (intermediate J8.2) in dichloromethane (47 μl) was cooled to 0° C. Trifluoroacetic acid (11.0 mg, 7.4 μl, 95.0 μmol) was added and the solution was left to warm to room temperature. After 7 hours trifluoroacetic acid (33.1 mg, 22.3 μl, 285 μmol) was added again and the mixture stirred at room temperature for another hour. Thereafter, the solvent was removed at reduced pressure. The residue was dissolved in water, then the aqueous layer was basified with a solution of sodium carbonate (2M) and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid (3-chloro-quinolin-8-yl)-amide (3.7 mg, 99%) was obtained as a light brown solid. MS (ISP): m/z=395.0 [M+H]+.
Reaction SMILES: C([O:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:7]=2[N:8]=1)C.Cl>C1(C)C(C)=CC=CC=1>[CH3:13][C:9]1[C:7]2[NH:8][C:4](=[O:3])[S:5][C:6]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOc1nc2c(C)cccc2s1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1cccc2sc(=O)[nH]c12
Yield: 81 %

Procedure:
Prepared analogous to Example 5 from 2-ethoxy-4-methyl-benzothiazole and concentrated hydrochloric acid with a yield of 81% of theory. M.p.: 207°-208° C. (xylene/gasoline 1:1)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:24][C:19]2[C:18]([NH2:25])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NCCCC1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 300 mg 3-(1-benzyl-piperidin-4-yl)-propionaldehyde (from Step D), 300 mg of 1,2-phenylenediamine and 200 mg sodium triacetoxyborohydride in THF and DMF using a procedure analogous to that described in Example 1, Step J.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C@@H:11]([NH:20][CH3:21])[C@H:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C@@H:4]1[N:20]([CH3:21])[C@H:11]([CH3:10])[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5]1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: O=Cc1ccccc1Br
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@@H](c2ccccc2)O[C@H](c2ccccc2Br)N1C

Procedure:
To a solution of 2-bromobenzaldehyde (18.78 g, 101.50 mmole, 1.0 eq) in toluene (100 mL) was added (-)-pseudoephedrine (16.73 g, 101.24 mmole, 1.0 eq). The mixture was refluxed for 16 h under an argon atmosphere using a Dean-Stark trap to remove the generated ,water. Concentration in vacuo gave 33.53 g (100%, corrected for 2 wt % toluene by 1H NMR) of a 40:1 mixture of title compound and a minor diastereomer as a light yellow oil.
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]([CH3:14])([CH3:13])[CH:10]=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
N-Boc-2-aminoisobutyric acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over NaSO4 and evaporated to yield N-Boc-2-amino-2-methylpropanal.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[N:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>O>[CH3:14][N:15]([CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCc1ccccc1
Reactant: C=Cc1cccc(C)n1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1cccc(CCN(C)Cc2ccccc2)n1

Procedure:
0.5 ml of glacial acetic acid was added to a solution of 10.0 g (84.0 mmol) of 6-methyl-2-vinylpyridine and 10.2 g (84 mmol) of N-methylbenzylamine in 100 ml of a mixture of methanol with water (1:1) and the mixture thus obtained was refluxed for 8 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3). A fraction containing the intended compound was concentrated to give the compound in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.Cl>CO.O1CCOCC1>[N+:10]([C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=1)[NH2:1])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
3,5-Dinitrobenzotrifluoride (10 g) was dissolved in a mixture of methanol (200 ml) and 1,4-dioxane (125 ml) and heated under reflux. To this solution was added concentrated hydrochloric acid (30 ml) and then in small portions, reduced iron powder (9 g). CARE: violent effervescence. Refluxing was continued for a further 1 hour and the reaction mixture allowed to cool to room temperature. The mixture was filtered through `Celite` and the pad washed well with dichloromethane. The solvents were removed under reduced pressure to give a residue which was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a brown semi-solid (8 g). This was chromatographed on silica gel using ethyl acetate-hexane (1:9) as eluant to give the title compound as fine golden crystals, yield 4.98 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.O1CCCCC1[N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1>>[CH3:10][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][NH:18][N:17]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: Cc1cc(-c2cc[nH]n2)ccc1C#N

Procedure:
The title compound was synthesized using the method of Example 34(b), but starting from 4-bromo-2-methylbenzonitrile and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H-NMR (400 MHz; CDCl3): δ 2.60 (s, 3H), 6.69 (d, 1H), 7.64 (m, 2H), 7.70 (d, 1H), 7.78 (s, 1H), 10.47 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[C:16]2[CH2:24][N:25]([CH3:28])[CH2:26][CH2:27][C:15]1=2)#[CH:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:28][N:25]1[CH2:26][CH2:27][C:15]2[N:14]([C:12]#[C:13][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[C:22]3[CH:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[C:16]=2[CH2:24]1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(S(N)(=O)=O)cc2)CCN(C)C1

