Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:32]3[N:8]([N:9]([CH3:33])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27]C(OC)=O)[N:21]=3)[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:34]([OH:36])=[O:35])[C:5]2=[O:37].CN1[CH2:44][CH2:43][O:42][CH2:41]C1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:32]3[N:8]([N:9]([CH3:33])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:2]4[CH:13]=[CH:12][CH:44]=[C:43]([O:42][CH3:41])[CH:3]=4)[N:21]=3)[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:34]([OH:36])=[O:35])[C:5]2=[O:37]
Reactant: COC(=O)Cn1nc(N2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn5c4c3OCN5C)CC2)ccc1=O
Reactant: CN1CCOCC1
Solvent: c1ccncc1
Product: COc1cccc(Cn2nc(N3CCN(c4c(F)cc5c(=O)c(C(=O)O)cn6c5c4OCN6C)CC3)ccc2=O)c1
Yield: 28 %

Procedure:
As described for compound 20a, 25 was obtained starting from 24 (300 mg, 0.99 mmol, 2.0 eq.), pyridine (4 mL,) N-methylmorpholine (0.2 mL, 4.0 mmol, 4.0 eq.) and TNOC (140 mg, 0.50 mmol, 1.0 eq.). The crude product was purified by T.L.C. preparative to afford the title compound (80 mg, 28%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[CH:15]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1)[C:16]1[S:31][C:19]2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21](=[O:26])[N:22]([CH3:25])[C:23](=[O:24])[C:18]=2[C:17]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>C1COCC1.[Pd]>[CH3:25][N:22]1[C:23](=[O:24])[C:18]2[C:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:16]([CH2:15][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=3)[S:31][C:19]=2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]1=[O:26]
Reactant: CCOC(=O)c1c(C(O)c2ccnc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Pd]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cc2ccnc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic anhydride (3.33 ml) was added to a solution of the product of step d) (7.34 g) and triethylamine (6.56 ml) in anhydrous THF (150 ml) at room temperature under nitrogen and the mixture stirred for 15 min. 10% palladium on charcoal (500 mg) was added and the mixture hydrogenated at 1 bar for 20 h. It was filtered through celite washing with saturated sodium bicarbonate solution (150 ml) then ethyl acetate (300 ml). The organic material was extracted into ethyl acetate (150 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 1:1 ethyl acetate/i-hexane, to give the sub-title compound as a solid (5.90 g). MS(ESI) 452 [M+H]+. δ 1HCDCl3 0.90 (6H,d), 1.37 (3H,t), 2.10-2.16 (1H,m), 3.39 (3H,s), 3.64 (2H,d), 4.45 (2H,q), 4.61 (2H,s), 7.29 (1H,d), 7.60 (1H,t), 7.75 (1H,t), 8.11 (1H,d), 8.16 (1H,d), 8.89 (1H,d)
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[N:27](C(C)(C)C)[C:26](=[O:35])[CH2:25]2)=[C:20]([CH3:36])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:35])[CH2:25]2)=[C:20]([CH3:36])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(C)c1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(C)c1
Yield: 74 %

Procedure:
A solution of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoate (450 mg, 0.871 mmol) in trifluoroacetic acid (3.00 mL) was heated in microwave reactor at 130° C. for 5 min. Solvent was removed in vacuo. The residue was purified with preparative LCMS to give the desired product (210 mg, 74%). 1H NMR (400 MHz, CD3OD): δ 7.45 (m, 1H), 7.2 (m, 2H), 5.47 (t, 1H), 4.34 (t, 1H), 3.81 (s, 3H), 3.3 (m, 2H), 3.25 (d, 1H), 3.13 (m, 1H), 2.49 (s, 3H); MF=C14H19N2O5S; LCMS found for C14H20N2O5S (M+H)+: m/z=327.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13](=[O:55])[CH:14]([NH:21][S:22]([C:25]1[CH:26]=[C:27]([CH:52]=[CH:53][CH:54]=1)[C:28]([O:30][C@H:31]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1)[CH2:32][C:33]1[C:38]([Cl:39])=[CH:37][N+:36]([O-:40])=[CH:35][C:34]=1[Cl:41])=[O:29])(=[O:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:11])(C)[CH3:9].Cl[C:57]1[CH:58]=[N+:59]([O-])[CH:60]=[C:61](Cl)C=1C[C@@H](C1C=CC(OC)=C(OC)C=1)OC(C1C=C(S(NC(C2C=CC=CC=2)C(O)=O)(=O)=O)C=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.N12CCC(CC1)[C@@H](O)C2>ClCCl.C1COCC1.C1(C)C=CC=CC=1>[O:55]=[C:13]([O:12][C@@H:8]1[CH:9]2[CH2:61][CH2:60][N:59]([CH2:58][CH2:57]2)[CH2:11]1)[CH:14]([NH:21][S:22]([C:25]1[CH:26]=[C:27]([CH:52]=[CH:53][CH:54]=1)[C:28]([O:30][C@H:31]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=1)[CH2:32][C:33]1[C:34]([Cl:41])=[CH:35][N+:36]([O-:40])=[CH:37][C:38]=1[Cl:39])=[O:29])(=[O:24])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(S(=O)(=O)NC(C(=O)O)c3ccccc3)c2)cc1OC
