Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30](=[O:38])[NH:31][S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([OH:23])=O)=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.C([N:48]1[CH2:56][C@H:55]2[C@H:50]([NH:51][CH2:52][CH2:53][CH2:54]2)[CH2:49]1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.[Pd].CO.CCOC(C)=O.O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:31][S:32]([N:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:51]4[CH2:52][CH2:53][CH2:54][C@H:55]5[CH2:56][NH:48][CH2:49][C@@H:50]45)=[O:23])=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C=C(C(=O)N1CCC[C@H]3CNC[C@H]31)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
To a solution of 13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (178 mg, 0.33 mmol) and (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine dihydrochloride (114 mg, 0.40 mmol) in DMF (3 mL) and TEA (0.2 mL) was added HATU (162 mg, 0.43 mmol). The reaction was stirred at rt for 2 h, then aq HCl (1.0N, 1.3 mL) and H2O (5 mL) were added under stirring. The resulting precipitate was collected via filtration, washed with H2O and dried to yield crude intermediate as an orange solid. This crude intermediate (260 mg) was dissolved into MeOH/EtOAc/95% EtOH and to this solution 10% Pd—C (catalytic) was added. The mixture was vigorously shaken under H2 (50 psi) at rt for 16 h, then filtered through Celite. The filtrate was concentrated and the residue was purified by prep HPLC (H2O/MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-((4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridin-1-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (129 mg, 0.20 mmol, 61%) as a yellow solid. 1H NMR (300 MHz, MeOD) δ ppm 8.11 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.59 (dd, J=8.4, 1.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.8, 2.6 Hz, 1H), 7.03-7.11 (m, 1H), 6.91-7.00 (m, 1H), 4.99-5.22 (m, 1H), 4.24-4.54 (m, 1H), 3.93 (s, 3H), 3.03 (s, 6H), 2.75-4.02 (m, 8H), 1.12-2.47 (m, 16H). LCMS: m/e 646 (M+H)+, Column C, Gradient time: 2 min, ret time 1.93 min.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][NH:21][CH2:22]2)[CH2:17]1)=[O:15].Cl[C:31]1[CH:40]=[N:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][N:21]([C:31]3[CH:40]=[N:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:22]2)[CH2:17]1)=[O:15]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CCN(c3cnc4ccccc4n3)CC21
Temperature: 80 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A mixture of trifluoro acetic acid salt of biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone (Intermediate 3, 122.0 mg, 0.3 mmol), 2-chloro quinoxaline (60.0 mg, 0.36 mmol), K2CO3 (166 mg, 4 mmol) in DMF (7 mL) was stirred at 80° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (120 mL). The organic layers were washed with water (2×30 mL), combined, dried (Na2SO4), filtered and concentrated. The crude residue was purified on HPLC (basic system) to yield the title compound (51 mg, 40%). MS (ESI) mass calcd. for C27H24N4O, 420.51; m/z found, 421 [M+H]+. 1H NMR (CDCl3): 8.44 (s, 0.55H), 8.17 (s, 0.45H), 7.97-7.87 (m, 1H), 7.76-7.71 (m, 0.5H), 7.65-7.50 (m, 2H), 7.48-7.30 (m, 7H), 7.09-6.94 (m, 2H), 7.20-7.12 (m, 0.5H), 4.78-4.49 (m, 1H), 4.02-3.78 (m, 1H), 3.76-3.58 (m, 2H), 3.55-3.48 (m, 0.5H), 3.32-3.23 (m, 0.5H), 3.15-2.97 (m, 1H), 2.74-2.39 (m, 1H), 2.12-1.54 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reactant: Clc1ncccn1
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1c1ncccn1
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.676 g) and 2-chloropyrimidine (716 mg) were combined, melted in an oil bath at 120° C., and stirred for 5 hr 30 min. Water (10 ml) was added and the mixture was stirred, extracted with ethyl acetate (30 ml), and washed with saturated brine. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size L, elution solvent: hexane/ethyl acetate) to give the title compound (333 mg).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11]C)=[O:10])=[N:7][CH:8]=1.O.O.[OH-].[Li+].C(OCC)C>O1CCOCC1>[F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cnc(CF)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)c1cnc(CF)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
Methyl 5-(fluoromethyl)pyrazine-2-carboxylate (94 mg) was dissolved in dioxan (1 mL) and water (1 mL) was added, followed by lithium hydroxide monohydrate (60 mg). After stirring at RT for 18 h, diethyl ether (20 mL) was added and the mixture was then extracted with NaOH (1 N, aq., 2×20 mL). The aqueous portions were acidified with 6N HCl to pH 1, extracted with EtOAc (2×40 mL), the combined organic portions dried over MgSO4 and evaporated to afford the title compound as a white solid (71 mg).