Procedure:
A mixture of 4-bromobenzenesulfonamide (200 mg, 0.84 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391 mg, 1.0 mmol), TBAF.3H2O (793 mg, 2.5 mmol) and dichloro bis(triphenyl phosphine) palladium (II) (29 mg, 0.042 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to afford crude material, which was purified by column chromatography using neutral alumina and 5% MeOH-DCM, followed by reverse phase HPLC to yield 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-benzenesulfonamide. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.92 (d, 2H), 7.7 (d, 2H), 7.58 (d, 1H), 7.38 (s, 1H), 7.23 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.96 (m, 1H), 3.63 (m, 1H), 3.37 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: COC1C=C(C=CC=1)N.[CH2:10]([O:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]2[CH2:41][CH:40]3[CH:26]([C:27](=[O:47])[N:28]([CH3:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH:35]4[C:37]([C:43]([OH:45])=[O:44])([NH:38][C:39]3=[O:42])[CH2:36]4)[CH2:25]2)[C:20]2[C:15](=[C:16](C)[C:17]([O:48][CH3:49])=[CH:18][CH:19]=2)[N:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:22]=[C:21]([O:23][CH:24]2[CH2:41][CH:40]3[CH:26]([C:27](=[O:47])[N:28]([CH3:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH:35]4[C:37]([C:43]([OH:45])=[O:44])([NH:38][C:39]3=[O:42])[CH2:36]4)[CH2:25]2)[C:20]2[C:15](=[CH:16][C:17]([O:48][CH3:49])=[CH:18][CH:19]=2)[N:14]=1)[CH3:11]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: COc1cccc(N)c1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)cc2n1

Procedure:
The title compound (4) was prepared from 3-methoxyaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=552 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[N:5]([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([CH2:19][CH2:20][S:21][S:22][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[O:10])[C:3](=[O:4])[CH:2]1[S:29]([O-:32])(=[O:31])=[O:30].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[N-]=[N+]=[N-].[Na+]>OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].O>[N:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:22][S:21][CH2:20][CH2:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]([O:8][N:5]1[C:6](=[O:7])[CH2:1][CH:2]([S:29]([OH:32])(=[O:30])=[O:31])[C:3]1=[O:4])=[O:10])=[O:18]
Reactant: O=C(CCSSc1ccccn1)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Product: O=C(CCSSc1ccccn1)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O

Procedure:
A 10 mM stock solution of the sulfosuccinimidyl 6-[3′-(2-pyridyldithio)-propionamido]hexanoate (Sulfo-LC-SPDP) is prepared by dissolving 1.3 mg Sulfo-LC-SPDP into 2.07 ml de-ionized water. The conjugation reaction is carried out in phosphate buffered saline (PBS) containing 20 mM sodium phosphate buffer, 150 mM NaCl, 1 mM EDTA and 0.02% sodium azide at pH 7.5. One milligram of lyophilized antibody is dissolved in 450 ml PBS, and 50 ml of Sulfo-LC-SPDP stock solution is added to the antibody solution. The mixture is allowed to react at room temperature for 60 minutes. The sample is applied to a 5 ml desalting polyacrylamide column previously equilibrated with 5 bed volumes (25 ml) of PBS. Fractions are eluted using PBS as the elution buffer, and the protein in the fractions is monitored using a COOMASSIE® Protein Assay (Pierce Chemical Co). Typically, 50 ul of the COOMASSIE® reagent is mixed with 50 ul of each fraction in a micro-titer plate. The COOMASSIE® Blue substrate reacts with the protein, producing a blue color, the intensity of which is dependent upon the amount of protein present in the fraction. The fractions which produce the most intense blue color are those containing the majority of the protein eluted. These fractions are pooled together to produce the disulfide form of the final derivatized product. This is typically the form used for contact printing.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34](C)[C:35](=O)OC(C)(C)C)=[CH:29][C:28]=3[F:43])[CH:23]=2)=[CH:20][C:19]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][N:45]=2)=[CH:18][N:17]=1)=O)(C)(C)C>C(Cl)Cl>[F:43][C:28]1[CH:29]=[C:30]([CH2:33][NH:34][CH3:35])[CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[C:22]([C:21]2[C:16]([NH2:15])=[N:17][CH:18]=[C:19]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:54])[CH3:55])(=[O:51])=[O:52])=[CH:46][N:45]=3)[CH:20]=2)[O:26][N:25]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4F)no3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.5 %

