Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([Cl:26])[CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>COCCOCCO.O.CCOC(C)=O.Cl[Pd]Cl>[Cl:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOCCO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)ccc2c1
Temperature: 110 °C
Yield: 46 %

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (200 mg, 1.04 mmol), 4-carboxy-2-chlorophenylboronic acid (247 mg, 1.24 mmol) and K2CO3 (369 mg, 2.70 mmol) in DEGME/H2O (7.0 mL/2.0 mL) was degassed three times under N2 atmosphere. Then PdCl2 (dppf) (75 mg, 0.104 mmol) was added and the mixture was heated to 110° C. for 3 hours under N2 atmosphere. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, yield 46%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[H-].[Na+].C(Br)C1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 273.5 %

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (237 mg, 0.65 mmol) in DMF (1mL) was treated with NaH (0.68 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C., and treated with a solution of benzyl bromide (142 mg, 0.83 mmol) in DMF and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a colorless oil. Purification by silica gel flash chromatorgraphy (20:1=hexanes:EtOAc) gave 4-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 242 mg (82%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ8.19 (½ABq, J=8.4 Hz, 2H, ArH), 7.81 (½ABq, J=8.4 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 7.38 (m, 3H, ArH), 7.17 (m, 2H, ArH), 6.92 (s, 1H, ArH), 4.93 (s, 2H, OCH2), 3.95 (s, 3H, OCH3), 1.67 (m, 4H, 2CH2), 1.29 (s, 6H, 2CH3), 1.26(s, 6H, 2CH3). The benzyloxy keto ester (204 mg, 0.46 mmol) in MeOH (2 mL) was treated with hydroxylamine hydrochloride (97 mg, 1.4 mmol) and KOH (156 mg, 2.8 mmol), and the mixture was heated at reflux for 3 h. After 6 h, the mixture was cooled to room temperature and the ethanol was removed in vacuo. The residue was taken-up in water and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (Na2SO4), filtered, and concentrated to give a white foamy solid. Recrystallization (THF/hexanes) gave cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbonyl]benzoic acid oxime (117) 186 mg (88%) as a white solid: mp 199-205° C. (d); IR (neat) 3500-3100 (br) m, 2963 s, 2934 s, 1694 s, 1613 w, 1505 w, 1321 m, 1265 m, 1024 w cm−1; 1H NMR (400 MHz, CDCl3) δ8.00 (½ABq, J=8.4 Hz, 2H, ArH), 7.56 (½ABq, J=8.4 Hz, 2H, ArH), 7.20 (m, 3H, ArH), 7.15 (s, 1H, ArH), 7.08 (m, 2H, ArH), 6.91 (s, 1H, ArH), 4.96 (s, 2H, OCH2), 1.69 (m, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3); HRMS (EI−, 70 ev) calcd. for C29H31NO4: 457.2253, found 457.2226; anal. calcd. for C29H31NO4; C176.12; H1 6.83; N1 3.06, found C1 75.83; H1 6.95; N1 2.90.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=399.1, tR (minutes, Method G)=2.57. [α]D20=+20.45 (c=2.20 mg/mL,CHCl3)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:34]=[CH:33][N:32]([CH2:35][C@@H:36]5[CH2:40][O:39]C(C)(C)[O:37]5)[N:31]=4)[C:26](=[O:43])[N:25]([CH3:44])[N:24]=3)[C:18]=1[CH2:45][OH:46])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:34]=[CH:33][N:32]([CH2:35][C@@H:36]([OH:37])[CH2:40][OH:39])[N:31]=4)[C:26](=[O:43])[N:25]([CH3:44])[N:24]=3)[C:18]=1[CH2:45][OH:46])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccn(C[C@@H](O)CO)n2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of (R)-6-tert-butyl-2-(3-(5-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one (135 mg, 0.21 mmol) in tetrahydrofuran (4 ml) was added a solution of hydrochloric acid (1.0 N, 4 ml) and the resulting solution was stirred at room temperature overnight. The resulting mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane (2×50 mL). The organic layers were combined and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue crystallized from dichloromethane and isopropyl acetate. The crystals were washed with ether and dried to give 6-tert-butyl-2-(3-{5-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (52 mg, 41%) as a light yellow solid: mp. 245-250° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 3.67-4.24 (m, 6H) 4.27-5.06 (m, 5H) 6.19 (d, J=2.27 Hz, 1H) 7.18-7.96 (m, 7H) 8.51 (d, J=2.27 Hz, 1H) 9.23 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N+:4]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[C:8]=1Cl)([O-:6])=[O:5]>>[CH2:1]([NH:3][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:12][C:7]=1[N+:4]([O-:6])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: CCNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Following the above procedure, two grams of a 70% aqueous solution of ethylamine was reacted with 2.6 grams (0.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene to yield 2 grams of N-ethyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 70°-73° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3c2)cn1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (120 mg, 0.29 mmol) and [6-(methyloxy)-3-pyridinyl]boronic acid (66 mg, 0.43 mmol) in DME/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (11.7 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 110° C. for 20 min. Water was added and the solids that precipitated were filtered. DCM was added and it was purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered. DMF was added along with some water and the solids that precipitated were filtered and dried to afford the title compound (57 mg, 43%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.69 (d, J=2.27 Hz, 1H) 8.62 (t, J=4.80 Hz, 1H) 8.39 (s, 1H) 8.22 (dd, J=8.72, 2.65 Hz, 1H) 8.15 (s, 1H) 7.87 (s, 1H) 6.97 (d, J=8.59 Hz, 1H) 5.89 (s, 1H) 5.15 (dt, J=13.07, 6.47 Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 3.92 (s, 3H) 2.22 (s, 3H) 2.12 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H). MS (ES) [M+H]+ 446.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)([O-])=O>CCO.C1COCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
The product from Example 183a (350 mg, 0.985 mmol), and Pt(IV)O2 (4 mg, 0.2 mmol) were placed in a 50 ml round bottom flask and dissolved in 1 ml of EtOH and 1 ml of THF. Reaction mixture placed under vacuum and backfilled with H2 using a balloon. Balloon was left on overnight and the next day the reaction mixture was purged and backfilled with N2, filtered and concentrated under vacuum giving the title compound (260 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC>>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH2:12][CH2:13][C:14]2=[O:16]
Reactant: O=C(O)CCc1c(Br)cccc1C(F)(F)F
Agent: [Li]CCCC
Product: O=C1CCc2c1cccc2C(F)(F)F