Reaction SMILES: [K].[CH2:2]([OH:4])[CH3:3].C(OC([CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18](OCC)=O)CC1)=O)C>C1(C)C=CC=CC=1>[N:13]12[CH2:14][CH2:15][CH:16]([CH2:18][CH2:17]1)[CH2:10][C:2](=[O:4])[CH2:3]2
Reactant: CCOC(=O)CN1CCCC(C(=O)OCC)CC1
Reactant: CCO
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1CC2CCN(CC2)C1
Reaction time: 14 h

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 1.55 g (39.69 g-atm.) potassium and 80 mL toluene. The mixture was heated to reflux and treated with 1.83 mL (39.69 mmol) ethanol. Refluxing continued until the potassium disappeared. Then 4.08 g (15.87 mmol) ethyl-N-ethoxycarbonylmethyl-perhydroazepine-4-carboxylate was added and refluxing was continued for 14 hours. The reaction was evaporated and the residue taken up in 100 mL 1N hydrochloric acid. This solution was refluxed for 22 hours, cooled, washed with methylene chloride, and adjusted to pH 12 with 6N sodium hydroxide. The aqueous layer was extracted with methylene chloride, which was dried over sodium sulfate and evaporated. The resulting foam, 700 mg (32%), was used directly below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]1.Cl.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:12][N:8]1[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22]2)[O:10][C:9]1=[O:11]
Reactant: CN1CC(CCCCCl)OC1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCCCN2CCN(c3ccccc3)CC2)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
A mixture of 5-(4-chlorobutyl)-3-methyl-2-oxazolidinone (10.0 g, 0.0524 mol), 1-phenylpiperazine hydrochloride (0.0524 mol, 10.39 g), potassium carbonate (28.94 g, 0.209 mol) and potassium iodide (1.0 g) was refluxed in 1-butanol (150 mL) for 24 hr and then stirred at room temperature for two days. The mixture was reheated to boiling and filtered hot. Methanolic hydrogen chloride was added to acidify the filtrate and addition of isopropyl ether caused a solid to precipitate. The solid was collected by filtration and dissolved in water. Potassium carbonate was added to make the solution basic and the product was extracted into two portions of ethyl acetate. The combined ethyl acetate layers were washed twice with water, three times with a saturated sodium bicarbonate solution and once with a saturated sodium chloride solution. The solution was dried (sodium sulfate), filtered, and evaporated under reduced pressure to an oil. Addition of isopropyl ether gave a solid which was recrystallized from isopropyl ether/methanol. The solid was collected by filtration, rinsed with light pet ether and dried under high vacuum to give 7.51 g (45% yield), mp 85°-88° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CCN(C2=Nc3ccccc3C(O)(c3ccccc3)C2(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (0.7g., 0.0025 mole) was dissolved in dry dioxan (10 ml.). Triethylamine (0.5g) followed by N-methylpiperazine (1.92g.) were added and the mixture stirred for 4 hours. The mixture was then evaporated down to a white solid residue which was recrystallised from isopropyl alcohol to give the title compound (0.60g., m.p. 268° - 269° C) [Found: C, 75.6; H, 8.1; N, 12.15% C22H27N3O requires C, 75.6; H, 7.8; N, 12.0%].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9](Br)=[CH:8]2)=[O:4].[C:26]1([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Temperature: 120 °C
