Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.Cl.CO>>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Cl)c23)CC1
Agent: Cl
Solvent: CO
Product: Clc1cncc2cccc(NC3CCNCC3)c12
Yield: 230.4 %

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 91 (53.5 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (50.8 mg) as light yellow powdery solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[S:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: Clc1csc(-c2cccnc2)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1sc(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
4-Chloro-2-(pyridin-3-yl)thiazole (1.00 g, 5.09 mmol) was placed in a dry flask and concentrated H2SO4 (2.50 g, 25.4 mmol) was added. The contents were cooled to 0° C., and fuming HNO3 (641 mg, 10.17 mmol) was slowly added. The mixture was stirred at 40° C. for 3 h and cooled to room temperature. The contents were slowly added to an ice-cold saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate (2×50 mL) and the extracts were combined, rinsed with brine and concentrated in vacuo to give 4-chloro-5-nitro-2-(pyridin-3-yl)thiazole as a peach-colored solid (985 mg, 80% yield): mp 110-112° C.; 1H NMR (300 MHz, CDCl3) 9.18 (d, J=2.1 Hz, 1H), 8.81 (dd, J=5.1, 1.8 Hz, 1H)), 8.27 (ddd, J=7.3, 4.2, 2.4 Hz, 1H), 7.49 (dd, J=7.8, 5.1 Hz, 1H); EIMS m/z 241 ([M+H])+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:31]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[CH:30][C:29]([F:47])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[F:47][C:29]1[CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[C:14]4[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[C:31]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:44])([CH3:45])[CH2:39][C:40]=43)[C:33]2=[O:46])[CH:30]=1
Reactant: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 135 °C
Yield: 37.2 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 146a (210 mg, 0.6 mmol), 230a (460 mg, 0.9 mmol), 1,2-dimethoxyethane (8 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (36 mg, 0.03 mmol) was added. The mixture was heated in microwave to 135° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride/diethyl ether/methanol to afford a 37% yield (140 mg) of 246a.
Reaction SMILES: [CH:1]12[CH2:11][CH:4]([C:5]3[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:3](O)[CH:2]2O.ClCCCl.I([O-])(=O)(=O)=O.[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH2:24]([N:31]1[CH2:2][CH:1]2[CH2:11][CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=32)[CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC1C2CC(c3ccccc32)C1O
Reactant: NCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: c1ccc(CN2CC3CC(C2)c2ccccc23)cc1
Reaction time: 1 h

Procedure:
1,2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol (40 g, 227.3 mmol) was stirred in H2O (1050 mL) and 1,2-dichloroethane (DCE) (420 mL) in a 2 L round bottom flask under nitrogen with cool water bath (˜10° C.). To this sodium periodate (NalO4) (51 g. 239 mmol) and triethylbenzyl ammonium chloride (Et3BnNCl) (50 mg) were added. The resulting mixture was stirred for 1 hour (slight initial exotherm), then the layers were separated and the aqueous layer was extracted with DCE (200 mL). The organic layer was washed with H2O (4×200 mL, or until no reaction to starch iodide is observed in the aqueous wash) then dried through a cotton plug. To this was added benzyl amine (25.5 g, 238.6 mmol) and the mixture was stirred for 2 minutes then immediately transferred into the sodium triacetoxyborohydride NaHB(OAc)3/DCE (see below) over 10 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH:37]=[CH2:38])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.183 mmol) in anhydrous toluene (3 mL) was degassed using argon. Tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) and tributyl(vinyl)tin (0.080 mL, 0.274 mmol) were added. The reaction vial was degassed using argon and the reaction mixture was stirred at 90° C. for 2 h. The resultant mixture was allowed to cool to RT and subjected to flash chromatography (SiO2, gradient 0 to 40% EtOAc in cyclohexane) to give the title compound as a gummy solid (81 mg, 90%). LCMS (Method G): RT=4.73 min, [M+H]+=494.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH:43]([CH3:45])[CH3:44]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH:43]([N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2)([CH3:45])[CH3:44]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (25 mg, 0.053 mmol), potassium carbonate (22 mg, 0.159 mmol) and 2-iodopropane (16 μl, 0.159 mmol) in anhydrous N,N-dimethylformamide (500 μl) to give an orange suspension. The reaction mixture was stirred at 80° C. for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 ml) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as an off-white solid (13 mg, 48% yield). 1H-NMR (500 MHz, CDCl3) δ 7.37 (1H, s), 7.10-7.28 (9H, m), 4.95 (1H, br s), 4.65-4.77 (3H, m), 2.05-2.60 (4H, m), 1.92-2.06 (1H, m), 1.65-1.80 (1H, m), 1.50 (6H, d), 1.00-1.45 (9H, br m). LCMS (Method A) RT=7.73 min, M+H+=514.15.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1)[CH2:2][CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:26][C:27]([F:40])([F:39])[S:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](F)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:35]([C:32]3[CH:33]=[CH:34][C:29]([S:28][C:27]([F:40])([F:26])[F:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])=[CH:13][CH:14]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CC[C@@H](c2ccc(N)cc2)C1
