Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[H-].[Na+].[CH3:26]I.[NH4+].[Cl-]>C1COCC1>[CH3:26][N:6]1[CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C(=O)NC[C@@H]1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of (R)-benzyl 2-oxooxazolidine-5-carboxylate (25a) (0.1 g 0.312 mmol) in THF (2 mL), cooled to 0° C., Sodium hydride (13.9 mg, 0.37 mmol, 50% dispersion in mineral oil) was added and stirred for 60 min. MeI (0.048 g, 0.343 mmol) was added drop-wise to the reaction mixture, slowly warmed to room temperature and stirred for further 2 h. After completion (by TLC), the reaction mixture was poured into saturated NH4Cl solution (10 mL) and extracted with EtOAc (2×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to provide the crude residue which was purified by column chromatography to afford 25b (0.070 g, 67%) as a brown syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N#N.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:23][C:15]1([CH3:22])[C:16]2[C:21]3=[C:20]([C:4]4[CH:3]=[C:2]([N:30]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]1=3)[CH:19]=[CH:18][CH:17]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccc(N(c4ccccc4)c4ccccc4)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
A degassed solution of 31 g (86.6 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine and 16 g (95.9 mmol) of diphenylamine in 1000 ml of dioxane is saturated with N2 for 1 h. Then firstly 0.9 ml (4.3 mmol) of P(tBu)3, then 0.48 g (2.1 mmol) of palladium(II) acetate are added to the solution, and 12.6 g (131 mmol) of NaOtBu in the solid state are subsequently added. The reaction mixture is heated under reflux for 18 h. After cooling to room temperature, 1000 ml of water are carefully added. The organic phase is washed with 4×50 ml of water and dried over MgSO4, and the solvent is removed in vacuo. The pure product is obtained by recrystallisation and final sublimation.
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.FC(F)(F)C[OH:31]>C(Cl)(Cl)Cl>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[C:10]([OH:31])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: OCC(F)(F)F
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
1.0 g. of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is reacted, under the conditions described in Example 46 but with 2,2,2-trifluoroethanol, thus obtained the 2,2,2-trifluoroethyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid, m.p. 192.9° C. [α]D25 = +130° (chloroform). UV: ε242 = 17,000 (methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21

Procedure:
A solution of the product of step 7 in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or until the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure to afford the product as a red-orange oil in quantitative yield. MS: MH+=439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:18][C:15]12[CH2:17][CH:11]([N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[CH:7][CH:6]=3)=[O:9])[CH2:16]1)[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)c3ccncc3)cc2)C1
Reaction time: 2 h

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (400 mg, 1.47 mmol) in dry THF (25 ml) was added dropwise a solution of isonicotinoyl chloride (312 mg, 2.20 mmol) in dry THF (20 ml). The mixture was stirred for 2 hrs. and evaporated followed by addition of water 20 (ml). The aqueous phase was extracted with EtOAc (2×20 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using first EtOAc (300 ml) followed by a 4% mixture of TEA in EtOAc as eluents. Pure fractions were collected and evaporated to dryness. The residue was crystallized from a mixture of diethyl ether (20 ml) and EtOAc (5 ml) affording after filtering and drying in vacuo at 50° C. 200 mg (36%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@@H:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][C@H:20]([C:31](OC)=[O:32])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH3:39][OH:40]>C1COCC1.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:18]2[CH2:19][C@@H:20]([C:31]([N:8]3[CH2:3][CH2:2][O:40][CH2:39][CH2:12]3)=[O:32])[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)=[O:16])[N:10]=[N:9]1
Reactant: CO
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2CO)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.05 g) was dissolved in THF (10 ml)-methanol (8 ml)-water (8 ml), 8M aqueous sodium hydroxide solution (600 μl) was added and the mixture was stirred at 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue, morpholine, 1-hydroxybenzotriazole (150 mg) and triethylamine (700 μl) were dissolved in acetonitrile (20 ml), WSC.HCL (555 mg) was added and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (764 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[NH2:18][C:19]([NH:21][C:22]1[NH:23][C:24]([C:30]2[CH:35]=[CH:34][C:33]([C:36](OCC)=[O:37])=[CH:32][CH:31]=2)=[CH:25][C:26]=1[C:27]([NH2:29])=[O:28])=[O:20].O>O1CCCC1.CO>[NH2:18][C:19]([NH:21][C:22]1[NH:23][C:24]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][OH:37])=[CH:32][CH:31]=2)=[CH:25][C:26]=1[C:27]([NH2:29])=[O:28])=[O:20]
Reactant: CCOC(=O)c1ccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Nc1[nH]c(-c2ccc(CO)cc2)cc1C(N)=O
Reaction time: 2 h
Yield: 66 %