Yield: 73.5 %

Procedure:
A mixture of (S)-3-bromo-5-hydroxy-2-oxo-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (350 mg, 0.87 mmol), PhSnBu3 (0.34 mL, 1.04 mmol), and PdCl2(PPh3)2 (122 mg, 0.17 mmol) in DMF (8 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 2-3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-35% EtOAc/hexanes+1% AcOH) to give 256 mg of the title compound as a yellow solid. MS: (+) m/z 401.36 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[CH3:13][CH:12]([NH:15][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:14]
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CC(C)N
Product: CC(C)NCCOc1ccc(O)cc1
Yield: 59 %

Procedure:
4-(2-Bromoethoxy)phenol (41 g) was added to 300 ml of isopropylamine and the solution was heated for 12 hours at 100° under nitrogen at 250 psi. Excess isopropylamine was removed in vacuo and 300 ml of water added to dissolve the residue. The solution was basified with solid potassium carbonate and the oil extracted with ether. The ether extract was dried over anhydrous potassium carbonate. After the solvent was removed in vacuo and the residue was crystallized from acetone-hexane to yield 21.8 g (59%) of 4-[2-(1-methylethyl)aminoethoxy]phenol, mp 78°-80°.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.FC(F)(F)C(C(F)(F)F)(OS(OC(C(F)(F)F)(C(F)(F)F)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:3]1([N:8]2[C:32](=[O:33])[C:11]3=[CH:12][N:13]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH:31]=[CH:30][CH:29]=[N:28]5)=[CH:25][CH:26]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)[CH2:4][CH2:5][CH2:6][CH:7]=[CH:2]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Agent: FC(F)(F)C(OS(OC(c1ccccc1)(C(F)(F)F)C(F)(F)F)(c1ccccc1)c1ccccc1)(c1ccccc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1C1C=CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 78 mg, 0.18 mmol) was suspended in dichloromethane (3 mL) and treated with bis[α,α-bis(trifluoromethyl)benzyloxy]diphenylsulfur (Martin's sulfurane, 0.18 g, 0.27 mmol, 1.5 equiv). After stirring for 1 hour, additional Martin's sulfurane (75 mg, 0.18 mmol, 1 equiv) was added and the mixture was stirred at ambient temperature for an additional 16 hours. The mixture was then placed into an oil bath preheated to 45° C. for 6 hours, cooled to ambient temperature, treated with sodium bicarbonate (1.5 mL, aqueous saturated) and stirred vigorously for 30 minutes. The mixture was poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 90:10; dichloromethane:methanol), providing partially purified material. The mixture was purified by preparative reverse phase HPLC (80:20 to 25:75; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted once with ethyl acetate (30 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.44 (1H, dd, J=4.6, 2.0 Hz), 8.42 (1H, s), 7.89 (1H, d, J=2.6 Hz), 7.72 (1H, d, J=1.8 Hz), 7.70 (2H, d, J=8.6 Hz), 7.46-7.43 (2H, m), 7.41-7.37 (1H, m), 7.28-7.28 (2H, m), 6.47 (1H, dd, J=2.4, 1.9 Hz), 6.03-5.98 (1H, m), 5.75 (1H, br d, J=9.8 Hz), 5.47 (2H, s), 5.29-5.22 (1H, m), 2.30-2.20 (1H, m), 2.14-1.98 (4H, m), 1.85-1.73 (1H, m) ppm; high resolution mass spectrometry (ES+) m/z 422.1981 [(M+H)+; calculated for C26H24N5O: 422.1975].
