Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH2:51])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:38]1[C:39]2[CH:40]([CH2:42][O:43][C:44](=[O:52])[NH:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][NH:51][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([NH:14][C:15]5[S:16][C:17]6[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=6[N:19]=5)=[N:4][C:5]=4[CH:10]=3)=[O:12])[C:41]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCNC(=O)OCC3c4ccccc4-c4ccccc43)ccc21
Yield: 75.5 %

Procedure:
[2-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (106 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), [2-(2-amino-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (80 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).
Reaction SMILES: [CH2:1]([N:8]([CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=1)[CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.CC(O)=O.[Fe].O.O.O.O.[Fe](Cl)Cl>[NH2:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH2:38][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@@H:10]([C:19]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:25]3[C:20]=2[CH:21]=[CH:22][C:23](=[O:37])[NH:24]3)[O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])=[CH:45][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl[Fe]Cl
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(N)cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
A mixture of 5-[(R)-2-{benzyl-[2-(4-nitrophenyl)ethyl]amino}-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (3.00 g, 4.52 mmol); iron (2.52 g, 45.2 mmol) and iron(II) chloride tetrahydrate (0.18 g, 0.90 mmol) in EtOH (27.3 mL) and AcOH (9.09 mL) was stirred at 80° C. overnight. The reaction mixture was filtered through a pad of Celite, washing with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without any further purification.
Reaction SMILES: BrN[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrNc1cccc2ccccc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
A mixture of 4-bromoaminonaphthalene (5.0 g) and di-tert-butyldicarbonate (5.9 g) in 100 mL toluene was heated at 70° C. for 15 hours, cooled to room temperature and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate, washed with 0.1 M HCl and brine, dried (MgSO4) and the volatiles removed in vacuo. Recrystallization of the residue from hot petroleum ether provided LXXXIV. 4-Vinylpyridine (0.86 mL) was added to a suspension of LXXXIV (2.0 g) in 5 mL of triethylamine, followed by palladium (II) acetate (0.014 g) and tri-ortho-tolylphosphine (0.038 g). The mixture was heated at 110° C. for four hours, cooled to room temperature, diluted with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the volatiles removed in vacuo. Purification of the residue by flash chromatography using 50% ethyl acetate in hexanes as the eluent and concentration of the product-rich fractions in vacuo provided naphthalene LXXXV. A solution of LXXXV (0.34 g) in 10 mL TFA was stirred one hour and the volatiles removed in vacuo to provided LXXXVI. LXXXVI and LXVII (Example 1) were reacted according to Method B to provide 6, m.p. 203° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cccc(NCc3cccnc3)c2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(-c2cccc(N(Cc3cccnc3)S(=O)(=O)CC(F)(F)F)c2)cc1

Procedure:
A solution of N-(3-(4-cyanophenyl)phenyl)pyrid-3-ylmethylamine (255 mg, 0.894 mmol) in 8 ml dichloromethane/2 ml pyridine was treated with 2,2,2-trifluoroethylsulfonyl chloride in 3 portions of 171 mg (0.94 mmol) over 1 h at 45° C. The solution was cooled and diluted with 60 ml diethyl ether and washed successively with water and saturated sodium bicarbonate solution. The organics were separated, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was purified by radial chromatography on a 2 micron silica plate eluting with 2 to 4% methanol/dichloromethane to afford the title compound. 1H NMR: 8.65 (bs,1H), 8.42 (bs,1H), 7.85 (m,1H), 7.75 (d,2H,J=8 Hz), 7.58 (d,2H,J=8 Hz), 7.30-7.55 (m,5H), 5.02 (s,2H), 3.78 (q,2H,J=8 Hz). MS calcd. 431.44; MS (M+1) 432.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)piperidine-1-carboxylate (step 1) (3.5 g, 8.11 mmol) in DMF (40 ml) was cooled to 0° C. 60% sodium hydride/oil (0.487 g, 12.17 mmol) was added. The solution was stirred at 0° C. for 15 mins and then was warmed to RT. Iodomethane (0.761 ml, 12.17 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with ammonium chloride (20 ml). The mixture was diluted with water (200 ml) and extracted with EtOAc (2×200 ml). The organic portion was dried using MgSO4, filtered and concentrated under reduced pressure. The residue was applied to an 80 g silica cartridge in DCM and eluted with 0-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[CH2:3]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:17]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.596 g, 2.62 mmol) in methanol (10 mL) was added with potassium carbonate (0.724 g, 5.24 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with dimethyl (1-diazo-2-oxopropyl)phosphonate (0.500 g, 2.62 mmol), and the mixture was stirred at room temperature for additional 4 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.393 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.ClC1C2[C:29](=[O:31])C3C(=CC=CC=3)C(=O)C=2C=CC=1>>[Cl:1][C:2]1[C:15]2[C:6](=[C:7]([CH:29]=[O:31])[C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2cc3ccccc3cc12
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Product: O=Cc1c2ccccc2cc2c(Cl)cccc12