Procedure:
Under ice-cooling, 1.0M diisobutylaluminum hydride in toluene solution (3.2 mL, 3.2 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-ethoxycarbonylphenyl)pyrrole-3-carboxamide (Compound No. 1-30, 0.28 g, 0.89 mmol) in anhydrous tetrahydrofuran (5 mL) and the mixture was stirred for 2 hours. Moreover, 1.0M diisobutylaluminum hydride in toluene solution (3.2 mL, 3.2 mmol) was added thereto and the whole was stirred for 2 hours, and then water (2 mL) and methanol (2 mL) were added thereto. The mixture was filtered with celite with 1,4-dioxane (10 mL) and the filtrate was concentrated in vacuo. The obtained solid was washed with diethyl ether (2 mL), dried under reduced pressure to give the target compound (0.16 g) as a pale yellow solid (Yield 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C.C(OCC)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1N
Yield: 70.2 %

Procedure:
A solution of 4-bromophenylhydrazine (2.76 g, 14.7 mmol) and ethyl (ethoxymethylene)cyanoacetate (2.50 g, 14.8 mmol) in ethanol (15 mL) was heated at reflux for 2 hours. Upon cooling, a tan precipitate formed. The suspension was diluted with diethyl ether and suction filtered to remove solid. The filtercake was rinsed with diethyl ether and vacuum oven dried to afford 3.20 g (70%) of product as a tan solid: 1H NMR (CDCl3) d 7.79 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:12](=[O:13])[CH2:11][CH2:10][S:9][C:8]1=[S:14].[BH4-].[K+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:14])[S:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C1CCSC(=S)N1c1ccccn1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCCCSC(=S)Nc1ccccn1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
The procedure of Example 24 is followed, but a suspension of 3-(pyrid-2-yl)-2-thioxo-perhydro-1,3-thiazin-4-one (22.4 g) in methanol (300 cc) and a solution of potassium borohydride (10.8 g) in distilled water (75 cc) are used as the starting materials at a maximum of 40° C. The reaction is allowed to proceed for 1 hour at between 25° and 40° C. The reaction mixture is evaporated to dryness and the residue (21.5 g) is dissolved in a mixture of ethyl acetate (70 cc) and cyclohexane (30 cc). The solution is chromatographed on silica (0.2-0.5 mm) (300 g) distributed in a column of diameter 4.5 cm. Elution is carried out with a mixture of ethyl acetate (520 cc) and cyclohexane (180 cc), this eluate being discarded, and then with a mixture of ethyl acetate (1,660 cc) and cyclohexane (540 cc). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. 3-Hydroxypropyl pyrid-2-yldithiocarbamate (12.2 g), which melts at 93° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:10][CH2:11][CH2:12]C[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C>[Pd].C1(C)C=CC=CC=1.ClCCl.[Cu](I)I>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:11]([CH3:12])[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1I
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: I[Cu]I
Agent: [Pd]
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc2cc(Br)cnc2o1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-3-iodopyridin-2-ol (1 equiv), copper iodide (3 equiv), palladium catalyst (0.05 equiv), TBAF (1 equiv), triethylamine (3.3 equiv) and alkyne (1 equiv) in toluene was stirred at room temperature until the reaction was deemed complete by TLC analysis. The reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate, and brine, dried over sodium bicarbonate, filtered through celite, concentrated, and purified on silica gel to give the product, 5-bromo-2-methylfuro[2,3-b]pyridine.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[O:31][CH3:32]>C1COCC1>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:13][C:12]=1[O:31][CH3:32]
Reactant: COc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1Cl
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 220 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.347 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-chloro-3-methoxyphenoxy)phenyl)pyridin-2-amine (359 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo and washed with IPE to give the title compound (306 mg) as a white solid. A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)[CH:5]=[C:4]([CH3:26])[C:3]=1[OH:27].[F-].[Cs+].[CH2:30]1[O:32][C@H:31]1[CH2:33][OH:34]>CN(C=O)C>[CH3:26][C:4]1[CH:5]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)[CH:7]=[C:2]([CH3:1])[C:3]=1[O:27][CH2:30][C@@H:31]([OH:32])[CH2:33][OH:34]
Reactant: OC[C@H]1CO1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OC[C@@H](O)CO
Temperature: 80 °C

