Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[O:26]=[C:20]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1ccc2ccccc2n1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a mixture of quinolin-2-amine (200 mg, 1.4 mmol) and triethylamine (210 mg, 2.1 mmol) in dichloromethane (10 mL) was added dropwise ethyl 2-chloro-2-oxoacetate (227 mg, 1.67 mmol). After stirring for 1 hour at room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1% ethyl acetate in petroleum ether to afford ethyl 2-oxo-2-(quinolin-2-ylamino)acetate as yellow solid (210 mg, 62%). (ES, m/z): [M+H]+ 245.1; 1H NMR (400 MHz, CDCl3): δ 9.65 (br s, 1H), 8.44 (d, J=8.8 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 1H), 7.53-7.49 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:24])=[O:2])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)cc(Cl)c1Cl
Yield: 1.9 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,3,5-trichlorophenylboronic acid (available from Alfa Aesar; 113 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,3′,5′-trichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (2.5 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.27 (br s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.47-7.53 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC>O1CCOCC1>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:4]=2[CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[NH+]1C2=c3ccccc3=NC2=C(c2ccccc2)c2cc(F)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A suspension of 2-fluoro-5-methyl-11-chloroquindoline from Example 24 (300 mg, 0.35 mmol) in dry dioxane (30 mL) was added to a 1.0 M solution of C6H5MgBr in ether (6 mL, 6.0 mmol, obtained from Aldrich Chemical Co.) at room temperature. The reaction mixture was stirred for 1 hour at room temperature, then heated for 1 hour at 50° C. The reaction mixture was cooled, poured into ice-water (300 mL), allowed to stand overnight to effect hydrolysis (pH ~7), and then extracted with EtOAc (4×50 mL) and chloroform (4×50 mL). The combined chloroform and ethyl acetate extracts were washed with water, dried, concentrated, and then purified by chromatography on a basic alumina column, eluting 0.5-1.5% MeOH in CHCl3. The product containing fractions were combined, acidified with 1.0 M HCl solution in ether and concentrated to afford 175 mg (45.8%) of the title compound as a yellow solid, mp 251.4-251.8° C.; 1H NMR (DMSO-d6) δ 12.44 (s, NH), 9.00 (dd, J=4.4, J=9.2, 1H), 8.85 (d, J=8.4, 1H), 8.17 (t, J=7.6, 1H), 7.93 (t, J=7.8, 1H), 7.81-7.79 (m, 4H), 7.74-7.70 (m, 2H), 7.62 (d, J=9.2, 1H), 7.54 (t, J=7.2, 1H), 5.12 (s, 3H); 13C NMR (DMSO-d6) δ 159.66 (J=249.1), 146.35, 138.27, 136.45, 134.13, 132.80 (J=4.2), 131.15, 130.34, 129.94, 129.60, 129.39, 126.20 (J=9.9), 121.88 (J=9.1), 121.72, 121.66, 121.46, 114.01, 113.49, 109.94 (J=24.1), 49.94; (LSIMS, m/z) 327 (MH+).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[C:11](=O)([O:17]C(C)(C)C)[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1.O.C(OCC)(=O)C>[C:13]([O:12][C:11]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 3-hydroxypiperidine hydrochloride (827 mg, 6 mmol) in dioxane (12 ml) and water (6 ml) cooled to 0° C. is added 1 N NaOH (12 ml, 12 mmol) and dit-butyl carbonate (827 mg, 6 mmol) in dioxane (35 ml) and the reaction mixture is stirred at 25° C. for 1 hr. The reaction mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, 1 N KHSO4, water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to give N-t-butoxycarbonyl-3-hydroxypiperidine (1.07 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[CH:12]=[CH:11]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)(=O)C(Cl)=O.ClCCl>[Br:1][C:2]1[S:3][C:4]([C:7]([C:12]2[C:13]3[C:18](=[N:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[O:9])=[CH:5][N:6]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(O)c1cnc(Br)s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cnc(Br)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A suspension of 2-Bromo-thiazole-5-carboxylic acid (98, 0.5 g, 0.002 mol) in oxalyl chloride (3 mL) was stirred at room temperature until it turned into a clear solution. Solvent was removed and the residue was dried over vacuum. A light yellow solid was obtained and was dissolved in dichloromethane (10 mL) and slowly added to a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 0.34 g, 0.0029 mol) in dichloromethane (30 mL) at −10° C. To the mixture was then added aluminum trichloride (2.6 g, 0.019 mol) in one portion with vigorous stirring. The reaction was held at −10° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with ice-water and acidified with hydrochloric acid (10%) to pH 4. The solution was then extracted with dichloromethane. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (99, 12 mg, 2%). MS (ESI) [M−H+]=369.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1.Cl[CH2:26][C:27]1[N:28]=[N:29][CH:30]=[CH:31][CH:32]=1.CC(C)([O-:36])C.[Na+]>C1(C)C=CC=CC=1>[C:14]([OH:23])(=[O:36])[CH3:13].[CH3:21][C:17]1([CH3:22])[CH2:16][NH:15][C:14](=[O:23])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:24]=[C:2]([NH:1][C:30]5[N:29]=[N:28][C:27]([CH3:26])=[CH:32][CH:31]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:20][C:19]=2[CH2:18]1