Procedure:
1-Chloroanthracene prepared from 1-chloroanthraquinone (Aldrich) by the method of H. O. House et al. (J. Org. Chem. 38. 1167 (1973)) was formylated by the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). A mixture of a 1- and 4-chloro-9-anthracenecarbaldehydes was obtained which was partially purified by preparative HPLC using PhCH3 as the eluting solvent. The solid from the purified fraction was then recrystallized 2× from PhCH3 /CH3OH to give pure 4-chloro-9-anthracenecarbaldehyde mp 129°-131°, (C, H, Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[O:15][C:13](=O)[C:12]2=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C(I)C.[O-]CC.[Na+].Cl>O1CCCC1.C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13]([OH:15])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:24]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:16]2=[O:17])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNCC(C)C
Reactant: O=C1OC(=O)c2cc(OCc3ccccc3)ccc21
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ccc(OCc3ccccc3)cc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
A solution of 4-benzyloxyphthalic anhydride (4.07 g, 16 mmol) and ethyl 2-(isobutylamino)acetate (2.86 g, 18 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (2.21 g, 16 mmol) and ethyl iodide (1.5 mL, 19.2 mmol) were added thereto. The mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL), and a solution (10.9 g, 32 mmol) of 20% sodium ethoxide in ethanol was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (70 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give ethyl 7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (4.21 g, 66.6%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[N:16][NH2:17])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1F)=[O:7])[CH3:2].[H-].[Na+].CS(O[CH2:26][C:27]1[CH:28]=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1)(=O)=O.[Cl-].[NH4+]>O>[Br:33][C:30]1[N:29]=[CH:28][C:27]([CH2:26][N:17]2[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:14])[C:6](=[O:7])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[N:16]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1ccc(Br)nc1
Reactant: CCOC(=O)C(=NN)C(=O)c1cccc(Cl)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2c(Cl)cccc2c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl-3-(3-chloro-2-fluorophenyl)-2-hydrazinylidene-3-oxopropanoate [(Example 60, Step 1), 1.9 g, 7.0 mmol] and (6-bromopyridin-3-yl) methyl methanesulfonate (2.4 g, 9.1 mmol, 1.3 equiv) were dissolved in degassed N,N′-dimethyl formamide, cooled to 0° C. and treated with sodium hydride (0.45 g, 11 mmol, 1.6 equiv). After stirring at 0° C. for 3 hours, additional (6-bromopyridin-3-yl)methyl methanesulfonate (0.55 g, 2.1 mmol, 0.3 equiv) and sodium hydride (84 mg, 2.1 mmol, 0.3 equiv) were added and stirred for an additional 5 hours. The mixture was treated with ammonium chloride (10 mL, aqueous saturated), poured into water (50 mL) and extracted three times with ethyl acetate. The combined organic extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol), providing the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N:12]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: NNC(=O)c1cc(Cl)ccn1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: NNC(=O)c1cc(N2CCNCC2)ccn1
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 4-chloropyridine-2-carboxylic acid hydrazide (9.37 g), piperazine (20.0 g) and sodium bicarbonate (15 g) in n-butanol (120 ml) was heated under reflux with stirring for 18 hours and then cooled and filtered. The filtrate was evaporated and the residue was chromatographed on silica gel. Elution with a mixture of chloroform, ethanol and concentrated aqueous ammonia solution (50:50:1) gave the product as a solid (8.10 g), m.p. 212°-217° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C([N:29]=[C:30]=[S:31])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:30](=[S:31])[NH2:29])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Product: CCOC(=O)C1CCCN(C(N)=S)C1
Yield: 92.5 %