Procedure:
Fourteen and nine-tenths grams of β-(2-bromo-6-trifluoromethylphenyl) propionic acid were cyclized with n-butyl lithium to yield 4-trifluoromethyl-1-indanone melting at about 32°-36° C.; yield = 6.2 g.; distilled at 67°-72° C. at 0.1 torr. 3 g. of the indanone were reductively aminated with ammonium acetate and sodium cyanoborohydride following the procedure of J.A.C.S., 93, 287-97 (1971). According to this procedure, 3 g. of 4-trifluoromethyl-1-indanone, 691 mg. of sodium cyanoborohydride, 11.6 g. of ammonium acetate and 45 ml. of methanol were mixed in the presence of a 3A molecular sieve (to absorb water). The reaction mixture was stirred at room temperature for about 3 days. It was then cooled in an ice-water bath and acidified with 12 N aqueous hydrochloric acid. Methanol was removed by evaporation and an additional 100 ml. of water were added. The reaction mixture was filtered and the acidic filtrate extracted with ether. The ether extract was discarded and the acidic aqueous solution cooled and then made basic with 5N aqueous sodium hydroxide. The alkaline layer was extracted three times with ether, and the ether extracts combined. The combined extracts were washed with saturated aqueous sodium chloride and then dried. Evaporation of the ether yielded 2 g. of an oil comprising 4-trifluoromethyl-1-aminoindane. The hydrochloride salt was made by the process of Example 1. Crystalline 4-trifluoromethyl-1-aminoindane hydrochloride thus prepared melted at 207°-211° C. with decomposition after recrystallization from an ethyl acetate-methanol solvent mixture; pKa = 8.58.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:29]2[N:47]2C(=O)C3=CC=CC=[C:49]3[C:48]2=[O:57])[C@@H:16]([CH2:58][O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>CO.C(N)CCC.O.CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][C@@H:28]2[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:29]2[NH:47][C:48](=[O:57])[CH3:49])[C@@H:16]([CH2:58][O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2N2C(=O)c3ccccc3C2=O)[C@@H]1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](NC(C)=O)[C@@H](OCc3ccccc3)O[C@@H]2COCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
A solution of benzyl 2-acetamido-4-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside (2.1 g, 2.3 mmol) in methanol (80 ml) and n-butylamine (20 ml) is heated for 48 hours at reflux temperature. Cooling and evaporation of the reaction mixture gives a solid that is slurried in water and lyophilized. The resulting solid is dissolved in the minimal volume of N,N-dimethylformamide and the solution applied to a column of silica gel (E. Merck, No. 7734, 70-230 mesh). Elution with 20:1 chloroform-methanol and evaporation of the appropriate fractions gives a chromatographically homogeneous solid that is dissolved in methanol (35 ml) and treated with acetic anhydride (2.5 ml) for 2 hours at room temperature. Evaporation of the reaction mixture and several coevaporations with toluene gives a solid that is crystallized from ethanol to afford pure benzyl 2-acetamido-4-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside; yield 1.1 g (69%), m.p. 252°-256° (dec.), [α]D25 +72° (c, 1.2, methanol). The 300-MHz nmr spectrum in methanol-d4 is in accord with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cu].ClC1C=CC=CC=1Cl>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:1]([C:2]2[CH:23]=[CH:22][C:5]([CH3:6])=[CH:4][CH:3]=2)[C:2]2[CH:23]=[CH:22][C:5]([CH:6]=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH:10]=[CH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=C3c4ccccc4C=Cc4ccccc43)cc2)cc1
Reaction time: 7 h
Yield: 149.9 %