Reactant: O=S(=O)(F)c1ccc(SC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(SC(F)(F)F)cc3)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-((S)-1-Propylpyrrolidin-3-yl)phenylamin (50 mg, 0.24 mmol) was dissolved in THF (5 ml) at −78° C. and potassium hexamethyldisilazide (146 mg, 0.73 mmol) added. The solution was stirred at −78° C. for 1 hour and then 4-(trifluoromethylthio)benzene-1-sulfonyl fluoride (64 mg, 0.24 mmol) was added and the solution was allowed to reach room temperature over night. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and NaOH (2M). The organic extract was separated, dried (MgSO4), filtered and concentrated to give the product (97 mg, yield 89%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)(OC)=[O:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:2][CH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 390 mg (0.91 mmol) of 3-[4-(carbomethoxy)phenyl]-5-(4-phenyl-5-trifluoromethyl-2-thienyl)-1,2,4-oxadiazole (from Step D) in 10 mL of CH2Cl2 at −78° C. was treated with 2.7 mL of 1.0 M DIBALH solution in CH2Cl2. The resulting solution was stirred cold for 1 h, then quenched with 5 mL of sat'd Rochelle salt solution. The mixture was partitioned between 100 mL CH2Cl2 and 50 mL of 1 N NaOH. The organic layer was separated, dried and concentrated. Chromatography on a Biotage 40 S cartridge using 4:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 325 mg (89%) of the title compound: 1H NMR (500 Mhz) δ 1.80 (app s, 1H), 4.80 (d, J=4.0, 2H), 7.46-7.48 (5H), 7.52 (d, J=8.0, 2H), 7.91 (q, J=1.5, 1H), 8.14 (d, J=8.0, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]([NH:33]C(=O)OC(C)(C)C)[CH3:32]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]([NH2:33])[CH3:32]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)N)c(Cl)c5)nn34)ccnc2c1

Procedure:
A solution of tert-butyl 1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate (100 mg, 178 μmol) in DCM (2 mL) and TFA (2 mL) was stirred for 30 min at 23° C. Solvents removed under reduced pressure (not-toluene azeotroping is suggested!) and residue dissolved in CHCl3/IPA (10 mL). Solution stirred as a suspension with Si-Carbonate (1.3 g; 1 mmol) for 30 min. Suspension filtered and filtrate reduced to an amber film (150 mg). Product purified on silica (12 g) eluting with 4-7% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C24H21ClN6O2: 460.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 106 using tert-butyl(3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (1.50 g, 4.10 mmol) and ethyl bromoacetate (460 μl, 4.10 mmol) as starting materials.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])=[O:38])=[N:35][CH:36]=2)[CH:12]=[C:13]([C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH:14]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])=[N:35][CH:36]=2)[CH:12]=[C:13]([C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)c2)cn1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(3-chloro-5-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)phenyl)picolinamido)propanoate (40 mg, 0.07 mmol) and the resulting mixture was stirred at room temperature. After 16 h the mixture was acidified with 2 M HCl and the aqueous phase was extracted with EtOAc. The combined organics were washed with water, dried (Na2SO4), and concentrated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:31])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([NH2:40])=[O:39].C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:31])(=[N:40][C:38](=[O:39])[C:37]([F:42])([F:41])[F:36])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NC(=O)C(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylsulfinyl)ethyl]-1-naphthalenecarboxamide (i.e. the title product of Step B) (180 mg), 2,2,2-trifluoroacetamide (75 mg), MgO (53 mg), and Rh2(OAc)4 (4 mg) in dichloromethane (4 mL) was added PhI(OAc)2 (160 mg) at room temperature. The resulting mixture was stirred for 5 h at room temperature, then filtered through a short pad of Celite® diatomaceous filter aid, and rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (3:7 to 1:9) as eluent to afford the title compound, a compound of the present invention, as yellow oil (100 mg, 46% yield).