Procedure:
1-Thiocarbamoyl-piperdine-3-carboxylic acid ethyl ester (400 mg) was prepared following general procedure D using piperdine-3-carboxylic acid ethyl ester (315 mg, 2.0 mmol), and Fmoc-isothiocyanate (562 mg, 2.0 mmol). Purification: (Silica gel, ethyl acetate/hexane 1:1). LCMS m/z 217.0 (M+1)+
Reaction SMILES: [C:1]([C:4]1([CH2:14][CH3:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Br:16]Br>CO>[Br:16][CH2:2][C:1]([C:4]1([CH2:14][CH3:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[CH2:5]1)=[O:3]
Reactant: BrBr
Reactant: CCC1(C(C)=O)Cc2ccc(F)cc2C1
Solvent: CO
Product: CCC1(C(=O)CBr)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
3.8 g of 2-acetyl-2-ethyl-5-fluoroindan and 35 ml of methanol were placed into a round-bottomed flask equipped with a thermometer, a mechanical stirrer and a dropping funnel. The reaction mixture was cooled in a cooling bath while stirring to a temperature between −5° C. and −8° C. and 0.7 ml of a Br2-solution in a small amount of methanol was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to a temperature between −5° C. and −8° C. and an additional 0.175 ml of Br2-solution in a small amount of methanol was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 1 to 2 hours. After chromatographic purification using methylene chloride as an eluent 2.51 g of 2-bromo-1-(2-ethyl-5-fluoro-indan-2-yl)-ethanone was obtained as a liquid (yield 69%).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)=[O:11])[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:13]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3[nH]ncc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (135 mg, 0.26 mmol) in methanol (4 mL) was added hydrochloric acid in dioxane (2 mL, 4N, 8 mmol). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as an off white solid (94 mg, 75%). LCMS (Method A): RT=7.67 min, [M+H]+=487. 1H NMR (DMSO-d6, 400 MHz) 13.20 (1H, s), 11.67 (1H, s), 9.94 (1H, s), 7.66 (1H, dd, J=10.30, 1.92 Hz), 7.47 (1H, d, J=8.79 Hz), 7.45-7.41 (1H, m), 7.22 (1H, s), 7.01 (1H, d, J=8.78 Hz), 6.92 (1H, t, J=8.64 Hz), 3.92-3.85 (1H, m), 3.76-3.58 (2H, m), 3.41-3.31 (2H, m).
Reaction SMILES: [OH-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:11]([NH:13][C:14]1[C:15](=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:16]([O:18]C)=[O:17])=[O:12].Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:11]([NH:13][C:14]1[C:15](=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)Nc2ccc(Cl)cc2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 20 ml of a 10% aqueous solution of sodium hydroxide and 10 ml of ethanol is added 0.95 g of methyl N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilate and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into 100 ml of water and after cooling, hydrochloric acid is added to make the mixture weakly acidic. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 0.7 g of N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid as colorless needles.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH:9]=1)(C)(C)C.C(N(CC)CC)C.[C@@H:38]1(C(O)=O)[CH2:42][CH2:41][CH2:40][C@@H:39]1[C:43]([OH:45])=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:10]2[CH:9]=[C:8]([NH:7][C:6]([C@H:38]3[CH2:42][CH2:41][CH2:40][C@H:39]3[C:43]([OH:45])=[O:44])=[O:5])[CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)[C@H]1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1)[C@H]1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
[3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-phenyl]-carbamic acid tert-butyl ester (111 mg, 0.269 mmol) was stirred in 5 mL EtOAc (saturated with HCl) at RT for 45 min. The mixture was evaporated, re-evaporated from EtOAc and pumped under high vacuum to give a solid. The crude product was dissolved in DMF (2 mL). To this solution, chilled in an ice bath, was added triethylamine (150 uL, 1.08 mmol), (cis)-cyclopentane-1,2-dicarboxylic acid (64 mg, 0.404 mmol) and HATU (154, 0.404 mmol) was added and then let stir at RT for 30 min. The reaction mixture was diluted with EtOAc (25 mL), washed with 1N HCl (10 mL), H2O (10 mL), saturated NaCl (10 mL), dried over MgSO4, filtered and evaporated to give a white solid. The crude product was purified by flash chromatography with a 0-55% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes to yield 64.8 mg of rac-(cis)-2-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenylcarbamoyl]-cyclopentanecarboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1ccc(-c2cc(O)no2)cc1
Product: CC(C)c1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 76.3 %

Procedure:
3-Hydroxy-5-(4-isopropylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 77%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13](O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(O)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=Cc3ccc(OC)cc3C3CCCCC23)cc1
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ol (184.3 mg, 0.54 mmol), p-toluene sulfonic acid (20.0 mg, 0.11 mmol), benzene (5 mL), stir, and reflux under nitrogen atmosphere. After 1.5 hours, cool reaction to ambient temperature, add ethyl acetate, wash sat sodium bicarbonate solution (aq), and then with brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using 0% to 20% ethyl acetate/hexanes to yield the titled compound (147.6 mg, 85%) as a clear oil. TLC Rf=0.51 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.53 (d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=7.9 Hz), 6.93 (m, 3H), 6.72 (m, 2H), 3.85 (m, 6H), 3.21 (m, 1H), 2.79 (m, 1H), 2.49 (m, 1H), 1.80 (m, 1H), 1.58 (m, 4H), 1.30 (m, 2H).