Procedure:
To 30 ml of o-dichlorobenzene, were added 7.90 g (26.7 mmol) of the 5-(4-aminobenzylidene)-5H-dibenzo[a,d]cycloheptene previously obtained, 22.0 g (101 mmol) of p-iodotoluene, 11.0 g (79.6 mmol) of anhydrous sodium carbonate and 2.2 g of copper powder. The mixture was refluxed with stirring for 7 hours in an oil bath kept at around 190° C. After the reaction was completed, the reaction was subjected to suction filtration and the filtrate was successively washed with an aqueous 35% sodium thiosulfate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the resulting residue was added about 60 ml of acetone, and the precipitated crystals were collected by filtration. The crystals obtained were further recrystallized using an ethyl acetate/n-hexane mixed solvent to obtain 9.52 g of 5-[4-(di-p-tolylamino)benzylidene)-5H-dibenzo[a,d]cyclo heptene. Yield: 75.0%; m.p.: 168.0 to 169.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:2].[CH:24](OCC)(OCC)OCC.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.O>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH:24]=[N:14][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(OCC)OCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc2ocnc2c1)NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of crude 3-(3-amino-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid ethyl ester (0.89 g, 2.74 mmol) in toluene (20 mL) was added triethyl orthoformate (0.57 mL, 3.36 mmol) and the mixture was heated to 75° C. under an atmosphere of argon for 3 hours at which time all starting material had been consumed. The reaction mixture was concentrated in vacuo to a black waxy solid which was dissolved in acetonitrile (25 mL) and di-tert-butyldicarbonate (0.80 g, 3.67 mmol) added. The mixture was stired at ambient temperature under an atmosphere of argon for 16 hours then poured into water (100 mL), diluted with brine (50 mL) and extracted with ethyl acetae (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to a black viscous oil. Purification by chromatography over silica gel eluted with 35% ethyl acetate/65% hexanes gave (S)-3-benzooxazol-5-yl-2-tert-butoxycarbonylamino-propionic acid ethyl ester as a colorless solid (0.54 g, 59%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8](B(O)O)=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:2].[OH:21]O>C(OCC)(=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:21])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2ccccc2)c2cc(B(O)O)ccc12
Reactant: OO
Solvent: CCOC(C)=O
Product: CCc1nn(-c2ccccc2)c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-ylboronic acid (1.4 g, 5.26 mmol, 1.00 equiv) in ethyl acetate (10 mL). To the resulting mixture was then added H2O2 (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 3-ethyl-1-phenyl-1H-indazol-6-ol as a white solid. MS: 239 (MH+).
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(O)noc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(N3CCNCC3)noc2c1
Temperature: 30 °C

Procedure:
Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)N3CCCC3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)N2CCCC2)CC1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (86.5 mg, 0.193 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (92.4 mg, 2.2 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight under a nitrogen atmosphere. The solvent was evaporated. Water (20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (4 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum to give {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (55.7 mg, 66%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s., 1H), 8.07 (br. s, 1H), 7.90 (dd, J=9.0, 6.5 Hz, 1H), 7.69 (s, 1H), 7.35 (td, J=8.5, 2.0 Hz, 1H), 3.78 (br. s., 4H), 3.22-3.43 (m, 5H), 3.09 (br. s., 2H), 2.42 (br. s., 3H), 1.81-1.97 (m, 4H), 1.67 (bd, 2H). MS cald. for C22H28FN2O4S [(M+H)+]: 434, obsd. 434.2.