Reactant: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Reactant: CC(C)(C)[O-]
Reactant: ClCc1cccnn1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)O
Product: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NCC(C)(C)C4)CCO3)nn1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
A mixture of Example 69 (100 mg, 0.29 mmol), chloromethylpyridazine (20 mg, 0.29 mmol), sodium tert-butoxide (80 mg, 0.8 mmol) and dichloro(1,1′-bis(di-tert-butylphosphino)ferrocene)palladium (10 mg, catalytic) in toluene (5 mL) was heated to 120° C. under microwave irradiation for 2 h. It was cooled to r.t., concentrated in vacuo and purified by prep HPLC to give the title compound (14 mg, 9%) as an off-white solid. δH (CD3OD/CDCl3) 1.11 (6H, s), 2.02 (3H, s), 2.54 (3H, s), 2.85 (2H, s), 3.12 (2H, s), 4.09-4.17 (2H, m), 4.29-4.35 (2H, m), 6.94 (1H, d, J 8.9 Hz), 7.10-7.30 (3H, m), 7.99 (1H, s). LCMS (ES+) 437 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH2:26]([N:22]1[CH2:23][C:24](=[O:25])[N:9]2[C@H:10]([CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][CH:4]=2)[C:21]1=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NS(C)(=O)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O

Procedure:
To a solution of Example 98 (0.2 g) in THF (5 mL) was added triethylamine (228 μL) and methanesulfonyl chloride (126 μL) and the solution was heated at reflux for 6 hours. After evaporation of THF, the residue was taken up in CH2Cl2, washed with water and dried over Na2SO4. After evaporation of CH2Cl2, the residue was purified by radial chromatography eluting with CH2Cl2 /MeOH (95/5) to give the title compound as a brown powder (30 mg) m.p.:188° C.
Reaction SMILES: Cl[CH:2]=[C:3](Cl)Cl.[CH2:6]([O:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:10][C:11](=[O:13])[C:12]1[C:12](=[CH:3][CH:2]=[CH:2][CH:3]=1)[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:13])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(C)=O
Reactant: ClC=C(Cl)Cl
Product: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Reaction time: 48 h

Procedure:
The procedure for preparing the solution is as follows. Carefully crush the 9.7 grams of Ixan-SGA resin with a mortar and pestle to yield a fine powder. Then, gradually add the Ixan powder to the 30 grams butylacetate while constantly stirring the solution to prevent clusters from forming. Complete dissolution is reached only after approximately 48 hours. After complete dissolution, add the 57.9 grams of trichloroethylene and stir the resulting solution constantly for another 24 hours to yield a clear yellow solution. The last two solvents are used as plasticizers. After filtering the Ixan solution through a millipore filtering apparatus with a filter having a 1.2 μm pore size and 47 mm. diameter, add the plasticizers and again stir the solution for another 12 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Cl[CH2:45][C:46]1[N:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[N:47]=1.ClCC1C=NC(OC)=NC=1>>[CH3:53][O:52][C:50]1[CH:49]=[C:48]([O:54][CH3:55])[N:47]=[C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[N:51]=1
Reactant: COc1cc(OC)nc(CCl)n1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: COc1cc(OC)nc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-4,6-dimethoxypyrimidine to replace 5-(chloromethyl)-2-methoxypyrimidine, 1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%): mp 169-170° C.; 1H NMR (300 MHz, CDCl3) δ7.21-7.11 (m, 2H), 7.06-6.95 (m, 1H), 6.81-6.67 (m, 1H), 6.49 (s, 1H), 6.37 (s, 1H), 5.89 (s, 1H), 4.98 (ABq, 2H), 4.80 (ABq, 2H), 4.23-4.00 (m, 4H), 3.80 (s, 6H); MS (ES+) m/z 447.9 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:50])[C:26]1[C:31]([NH:32][CH:33]([CH2:37][CH3:38])[CH:34]([OH:36])[CH3:35])=[CH:30][C:29]([CH3:39])=[N:28][C:27]=1[O:40][C:41]1[C:46]([CH3:47])=[CH:45][C:44]([Cl:48])=[CH:43][C:42]=1[CH3:49]>>[CH3:23][O:24][C:25](=[O:50])[C:26]1[C:31]([NH:32][CH:33]([CH2:37][CH3:38])[C:34](=[O:36])[CH3:35])=[CH:30][C:29]([CH3:39])=[N:28][C:27]=1[O:40][C:41]1[C:46]([CH3:47])=[CH:45][C:44]([Cl:48])=[CH:43][C:42]=1[CH3:49]
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O

Procedure:
The title compound was prepared by Dess-Martin oxidation of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic acid methyl ester. A, white solid was obtained after silica gel column chromatography. 1H NMR(CDCl3) d 8.6(d,1H), 7.01(s,2H), 5.899s,1H), 3.9-4.0(m,1H), 3.90(s,3H), 2.17(s,3H), 2.07(s,3H), 2.05(s,3H), 1.859m, 1H), 1.93(m, 1H), 1.00(t,3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24]([CH:35]=[CH2:36])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24](/[CH:35]=[CH:36]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH3:12])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)ccc1/C=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 54.7 %