Reaction SMILES: [C:1]([CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])#[N:2].C1(C)C=CC=CC=1.Cl.S(O)(O)(=O)=O.[NH2:23]O>C(N(CC)CC)C.CO>[NH2:2][C:1]1[CH:3]=[C:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[O:9][N:23]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)no1
Reaction time: 23 h
Yield: 143.8 %

Procedure:
To a suspension of cyanopinacolone (75.102 g) in a mixture of anhydrous toluene (150 ml) and anhydrous methanol (26.7 ml) is introduced gaseous hydrogen chloride (26.3 g) with cooling at 5° to 10° C. and stirring, and the whole mixture is allowed to stand at 10° to 12° C. for 23 hours. To the reaction mixture is dropwise added anhydrous methanol (750 ml), then triethylamine (185.178 g) with cooling and stirring to make a complete solution. The reaction mixture is treated with hydroxylamine sulfate (51.704 g) and stirred at 50° C. for 2 hours. Then, conc. hydrochloric acid (112.629 g) is dropwise added to the mixture, which is stirred at 50° C. for 1 hour. After evaporating the solvent under reduced pressure from the reaction mixture, the residue is made alkaline with 48% aqueous sodium hydroxide with cooling, and the aqueous solution is shaken with toluene. The organic layer is washed with water, subjected to azeotropic distillation under atmospheric pressure, and evaporated to dryness to remove the solvent, whereby 3-amino-5-t-butylisoxazole (79.480 g) is obtained. Melting point is 106° to 109° C. Yield is 94.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[F:22][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)(=O)c1ccc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-methanesulfonylbenzene boronic acid (CAS 1491 04-88-1). MS (FIA) 489 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.N1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(Cl)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 63.4 %

Procedure:
4-BROMO-3-CHLOROBENZENESULFONYL CHLORIDE (10.0 g, 0.0345 mol) and 2-AMINOTHIAZOLE (3.80 g, 0.0379 mol) were mixed in Pyridine (40 mL, 0.5 mol). The reaction was allowed to stir at room temperature for 9 days. The reaction was concentrated in vacuo to a total volume of approximately 40 mL. The residue was triturated with acetonitrile and the solid collected by filtration. The filtrate was concentrated in vacuo and the residue triturated with 1N HCl. The solid was collected by filtration and rinsed with acetonitrile then ethyl ether. The combined solid from steps 4 and 5 was dissolved in boiling acetonitrile and treated with activated carbon then filtered through a celite pad. The filtrate was reduced to ⅓ its original volume by distillation. The mixture was cooled to room temperature. The crystals were collected by filtration and rinsed with ethyl ether. Vacuum drying gave 7.73 g of yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5](O)=[O:6].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.N.Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([NH2:21])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)c(Br)c1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2cccc(F)c2)c(Br)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A mixture of 3-bromo-4-(3-fluorophenoxy)benzoic acid (step 2, 550 mg, 1.77 mmol) and 1,1′-carbonyldiimidazole (430 mg, 2.65 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C. for 1 h. After cooling to 0° C., 25% ammonia solution was added slowly to the mixture. The resulting mixture was stirred at room temperature for 16 h. The mixture was pored into 2 M hydrochloric acid (100 mL) and the whole was extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to give 441 mg (80%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.14 (1H, d, J=2.2 Hz), 7.74 (1H, dd, J=8.6, 2.2 Hz), 7.36–7.27 (1H, m), 6.97–6.59 (6H, m).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[C:25]([OH:27])=[O:26])=[C:12]([C:38]1[CH:43]=[CH:42][C:41]([O:44]C)=[CH:40][CH:39]=1)[CH:11]=[CH:10]2.O.C(#N)C>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[C:25]([OH:27])=[O:26])=[C:12]([C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)C(CCCCCCCc1c(-c2ccc(O)cc2)ccc2cc(O)ccc12)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M, 8.5 ml, 8.47 mmol) was added dropwise to a solution of 9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (820 mg, 1.41 mmol) in dichloromethane (20 ml) at −78° C. under argon atmosphere. The reaction mixture was warmed with stirring to 0° C. over 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=3/2), followed by column chromatography on reversed-phase silica gel RP-18 (eluent: acetonitrile containing 0.1% trifluoroacetic acid/water=3/2), to give 9-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (633 mg, Yield 81%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]3[CH2:28][C:27]4[C:26]5[C:21](=[CH:22]C=[C:24](OC)[CH:25]=5)[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(Cl)Cl.[CH3:34][OH:35]>>[C:5]1([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]3[CH2:28][C:27]4[C:26]5[C:21](=[CH:22][C:34]([OH:35])=[CH:24][CH:25]=5)[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH2:10]2)[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C2CCCN(CC3CCc4[nH]c5ccc(OC)cc5c4C3)C2)c1
Reactant: CO
Solvent: ClCCl
Product: Oc1ccc2c3c([nH]c2c1)CCC(CN1CCCC(c2ccccc2)C1)C3

Procedure:
3-(3-m-methoxyphenylpiperidinomethyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole, Rf 0.7 (CH2Cl2 /methanol 9:1)