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c3ccccc3)c2)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O[C@H]1CN2CCC1CC2
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc(S(=O)(=O)NC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1OC
Temperature: 0 °C

Procedure:
Trifluoroacetic acid (5.0 mL) was added to a stirred solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[(2-tert-butoxy-2-oxo-1-phenyl-ethyl)sulfamoyl]benzoate (1.0 g, 1.39 mmol) in dichloromethane (5.0 mL) at 0° C., and stirring was maintained at 0° C. for 2.5 hours. The reaction mixture was then stirred at ambient temperature for 30 minutes, after which time toluene (50 mL) was added and the solvent removed under reduced pressure to yield a yellow solid, inferred as the intermediate 2-[[3-[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethoxy]carbonylphenyl]sulfonylamino]-2-phenyl-acetic acid. The crude was subsequently dissolved in THF (20 mL), and N,N′-dicyclohexylcarbodiimide (431 mg, 2.09 mmol), 1-hydroxybenzotriazole hydrate (282 mg, 2.09 mmol) and (R)-quinuclidin-3-ol (355 mg, 2.79 mmol) were sequentially added. The resulting reaction mixture was stirred at ambient temperature for 18 hours, after which time the reaction mixture was filtered through a pad of Celite®, washing with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure and the resulting crude was partitioned between ethyl acetate (20 mL) and water (10 mL), the organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude was triturated in diethyl ether, and final purification was achieved by preparative HPLC and subsequent SFC to afford the title compound as a pale yellow solid (17.9 mg, de=100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][C:6](=O)C(F)(F)F)=[O:4].O[CH2:15][N:16]([N+:18]([O-:20])=[O:19])C>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]([O:5][CH2:6][N:16]([N+:18]([O-:20])=[O:19])[CH3:15])=[O:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(CO)[N+](=O)[O-]
Solvent: ClCCl
Product: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]

Procedure:
Trifluoroacetic anhydride (80 ml, 118.4 g, 0.56 moles) was added to a stirred solution of 1-hydroxy-2-nitro-2-azapropane (40.0 g, 0.38 moles) in dichloromethane (60 ml) at -5° to 0° C. during 11/2 hours. The resulting solution was then distilled without warming at 20 mm, then to 3 mm. The product was distilled at 1.5 mm, 65° C., to give 2-nitro-2-azapropyl trifluoroacetate; yield: 48 g (63%).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:26])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CC(=O)CC.O>[C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
—Aluminium isopropoxide (18.1 g) was added to a solution of (3β,20S)-pregn-5-ene-3,20-diol 20-acetate (21.9 g) in dry toluene (252 ml) and dry 2-butanone (156 ml). The mixture was heated under reflux for 2 h, then cooled, whereupon a solution of potassium sodium tartrate tetrahydrate (91.4 g) in water (90 ml) was added. The mixture was stirred for 30 min. and filtered. The filtrate was poured into brine and the product extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (20S)-20-(acetyloxy)pregn-4-en-3-one (compound 6; 17.9 g).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH:16]([CH3:18])[CH3:17])[NH2:12].[CH3:19][CH:20]([CH2:24][CH2:25][CH3:26])[C:21](Cl)=[O:22]>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:21](=[O:22])[CH:20]([CH3:19])[CH2:24][CH2:25][CH3:26])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CCCC(C)C(=O)Cl
Reactant: CC(C)c1ccc(N)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCC(C)C(=O)Nc1ccc(C(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