Procedure:
1-Bromo-2-methyl-4-(trifluoromethyl)benzene (1.144 g, 4.79 mmol), 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78; 1.27 g, 3.99 mmol), palladium(II) acetate (0.045 g, 0.199 mmol), triethylamine (10.56 ml, 76 mmol), tri-o-tolylphosphine (0.243 g, 0.798 mmol) and acetonitrile (8 ml) were combined. The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes before being quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford an orange gum. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-[(E)-2-[2-methyl-4-(trifluoromethyl)phenyl]ethenyl]pyridazine as a white solid (1.04 g, 55%).
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.[Cl:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1.CCOCC>[Cl:17][CH2:18][C:19]([C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:3]=2[CH:2]=1)=[O:20]
Reactant: CON(C)C(=O)CCl
Reactant: Cc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2sc(C(=O)CCl)cc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 3-bromo-4-methylbenzo[b]thiophene (2 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 4.58 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of 2-chloro-N-methoxy-N-methylacetamide (1.04 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, then the mixture was stirred at −70° C. for 5 hours, allowed to stand at ambient temperature for 18 hours and quenched by the addition of saturated aqueous ammonium chloride solution (40 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (40 ml), and dried (MgSO4). The solvents were removed in vacuo to give 2-chloro-1-(4-methylbenzo[b]thiophen-2-yl]ethan-1-one (1.65 g) as a brown oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1.O>C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([NH:9][C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)ccc1O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
A mixture of 5-bromo salicylamide (2.5 g, 11.6 mmol), N—BOC-4-piperidone (2.30 g, 11.6 mmol) and pyrrolidine (0.96 ml, 11.6 mmol) in toluene (40 ml) was heated to reflux under N2 atmosphere. After 3 h, the mixture was cooled down to RT, poured into water and extracted with AcOEt. The organic phase was washed with a 2 M solution of NaOH (150 ml) and then with 2 M HCl (150 ml), dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH 90/10 as eluent, to give 1.82 g of 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester as a white solid (40%). Reaction with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, gave (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 71%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25]OS(C)(=O)=O)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:31]([CH2:25][CH2:24][O:23][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:32]=[N-:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCOS(C)(=O)=O)c2cccc(F)c2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN=[N+]=[N-])c2cccc(F)c2F)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (4.2 g, 9.4 mmol) and solid NaN3 (0.92 g, 14.1 mmol) in anhydrous DMF (30 mL) was heated to 80° C. overnight. The reaction mixture was cooled to rt and diluted with ethyl acetate (80 mL), the organic phase was washed with water (30 mL×3), dried over Na2SO4 and evaporated. The residue was separated on a silica column to give (3R)-tert-butyl 3-((2-azidoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (3.4 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.14 (m, 3H), 4.50 (q, 1H), 4.10 (m, 1H), 3.40 (m, 4H), 2.70 (m, 2H), 1.90 (m, 2H), 1.65 (m, 1H), 1.41 (d, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[Na+]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
tert-Butyl-2-bromoacetate (1.95 g, 10.0 mmol) was added to a mixture of 4-fluorophenol (1.12 g, 10.0 mmol) and NaOH (400 mg, 10.0 mmol) in N,N-dimethylformamide (15 ml) and stirred at room temperature for 17 hours. The reaction was quenched with H2O (50 ml) and extracted by ethyl acetate (50 ml×3). The combined organic phase was washed with H2O (50 ml×4) and brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 2-(4-fluorophenoxy)acetate (2.16 g, 95%) as yellow oil: LC-MS: 171 [M−55]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.3 mN) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (95 mg, 0.6 mM) was added and the resultant mixture stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 120 mg (88%) of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.2 (m, 7H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (br s, 1H), 6.0 (br s, 1H), 5.55 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (KBr, cm−1) 1763 and 1673. MS (ES) m/e 457.