Procedure:
TFA (1.724 g, 1.165 mL, 15.12 mmol) was added to a stirred solution of tert-butyl N-[[4-[5-[2-[bis(tert-butoxycarbonyl)amino]-5-(5-isopropylsulfonyl-2-pyridyl)-3-pyridyl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (198.7 mg, 0.1652 mmol) in DCM (7 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (6 mg, 7% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.22 (d, J=6.8 Hz, 6H), 2.20-2.30 (m, 3H), 3.50-3.60 (m, 1H), 3.75 (s, 2H), 7.05 (br s, 2H), 7.35-7.45 (m, 2H), 7.50 (s, 1H), 7.90-8.00 (m, 1H), 8.25-8.40 (m, 2H) and 8.80 (s, 1H) ppm; MS (ES+) 482.0.
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.[N+:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18].C(OCC)C.C>CO>[N+:17]([CH:20]([CH:5]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:19])=[O:18]
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Dibenzosuberenol (42 g, 0.2 mol) is combined with ethyl nitroacetate (25 mL, 0.23 mol) and the mixture is heated at 120° C. (oil bath) until melted and then kept at 110° C. for 2.5 hours. The oil bath is removed and the cooled reaction mixture is dissolved in 50 mL of methanol and taken up into 350 mL of boiling diethyl ether. The dark solution is treated with charcoal, filtered, and cooled overnight. A precipitate is collected by filtration, washed with hexane, diethyl ether, dried under vacuum at room temperature to give 26.7 g of the title compound; mp 101°-103° C.
Reaction SMILES: [OH:1][N:2]1[C:6]([I:7])=[C:5]([I:8])[CH:4]=[N:3]1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[I:8][C:5]1[CH:4]=[N:3][N:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[I:7]
Reactant: On1ncc(I)c1I
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ncc(I)c1I)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4,5-diiodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (76%, crystals).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-]>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[CH:1]/[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=3)[N:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(/C=C/c2ccc3cc(C(=O)O)ccc3n2)cc1
Yield: 24.8 %

Procedure:
A mixture of 2-methyl-6-quinolinecarboxylic acid (200 mg, 0.936 mmol), 4-methoxybenzaldehyde (228 mg, 0.936 mmol), acetic anhydride (630 mg, 6.18 mmol) and a catalytic amount of zinc chloride was heated at 140° C. for 12 h with stirring. The cooled reaction mixture was extracted with water and ethyl acetate. The organic layer was collected, dried (MgSO4) and the solvent was removed under reduced pressure to give dark brown solid. This material was applied to a silica gel column and the product was eluted with ethyl acetate/n-hexane (1/4). Fractions containing the required product (RF=0.20 ethyl acetate/n-hexane 2/1, fluorescent under UV lamp) were collected and the solvents were removed under reduced pressure. The residue as a yellow solid was triturated with n-hexane and filtered to give the title compound (71 mg, 25%), m.p.=274-277° C. (sublimed around 240° C.).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:31])[CH:6]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[N+:28]([O-])=O)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)[CH3:3].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH2:2]([O:4][C:5](=[O:31])[CH:6]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[NH2:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)[CH3:3]
Reactant: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(c1ccc(CN2CCOCC2)cn1)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt (100 g, 223.7 mmol) was slurried in toluene at room temperature and a solution of sodium hydrogen carbonate (47 g, 559 mmol) in water (500 ml) was added and the reaction mixture stirred at room temperature for 45 mins. The organic phase was separated and washed twice with water (500 ml) then concentrated by distillation under vacuum to 229 ml. Dimethylformamide (846 ml) was then added followed by Degussa® [CF1082 RV/W®; Platinum (3%) and Vanadium (0.6%)] on active carbon (20 g, 20 w/w %) and the reaction mixture degassed with nitrogen followed by heating to 40° C. then hydrogen (g) was added to a pressure of 3-4 bar g and left for 30 min then heated to 70° C. and stirred for 6 hrs under an atmosphere of hydrogen. After cooling to room temperature the reaction mixture was purged with nitrogen and the catalyst filtered off and the filtrate concentrated to 395 ml. (The solution was used in the next step; Example 12). An aliquot was taken out and purified by column chromatography on silica eluting with dichloromethane/methanol (1% ammonium hydroxide) (25:1) gave (2-Amino-5-cyano-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a pale orange oil.