Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH:13]3[C:17]([OH:19])([CH3:18])[CH:16]([OH:20])[CH:15]([CH2:21][OH:22])[O:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1.S([CH2:33][N+:34]#[C-:35])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[O:12][CH:35]=[N:34][CH:33]=3)=[CH:9][N:8]([CH:13]3[C:17]([CH3:18])([OH:19])[CH:16]([OH:20])[CH:15]([CH2:21][OH:22])[O:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(O)C(O)C(CO)OC1n1cc(C=O)c2c(Cl)ncnc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(Cl)ncnc21

Procedure:
To the compound from Step 1 is added tosylmethyl isocyanide (1 eq.) in MeoH containing K2CO3 (1 eq.) and the mixture is heated to reflux until starting material is consumed. The solvent is removed in vacuo and the crude mixture purified by RP HPLC on a Phenominex column (250×20 mm) using a gradient of acetonitrile in water from 0 to 30% over 30 minutes at 10 mL/minute.
Reaction SMILES: COC(=O)[O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[C:18]([CH3:21])([CH3:20])[CH3:19].COC(=O)OC1C([N+]([O-])=O)=CC(C(C)(C)C)=CC=1C(C)(C)C.[OH-].[K+].Cl>CO>[C:18]([C:6]1[CH:7]=[C:8]([C:14]([CH3:16])([CH3:15])[CH3:17])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[OH:4])([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(C)(C)C
Agent: COC(=O)Oc1c([N+](=O)[O-])cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
The mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then made acidic (pH 2-3) by adding conc. HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO4), concentrated and purified by column chromatography (0-5% ethyl acetate-hexanes) to provide 2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 steps) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol: 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: 1H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[N:11]([Si](C(C)(C)C)(C)C)[C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[CH3:7])=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]([C@H:8]1[NH:11][C:10](=[O:19])[C@@H:9]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH3:21])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyldimethylsilyloxyethyl)-1-t-butyldimethylsilyl-2-azetidinone (46.3 g) in dry tetrahydrofuran (60 ml) was treated with a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (96 ml) at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with brine (60 ml). The washing was extracted with ethyl acetate (50 ml). The extract and the ethyl acetate layer were combined together, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-ethoxycarbonylethyl)-3-(1-(R)-t-butyldimethylsilyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C:5]1[C:6]3[C:19]([NH:20][CH:21]=1)=[CH:18][CH:17]=[CH:16][C:7]=32.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:20]1[C:19]2[C:6]3=[C:7]([CH:16]=[CH:17][CH:18]=2)[C@H:8]2[C@H:3]([CH2:4][C:5]3=[CH:21]1)[N:2]([CH3:1])[CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2[C@H]2c3cccc4c3c(cn4C)C[C@@H]21
Reaction time: 1 h

Procedure:
3 g of trans-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine are dissolved in 60 ml of dimethylformamide. The solution is cooled to -25°, and mixed whilst stirring with 280 mg of a 55% sodium hydride dispersion. The resultant suspension is allowed to warm to 0° over the course of 40 mins., and then 0.81 ml of methyl iodide, dissolved in 10 ml of dimethylformamide, are added in drops. The black reaction solution is stirred for a further 1 hour at 0°, and the dimethylformamide is subsequently removed under a high vacuum. The residue of evaporation is taken up in methylene chloride/methanol=95/5, extracted with water, and the combined organic phases dried, filtered and concentrated. The residue of evaporation is chromatographed on silica gel with methylene chloride/methanol=98/2 (methylene chloride 10% saturated with NH3). The title compound which crystallises from the solvent mixture used for chromatography is thus obtained. After washing with ether and subsequent drying, it melts at 184°- 185°.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.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:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([C:33]4[CH:32]=[C:31]5[C:36](=[CH:35][CH:34]=4)[N:28]([CH3:27])[N:29]=[CH:30]5)[CH:42]=3)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cn1ncc2cc(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)ccc21
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C