To 36 ml of toluene were added 1.0 g (5.9/1000 mole) of 3-chloro-4-isopropylaniline and 0.7 g of pyridine, and 0.9 g (5.9/1000 mole) of 2-methylvaleryl chloride was added. The mixture was stirred at room temperature for 20 minutes. The crystals that precipitated were separated by filtration. Water (70 ml) was added to the filtrate, and the mixture was extracted with toluene. The toluene solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The resulting dried solution was concentrated by an evaporator. Recrystallization of the resulting crude crystals from methanol gave 1.2 g of N-(3-chloro-4-isopropylphenyl)-2-methylvaleramide in a yield of 76.0 % based on 3-chloro-4-isopropylaniline.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[C:26]([CH3:27])=[N:25][N:24]=[N:23]1)[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28][CH2:29][CH2:30][CH2:31][S:32](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:21][CH2:20][CH:19]([N:22]1[C:26]([CH3:27])=[N:25][N:24]=[N:23]1)[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)n1nnnc1C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnnc1C

Procedure:
3-Hexadecylthio-2-(5-methyl-1H-tetrazol-1-yl)propylamine IVi1 is allowed to react and worked up by the same procedure as described in (4). m.p. 62°-62.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl[N:2]1[C@@H:6]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)[CH2:5][C@H:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:3]1([CH3:26])[CH3:25].C[O-].[Na+]>O>[CH3:25][C:3]1([CH3:26])[N:2]=[C:6]([C:7]2[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=2)[CH2:5][CH:4]1[C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1
Reactant: COc1cc([C@H]2C[C@H](c3ccncc3)C(C)(C)N2Cl)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C2=NC(C)(C)C(c3ccncc3)C2)cc(OC)c1OC

Procedure:
9.8 G. of 4-[trans-1-chloro-2,2-dimethyl-5-(3,4,5-trimethoxyphenyl)-3-pyrrolidinyl]-pyridine are treated with 52 ml. of sodium methylate solution (10 g. of sodium per 100 ml. of methanol) and heated at 50° C. for 3 hours. Then the reaction mixture is treated with water and extracted three times with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is crystallized with ethyl acetate/isopropyl ether to yield 4-(5,5-dimethyl-2-(3,4,5-trimethoxyphenyl)-1-pyrrolin-4-yl)-pyridine, melting point 143°-144° C. This compound is, as in Example 37, reduced with sodium borohydride to the cis-pyrrolidinyl compound. This example shows therefore the isomerization of trans/pyrrolidines by way of a pyrroline to the corresponding cis-pyrrolidine.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([OH:19])[C:14](=[NH:18])[O:15]CC.O1CCCC1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:19][C:1](=[O:2])[NH:15][C:14]1=[O:18]
Reactant: CCOC(=N)C(O)c1ccccc1F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2F)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 2 hours at room temperature was employed following the phosgene perfusion step, ethyl 1-(2-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (14.5 g., 0.062 mole) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2fluorophenyl)oxazolidine-2,4-dione (7.32 g., 60%; m.p. 129°-131° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][OH:48].[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>N1C=CC=CC=1>[C:49]([O:48][CH2:47][C:3]1[CH:4]=[C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: c1ccncc1
Product: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
To a solution of alcohol 103 (9.9 g, 14.88 mmol) in pyridine (36 mL) was added benzoyl chloride (1.9 mL, 16.37 mmol) at room temperature. The mixture was stirred at room temperature for 6 hours. The mixture was washed with aq. saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the mixture of anomers of the title compound (10.5 g). The anomeric mixture of 104 was recrystallized with IPA (150 mL). The precipitate was collected by filtration and washed with cold IPA (50 mL) and dried under high vacuum to obtain β-anomer of the title compound 104 (6.13 g, 54%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>CN(C)C=O>[Br:14][C:12]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2)=[C:4]([CH2:3][NH:2][C:17](=[O:19])[CH3:18])[CH:13]=1
Reactant: NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