Reaction SMILES: [C:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)([O:3][CH3:4])=[O:2].[C:18]1([CH:25]=C[CH:23]=[C:21](O)[CH:20]=1)[OH:19].P(Cl)(Cl)(Cl)=O.O>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1[C:1](=[O:2])[O:3][C:4]3[CH:25]=[C:18]([OH:19])[CH:20]=[CH:21][C:23]=3[C:6]=1[CH2:7][CH2:8]2
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)C1C(=O)CCc2cc(OC)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2c(=O)oc2cc(O)ccc12
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a solution of 1-carbomethoxy-6-methoxy-2-tetralone (see, Colvin, Martin, and Shroot, Chemistry and Industry, 2130 (1966)) (18.0 g, 76.8 mmol) and resorcinol (8.9 g, 80.7 mmol) stirring at ambient temperature in toluene (450 mL) was added phosphorus oxychloride (12.0 g, 7.3 mL, 18.3 mmol) dropwise, and the mixture warmed to 80° C. for 12 h. After cooling to room temperature, the mixture was poured into water (500 mL) and filtered, rinsing the precipitate with ether. The filtrate layers were separated, the aqueous layer was extracted with ethyl acetate (3×500 mL), and the combined organic layers were dried (sodium sulfate) and concentrated. Recrystallization of the residue from methanol provided 16.0 g of the title compound as a yellow solid, mp 244-249 d°C.: 1 H NMR (300 MHz, DMSO-d6) d 10.55 (br s, 1H), 8.24 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 6.6-7.0 (m, 4H), 3.76 (s, 3H), 2.8-3.0 (m, 4H); 13C NMR (125 MHz, DMSO-d6) d 170.3, 160.3, 158.3, 158.1, 153.3, 147.7, 137.5, 127.4, 125.8, 122.5, 114.5, 112.6, 112.4, 110.9, 101.4, 54.6, 26.3, 22.7; IR (KBr) 3250, 1676, 1618 cm-1 ; MS (FD+) m/e 294 (M+); Anal. calc'd. for C18H14O4 : C, 73.45; H, 4.80. Found: C, 73.15; H, 4.86.
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C@H:14]2[OH:17])=[CH:10][CH:9]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O[C@@H]1CCc2ccc(Cl)cc21
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To a solution of borane-tetrahydrofuran (1.8 mL, 1.8 mmol, Aldrich, 1 M solution in THF) and (S)-MeCBS (0.3 mL, 0.3 mmol, Aldrich, 1 M solution in toluene) was added a solution of 6-chloro-1-indanone (0.5 g, 3.0 mmol) in anhydrous tetrahydrofuran slowly over 30 min at room temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched with 2N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated to afford 500 mg of (R)-6-chloroindan-1-ol.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(Cl)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-chlorobenzoyl chloride (11 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: N([O-])=O.[Na+].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)N.OS(O)(=O)=O.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:7]1([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]([C:5]([OH:14])=[O:13])=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1ccccc1C=Cc1ccccc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
20.7 g of sodium nitrite in 50 ml of water are added dropwise at 0°-5° C. to 41.1 g of anthranilic acid and 24 ml of conc. H2SO4 in 300 ml of water and the mixture is stirred at this temperature for 20 minutes. An excess of nitrite which may be present is destroyed by addition of sulphamic acid. The solution of the diazonium salt prepared in this way is added dropwise at about 60° C. to a rapidly stirred mixture of 62.4 g of styrene and 20 ml of water, and immediately after the start of addition the mixture is treated with 68 mg of Pd(OAc)2. After addition and evolution of gas are complete, the mixture is allowed to cool and the solid is filtered off with suction, washed with warm water and dried at 60° C. 62.5 g (93%) of stilbene-2-carboxylic acid of m.p. 158°-159° C. are obtained, Lit 158 -160° C., Chem. Ber. 27, 2506 (1894).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][OH:10])[CH2:2][NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Product: O=C(O)CC[C@H](NCC(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-ribose and L-(+)-glutamic acid using Raney nickel as a catalyst under the conditions of the above examples. A resin-like product was obtained with a RF -value of 0.80 (determined as indicated under Example M).