Procedure:
The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (300 mg, 0.65 mmol), 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole (260 mg, 0.78 mmol), Pd(PPh3)4 (75 mg, 0.065 mmol), 2N K2CO3 (1.6 mL) in dioxane (5 mL) was heated at 95° C. for hours. After the reaction finished, the reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C33H36BrN3O3S: 634.2 (M+H+); Found: 634.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[CH3:22][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:20])[CH3:21])[CH:12]=1)[CH2:5][OH:6]
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(CO)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy) benzaldehyde (4.1 g, 15.2 mmol, Example 28, step a) in methanol (35 mL) at 0° C. was slowly added NaBH4 (1.16 g, 30.5 mmol). The reaction mixture was stirred at room temperature for 5 h and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl alcohol as a white solid (3.4 g, 83%, m.p.: 78-80° C.): 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 2 H), 6.80 (d, J=3.3 Hz, 2 H), 6.67 (d, J=9.0 Hz, 1 H), 6.36 (dd, J=3.0, 8.7 Hz, 1 H), 4.68 (s, 2 H), 3.80 (s, 3 H), 3.35-3.25 (m, 1 H), 2.16 (s, 6 H), 1.19 (d, J=7.2 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:4); Rf=0.5.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](Br)[N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(=O)C1(c2cccc(Br)n2)CC1
Product: C[C@@H](c1ccc(-c2cccc(C3(C(=O)N(C)C)CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 66 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid dimethylamide following a procedure analogous to that described in Example 1. Yield: 66% of theory; LC (method 1): tR=2.00 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:28]I.Cl>O1CCCC1>[CH:1]([N:5]([CH3:28])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CI
Reactant: CCC(C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate (133.6 mg, 0.40 mmol, 1.00 equiv) in tetrahydrofuran (12 mL), and sodium hydride (96 mg, 4.00 mmol, 10.03 equiv). The resulting solution was stirred 1 h at room temperature. Then a solution of methyl iodide (284 mg, 2.00 mmol, 5.01 equiv) in tetrahydrofuran (1 mL) was added dropwise with stirring. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solution was concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/petroleum ether (10:1). The crude product (130 mg) was purified by Prep-HPLC under the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 80% in 6 min, up to 100% in 1 min, down to 60% in 1 min); Detector, UV 220 254 nm. This resulted in 52 mg (39%) of 3-(sec-butyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.[NH:30]1[CH:34]=[C:33]([C:35](O)=O)[N:32]=[CH:31]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:35]([C:33]5[N:32]=[CH:31][NH:30][CH:34]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: c1ccc(-c2cc3c(ccn4c(-c5c[nH]cn5)nnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-4 (0.2 g, 0.5 mmol), 1H-imidazole-4-carboxylic acid (0.06 g, 0.5 mmol), HOBT (0.06 g, 0.5 mmol), and DIEA (0.2 ml, 1.4 mmol) in DMF (2 ml) was added EDC (0.1 g, 0.6 mmol). The solution was stirred at room temperature for 45 min and was then heated at 80° C. in the microwave for 15 min. The solvent was removed in vacuo. The residue was taken up in DMF (0.5 ml) and was treated with glacial AcOH (2.0 ml). The reaction mixture was heated at 80° C. for 45 min. The reaction was then quenched with water (10 ml) and extracted into EtOAc (3×20 ml). The combined organic layers were concentrated in vacuo to give 22-1 as a brown residue.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14](OCC)=[O:15])[CH:11]=[C:10]([CH3:19])[N:9]=1.C(O)(=O)C>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH3:19])[N:9]=1
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Lithium aluminium hydride (350 mg, 9.26 mmol) was added in portions to a solution of ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (1.85 g, 9.26 mmol) in THF (40 ml) cooled at 0° C. The mixture was stirred for 15 minutes at 0° C. and acetic acid (2 ml) was added. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 5 % aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (35/65) to give 2-chloro-4-hydroxymethyl-6-methylpyridine (1.28 g, 88%).
Reaction SMILES: [CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1.C(=O)=O.CO.FC(F)(F)C1C=CC(C2N=CC(C=O)=CN=2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.[OH-].[Na+]>O>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C=O
Agent: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(Nc1ccc(C(=O)N(C)CCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 88.2 %