50 mg (0.19 mmol) of 5-aminomethyl-7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline hydrochloride are suspended in 4 ml of N,N-dimethylformamide and stirred at 20° C. for 24 hours with 0.02 ml (1.2 equiv.) of acetic anhydride and 0.059 ml (2.2 equiv.) of triethylamine. The solvent is concentrated by evaporation, and the solid is suspended in diethyl ether, filtered off and washed with methanol and diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)(=O)OCC)C.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>O1CCCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]/[CH:40]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Potassium tert-butoxide (5.78 g, 50.0 mmol) was added to a solution of 4-(trifluoromethyl)benzylphosphonic acid diethyl ester (14.8 g, 50.0 mmol) in tetrahydrofuran solution (40 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, a tetrahydrofuran solution (10 ml) of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (11.4 g, 50.0 mmol) was added thereto dropwise at 0° C., warmed to room temperature, and then stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=86:14) to afford the title compound as a colorless oil (8.6 g, yield 47%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])(=[O:39])=[O:38])[CH2:10]3)[CH:16]=1
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S(=O)(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.064 mmol, 20 mg) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0.128 mmol, 17.8 μL) followed by 2-chlorobenzenesulfonyl chloride (0.064 mmol, 13.6 mg) and the solution stirred at room temperature overnight. The reaction was concentrated to dryness to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give the title compound (9.8 mg, 0.02 mmol, 31.5%) MS (ESI): m/z [M−H]− 484.4.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.[CH2:49]([C:56]1[CH:61]=[CH:60][N:59]=[C:58]([F:62])[C:57]=1[CH2:63][CH2:64][OH:65])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:49]([C:56]1[CH:61]=[CH:60][N:59]=[C:58]([F:62])[C:57]=1[CH2:63][CH2:64][O:65][C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COc1ccc2c(I)ccnc2c1
Reactant: OCCc1c(Cc2ccccc2)ccnc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCc3c(Cc4ccccc4)ccnc3F)ccnc2c1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A 10 mL, Biotage microwave vessel was charged with racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.093 g, 0.23 mmol), palladium(II) acetate (0.048 g, 0.21 mmol), a stir bar, and 1 mL toluene. The flask was sealed and swept with Ar by piercing the septa with an Ar inlet and an 18-gauge needle. The solution was heated to 70° C. for 20 minutes. To the solution was added cesium carbonate (0.076 g, 0.23 mmol), 4-iodo-7-methoxyquinoline (0.067 g, 0.23 mmol), and 2-(4-benzyl-2-fluoropyridin-3-yl)ethanol (0.0493 g, 0.21 mmol). The reaction was heated for 24 h at 70° C. and cooled. The solution was treated with 1 mL water, and the stirred for 20 min. The two phases were loaded onto an unbuffered, 10 mL Varian Chem elute CE 1005 (PN 12198007) and extracted with 5×5 mL CH2Cl2. The combined extracts were concentrated in vacuo. The residue was loaded onto a 30×100 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942; Gradient: 0→5 min@35 mL/min, 25% B; 5→20 min@35 mL/min, linear gradient to 55% B; 20→24.9@35 mL/min, isocratic at 55% B, 25→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 25% B; 40 min end). A=10 mM NH3HCO3 in water (pH 9.6); B=ACN. A band that eluted from 20.9-21.6 minutes was isolated. The solvent was evaporated in vacuo to afford 4-(2-(4-benzyl-2-fluoropyridin-3-yl)ethoxy)-7-methoxyquinoline. 1H NMR (400 MHz, CDCl3) δ ppm 3.30 (t, J=6.70 Hz, 2 H) 3.94 (s, 3 H) 4.19 (s, 2 H) 4.22 (t, J=6.75 Hz, 2 H) 6.48 (d, J=5.38 Hz, 1 H) 6.99 (d, J=4.99 Hz, 1 H) 7.08-7.12 (m, 2 H) 7.14 (dd, J=9.15, 2.49 Hz, 1 H) 7.21-7.32 (m, 3 H) 7.39 (d, J=2.25 Hz, 1 H) 8.02 (d, J=9.19 Hz, 1 H) 8.05 (d, J=4.99 Hz, 1 H) 8.61 (d, J=5.48 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ ppm 25.39 (s, 1 C) 38.56 (d, J=3.47 Hz, 1 C) 55.52 (s, 1 C) 66.76 (s, 1 C) 99.27 (s, 1 C) 106.74 (s, 1 C) 115.76 (s, 1 C) 118.19 (d, J=30.34 Hz, 1 C) 118.66 (s, 1 C) 123.00 (s, 1 C) 123.49 (d, J=3.90 Hz, 1 C) 126.99 (s, 1 C) 128.69 (s, 2 C) 128.95 (s, 2 C) 137.96 (s, 1 C) 145.60 (s, 1 C) 145.77 (s, 1 C) 151.12 (d, J=6.50 Hz, 1 C) 153.72 (d, J=5.20 Hz, 1 C) 161.19 (s, 1 C) 161.52 (br. s., 1 C) 163.03 (d, J=237.12 Hz, 1 C). MS (ESI pos. ion) m/z (MH+): 389.1, calcd for C24H21FN2O2+H+=389.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][CH2:37][C:38](O)=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH3:28])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC1CCCCN1CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(2-methylpiperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-(2-methylpiperidino)butyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.