Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:37]>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:37]=2)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol) was dissolved in m-xylenes (4 mL) and heated at 135° C. Solid ammonium acetate (200 mg, 2.58 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (162 mg, 0.329 mmol): LCMS-ESI+: calc'd for C21H26BrN5O4: 492.4 (M+); Found: 492.3/494.3 (M+H+).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@@H:12]2[N:20](C(OC(C)(C)C)=O)[C:21]([NH:23]C(OC(C)(C)C)=O)=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2.[ClH:41]>CCOCC.O>[ClH:41].[ClH:41].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@@H:12]2[NH:20][C:21]([NH2:23])=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2
Reactant: CO[C@@]12CC[C@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CO[C@@]12CC[C@H](NC(=N)N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5

Procedure:
A solution of Compound 18 (50 mg, 0.089 mmol) in Et2O (3 ml) was mixed through to a clear acidic reaction with ethereal HCl and with 4 drops of H2O. The mixture was subjected to ultrasound for 1.5 h at room temperature and then evaporated. The residue (40 mg of white foam resin) was dissolved in H2O and freeze dried. Yield: 35 mg (92%) 19.2 HCl as white lyophilisate: 1H-NMR (CDCl3): δ 9.29 (s, br, NH+); 9.20 (s, OH—C(3)); 7.57 (d, J=8.8, C(6)-NH—); 7.46 (s, br, C(6)-NH—C(NH2)2+), 6.76 (d, J=8.1, 1 arom. H); 6.62 (d, J=8.1, 1 arom. H); 4.70 (d, J=4.0, H—C(5)); 3.36 (s, CH3O—C(14)); 2.88 (s, CH3N).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[S:9]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH2:8])=[CH:3][CH:4]=1)([OH:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: NCc1ccccc1
Product: NCc1ccc(S(=O)(=O)O)cc1
Yield: 40 %

Procedure:
p-Sulfobenzylamine was synthesized in 40% yield from benzylamine and fuming sulfuric acid, by an adaptation of the method described in Jacobson et al., J. Med. Chem., 35, 4143-4149 (1992), and was recrystallized from a solution in ammonium hydroxide, upon neutralization with hydrochloric acid. NMR DMSO, d6 δ8.10 (br.s, 3H, NH3+), 7.62 (d, J=8.1 Hz, 2H, o- to sulfo), 7.38 (d, J=8.1 Hz, 2H, m- to sulfo), 4.02 (s, 2H, CH2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])[CH2:9][C:10]([NH:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1)=O)([CH3:4])([CH3:3])[CH3:2]>COCCO>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])[CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]2=[N:13][N:12]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2ccccc12)Cc1cc(F)ccc1F
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2c3ccccc3ccn12

Procedure:
The crude residue from Step A was treated with 5 mL of 2-methoxyethanol, and the mixture was stirred at reflux for 1 h. The residue obtained upon concentration was flash chromatographed on silica gel (1-2.5% methanol in dichloromethane) to provide the title compound as a light tan solid, mp 185-187° C. (decomposition). LC-MS 439 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([NH2:37])=[CH:32][C:31]=1[NH2:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:7])[NH:37][C:33]1[CH:32]=[C:31]([NH2:38])[C:30]([F:29])=[CH:35][C:34]=1[CH3:36]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(F)c(N)cc1N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c(N)cc1NC(=O)OCC[Si](C)(C)C
Temperature: 50 °C
Yield: 28 %

Procedure:
To a solution of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C. under an atmosphere of argon was added DMAP (12 mg, 0.1 mmol), DIEA (0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. The resulting solution was heated to 50° C. for 48 h. The reaction mixture was quenched with saturated NaCHO3 (aq), extracted with EtOAc (3×20 ml). The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et2O then washed with 3 N NaOH (aq), water, brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (2:8-7:3 ethyl acetate-hexane) gave (5-amino-4-fluoro-2-methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd 634, found 634.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=S(=O)(N=C(NN1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.42 gram, 3.00 mmol) and phosphorus pentachloride (PCl5) (0.63 gram, 3.03 mmol) in chlorobenzene (15 mL) is heated at reflux temperature for 1 hour. After thorough concentration in vacuo, the formed 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride is suspended in dry dichloromethane (30 mL) and reacted with 1-aminopiperidine (1.08 mL, 10.0 mmol). After stirring at room temperature for 16 hours, the mixture is twice washed with water and concentrated in vacuo. The residue is crystallised from methyl-t-butyl ether (MTBE) to give pure 3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(piperidin-1-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (0.57 gram, 34% yield). Melting point (MP): 213-214° C. MS ESI+: 556 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([NH2:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[F:34].FC1C=C2C(=CC=1)C(N)CC2>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH:35]([C:30]1[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=1)[CH3:36]
Reactant: CC(N)c1ccc(F)c(Cl)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: NC1CCc2cc(F)ccc21
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)c(Cl)c1
Yield: 65 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1.0 mmol) with 1-(3-chloro-4-fluoro-phenyl)-ethylamine Isomer 1 (226 mg, 1.3 mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane (1:7) to give 7-chloro-6-[1-(3-chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (293 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH:5]21.Cl.[NH2:18]O.C([O-])(=O)C.[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(O)C.O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]1[CH:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:5]21
Reactant: O=C1CCCCC2c3cc(Br)ccc3NC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CO
Solvent: CCO
Product: NC1CCCCC2c3cc(Br)ccc3NC12
Reaction time: 0.25 h