Procedure:
The title compound is obtained by a method analogous to the one described for example 1.23 except tert-butyl 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoate used in the synthesis was resolved by chiral chromatography; Column: Chiralpak AD-H. Dimensions: 10 mm×250 cm. Mobile Phase: 65/35 CO2/methanol. Flow Rate: 10 mL/min. Modifier: none. Retention time: 4.23 min (peak 1), 6.81 min. (peak 2; >99% ee). Peak 2 (1.15 g, 2.02 mmol) was then deprotected under the TFA/DCM previously reported. Concentration of the reaction mixture under reduced pressure provide a crude orange gum. Water (150 mL) added to the gum and NaOH 1M aq. added slowly until reaching pH 11 to obtain a clear solution of the crude. Acidification to pH4 with 1N HCl followed by filtration of the solid formed (washed with plenty of water) provide 3-(N-methyl-6-((3-methyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)butyl)amino)nicotinamido)propanoic acid (915 mg, 88.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.91 (d, 3H) 0.95 (d, J=6.46 Hz, 3H) 1.49-1.59 (m, 1H) 1.61-1.71 (m, 1H) 1.71-1.82 (m, 1H) 2.52-2.55 (m, 2H) 2.92 (s, 3H) 3.53 (t, J=7.24 Hz, 2H) 5.09 (br. s., 1H) 6.56 (d, J=1.17 Hz, 1H) 7.44 (d, J=9.39 Hz, 1H) 7.50 (d, J=8.22 Hz, 2H) 7.54-7.65 (m, 1H) 7.67 (d, J=8.02 Hz, 2H) 7.75-7.82 (m, 2H) 7.83-7.89 (m, 2H) 8.00 (d, J=2.15 Hz, 1H) 12.27 (br. s., 1H); MS (M+1): 514.4.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)=O.C(O)(C)C.C1([Mg]Br)C=CC=CC=1.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])([O-:13])=[O:12]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Agent: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
To a solution of 1-iodo-2,6-dinitrobenzene (1.55 g, 5.27 mmol) in anhydrous tetrahydrofuran (18 mL) cooled at minus 53° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.16 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 45° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (0.957 mL, 10.54 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (5 mL) and poured into water (50 mL)/dichloromethane (100 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (50 mL each). Combined organic extract was washed with water (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(2,6-dinitrophenyl)-2-methyl-1-propanol (0.375 g, 30%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 2 H, J=8.0 Hz, Ph-H), 7.59 (t, 1 H, J=8.0 Hz, Ph-H), 4.84 (dd, 1 H, J=7.6 and 9.2 Hz, Ph-CH), 2.87 (d, 1 H, J=7.6 Hz, OH), 2.18 (m, 1 H, CHCH(CH3)2), 1.12 (d, 3 H, J=6.4 Hz, CH3), 0.77 (d, 3 H, J=6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 150.82 (C), 130.62 (C), 129.31 (CH), 127.30 (CH), 74.52 (CH), 34.19 (CH), 19.84 (CH3), 19.14 (CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:24]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:24])(=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CS(=O)(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide in 150 ml of acetic acid is added 55 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at 40°-50° C. on a water bath for 4 hours and poured into an excess amount of water. The precipitated crystals are collected by filtration and recrystallized from 50% aqueous solution of acetic acid to give 2.9 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6,6-dioxide, melting at 168°-170° C., as a colorless powder.
Reaction SMILES: ClC1C(C#N)=C2C(=CC=1)N(CC(O)=O)C(C)=C2S(C1C=CC(Cl)=CC=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[N:47])[CH:44]=3)[N:39]([CH2:48][C:49]([O:51]C)=[O:50])[C:38]=2[CH3:53])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[N:47])[CH:44]=3)[N:39]([CH2:48][C:49]([OH:51])=[O:50])[C:38]=2[CH3:53])=[O:36])=[CH:33][CH:34]=1
Reactant: COC(=O)Cn1c(C)c(S(=O)c2ccc(Cl)cc2)c2cc(C#N)ccc21
Agent: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc2n1CC(=O)O
Product: Cc1c(S(=O)c2ccc(Cl)cc2)c2cc(C#N)ccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method of example 5 part (d) using the product of step (c).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C.Cl[C:37]1[O:38][C:39]2[C:40](=[C:42]([C:54]#[N:55])[C:43]([CH3:53])=[C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]=2[F:46])[N:41]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:46][C:45]1[C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:43]([CH3:53])[C:42]([C:54]#[N:55])=[C:40]2[C:39]=1[O:38][C:37]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[N:41]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3cnccn3)nc2c1C#N
Temperature: 125 °C
Yield: 59.8 %

Procedure:
2-Tri-n-butylstannylpyrazine (409 mg, 1.11 mmol), dichlorobis(triphenylphosphine)palladium(II) (51.9 mg, 0.074 mmol) and 2,6-di-tert-butylcresol (32.6 mg, 0.148 mmol) were added to a toluene (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (212 mg, 0.739 mmol), followed by heating under reflux in an oil bath at 125° C. for 2 hours. The solvent was evaporated away under reduced pressure, then the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to obtain the entitled compound (146 mg, 59.8%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl.O>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:36](=[O:38])[CH3:37])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.391 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and acetyl chloride (61 mg, 0.777 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.