Procedure:
To a solution of to 2-bromo-5a,7,8,9,10,10a-hexahydrocyclohepta[b]indol-6(5H)-one (1.5 g, 5.4 mmol) in ethanol (14 mL) was added solutions of hydroxylamine hydrochloride (750 mg, 11 mmol) in water (10 mL) and sodium acetate (1.46 g, 18 mmol) in water (10 mL). The reaction mixture was heated at reflux for 5 h, cooled and concentrated. The residue was diluted with ethyl acetate and washed with water (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to a brown solid. The oxime was dissolved in THF (54 mL) and LAH (1.0 M in THF, 16.2 mL, 16.2 mmol) was added dropwise. The reaction was heated at reflux for 4 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous NaHSO3 and stirred vigorously for 15 min and extracted with ethyl acetate (2×150 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2-bromo-5,5a,6,7,8,9,10,10a-octahydrocyclohepta[b]indol-6-amine as a brown oil. The oil was diluted in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2-bromo-5,5a,6,7,8,9,10,10a-octahydrocyclohepta[b]indol-6-amine hydrochloride (980 mg, 57%). as a light brown solid. 1H-NMR (CD3OD): δ 7.65 (s, 1H), 7.28-7.21 (m, 2H), 4.68-4.66 (m, 1H), 3.08-3.01 (m, 1H), 2.84-2.76 (m, 1H), 2.33-2.25 (m, 1H), 2.15-1.93 (m, 4H), 1.65-1.55 (m, 1H); MS m/z (M−1) 277, 279.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:16][CH:15]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:10][CH:11]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1(N)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Reaction time: 2 h

Procedure:
A mixture of 146b (0.14 g, 0.20 mmol), TFA (2 mL) in DCM (5 mL) was stirred for 2 hours. The solvents were removed under reduced pressure to give crude methyl (4R)-6-[[7-amino-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate in TFA salt form. MS: calc'd (MH +) 592, exp (MH+) 592. This TFA salt (35 mg, 0.051 mmol) was dissolved in a mixture of TEA (20.6 mg, 0.204 mmol) in DCM (3 mL). To it was added CH3SO2Cl (11.7 mg, 0.102 mmol). The resulting mixture was stirred for 12 hours at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give two products, Example 146 and Example 147.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][CH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][CH2:28][OH:29]
Reactant: OCCBr
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCCO)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 2-bromoethanol, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: Br[C:2]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([Br:7])=[CH:5][CH:6]=1.C([Li])CCC.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[Cl-].[NH4+]>C(OCC)C>[Br:7][C:4]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
t-Butyl 2,5-dibromo-1H-pyrrole-1-carboxylate (10.98 g, 33.8 mmol) synthesized in Example (66a) was dissolved in diethyl ether (135 mL), and cooled to −78° C. n-Butyl lithium (2.77M hexane solution, 12.8 mL, 35.5 mmol) was added dropwise slowly, and stirring was carried out for 1 hour. To the reaction solution, benzyl chloroformate (6.25 mL, 44.0 mmol) was added dropwise slowly, and stirring was carried out for 30 minutes. With the temperature of the reaction solution being gradually raised to room temperature, stirring was carried out for 1 hour. To the reaction solution, were added a saturated aqueous ammonium chloride solution (200 mL) and diethyl ether (300 mL), and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-45%) to afford the desired compound (8.80 g, yield 68%) as a reddish brown oil.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[NH:3][CH2:2]1.Br[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=O>[Cu].CN(C=O)C>[O:5]=[S:4]1(=[O:6])[CH2:7][CH2:1][CH2:2][N:3]1[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: O=S1(=O)CCCN1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A mixture of 1,3 propanesultam (prepared as in White et al, J. Org Chem. 1987, 52: 2162) (0.081 g, 0.66 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.10 g, 0.27 mmol), potassium carbonate (0.092 g, 0.66 mmol) and copper powder (0.017 g, 0.27 mmol) under an atmosphere of argon was stirred at 160C for 16 hr. The reaction was allowed to cool to room temperature and the residue was treated with DMF (5 mL) and TFA (1.5 mL) and filtered through a pad of celite to remove the solids. The filtrate was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:11][C:6]=2[O:5][CH2:4][S:3]1(=[O:37])=[O:36]>C(O)(C(F)(F)F)=O>[NH2:22][C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:10]3[C:9]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:8][C:7]4[N:2]([CH3:1])[S:3](=[O:37])(=[O:36])[CH2:4][O:5][C:6]=4[N:11]=3)=[CH:17][CH:16]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CN1c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2OCS1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1c2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2OCS1(=O)=O
Reaction time: 0.01 h
Yield: 79.1 %

Procedure:
tert-Butyl (1-(4-(1-methyl-2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.096 mmol) was dissolved in TFA (3 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (32 mg, 62% yield). 1H-NMR (500 MHz, MeOD) δ 7.58 (1H, s), 7.41 (2H, d), 7.37 (2H, d), 7.25-7.33 (3H, m), 7.17-7.25 (2H, m), 5.45 (2H, s), 3.35 (3H, s), 2.66-2.78 (2H, m), 2.46-2.57 (2H, m), 2.12-2.25 (1H, m), 1.85-1.97 (1H, m). LCMS (Method A) RT=3.98 min, M+2H+=423.13.
Reaction SMILES: P(=O)(O)(O)[OH:2].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:15]=[C:14]([OH:2])[C:13](=[CH:12][CH:11]=1)[OH:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=P(O)(O)O
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 52 %

Procedure:
The procedure of Comparative Example 1 was repeated, except phosphoric acid was added as a reaction catalyst in an amount corresponding to 1% by weight based on the amount of para-tert.-butyl phenol used. Consequently, the conversion of para-tert.-butyl phenol was 5.3%, 4-tert.-butyl pyrocatechol was formed in a yield of 52% based on the converted butyl phenol, and the conversion of peracetic acid was 96.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1CC([O-])=O.CC1C=C(C=C(C)C=1)CCC([O-])=O>>[C:2]1([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(C)c(CC(=O)[O-])c(C)c1
Agent: Cc1cc(C)cc(CCC(=O)[O-])c1
Product: Cc1cc(C)cc(C)c1

Procedure:
In the comparative example performed without any catalyzer being present, the current yield is 35% and the stoichiometric yield is 61% and the mixture of isomeric acetates contains 93% of 2,4,6-trimethylphenylacetate and 7% of 3,5-dimethylbenzylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[OH:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([N:28]4[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]4)[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1nc(Cl)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(N2CCC(CCO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A mixture of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g), 4-(2-hydroxyethyl)piperidine (3.2 g), N,N-diisopropylethylamine (3.2 g) in ethanol (15 mL) was heated at reflux for 5.5 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=2:1) to obtain 2-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-ethanol as a white solid (6.41 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S:15](=[O:19])(=[O:18])([OH:17])O>>[F:1][C:2]1[C:3]([S:15]([OH:17])(=[O:19])=[O:18])=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:15]([OH:17])(=[O:19])=[O:18])[C:11]([F:14])=[C:10]([S:15]([OH:17])(=[O:19])=[O:18])[CH:9]=2)=[CH:6][C:7]=1[S:15]([OH:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Fc1ccc(-c2ccc(F)cc2)cc1
Product: O=S(=O)(O)c1cc(-c2cc(S(=O)(=O)O)c(F)c(S(=O)(=O)O)c2)cc(S(=O)(=O)O)c1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
The same procedure as 5a is used with 9.51 g dry 4,4′-difluorobiphenyl (50 mmole, fw=190.19) and 106.8 g 30% fuming sulfuric acid (400 mmole, fw=80.06) which are stirred at 30° C. for 24 hour and then heated with stirring at 110° C. for another 72 hours. Crystallization was effected using 29.6 g distilled water and 185 mL propionitrile. Yield was 17.2 g (65%) of the tetrasulfonated product as white crystals of the monohydrate.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1cc2ccccc2c2ccccc12
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: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under the atmosphere of argon, 25.7 g of 9-bromophenathrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetrakis(triphenylphosphine)palladium (0) were placed in a flask. To the resulting mixture, 340 mL of DME and 170 mL of an aqueous 2M sodium carbonate solution were added, followed by stirring under reflux while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 25.0 g (yield 89%) of 9-(2-formylphenyl)phenanthrene as an intended product was obtained.