Procedure:
A mixture of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenol (36.7 mg, 99 μmol) and cesium fluoride (1.5 mg, 9.9 μmol) in anhydrous DMF (0.5 mL) was stirred at 25° C. for 1 h. (S)-(−)-glycidol (14 μl, 207 μmol) was then added, and the resulting mixture was heated under argon at 80° C. for 7 d. The reaction mixture was subsequently cooled to 25° C., filtered through Celite, diluted with DMSO (1.5 mL), and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide (S)-3-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenoxy)-propane-1,2-diol as a light yellow solid. MS (ESI) m/z: Calculated: 446.2; Observed: 447.2 (M++1).
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].[Cl:11][C:12]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C1COCC1>[Cl:11][C:12]1[N:19]=[C:18]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(Cl)c(C#N)cc2F)n[nH]1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 5-isopropoxy-1H-pyrazol-3-amine (0.96 g, 6.8 mmol), 2,6-dichloro-5-fluoronicotinonitrile (1.3 g, 6.8 mmol), and triethylamine (0.9 g, 8.8 mmol) in THF (30 ml) was heated to 60° C. for 4 days, and then cooled to 25° C., at which point the product precipitated. The resulting solid was filtered and washed with hexanes (100 ml) to give the title compound (1.0 g, 50%). MS: Calcd.: 295. Found: [M+H]+ 296.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([O:20][CH2:21][C:22](O)=[O:23])[CH3:19]>>[CH2:18]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 96.4 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 μL (0.10 mMol) ethoxyacetic acid, 15.2 mg (97%) of the title compound were recovered.
Reaction SMILES: O[C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:29][C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of ethyl 4-hydroxy-9-iodo-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (350 mg, 0.85 mmol, 1.00 equiv) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (271 mg, 1.68 mmol, 2.00 equiv) at 0° C. After being stirred overnight at room temperature the resulting mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:20) to give 200 mg (57%) of the titled compound as a white solid; LC-MS (ES, m/z) 417 [M+H]+.
Reaction SMILES: C1([O:11][C:12]([C@H:14]2[CH2:26][CH2:25][N:17]3[C:18]4[C:23]([CH:24]=[C:16]3[CH2:15]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:13])(C)CCC(C(C)C)CC1.S(=O)(=O)(O)O>>[CH:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[C:16]1[CH2:15][C@@H:14]([C:12]([OH:13])=[O:11])[CH2:26][CH2:25][N:17]12
Reactant: CC(C)C1CCC(C)(OC(=O)[C@H]2CCn3c(cc4ccccc43)C2)CC1
Agent: O=S(=O)(O)O
Product: O=C(O)[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To 40 g (114 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-carboxylic acid l-menthyl ester were added 50 ml of concentrated sulfuric acid and the mixture obtained was stirred until all starting material had dissolved (about 20 minutes). The solution was poured carefully into 1500 ml of ice-water and the resulting precipitate was filtered off, washed with petroleum ether/toluene (3:1) and dried to give 24.2 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-carboxylic acid as a white solid of melting point 251°-253° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@@H:4]([CH2:22]CS([O-])(=O)=O)[O:3]1.[K].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12>>[O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([CH2:22][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[O:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1CCCCN1c1ccc2c(c1)OC[C@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCCCC4=O)cc3OC[C@@H]12
Yield: 79.4 %

Procedure:
Using compound ((3R,3aS)-1-oxo-7-(2-oxopiperidin-1-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (0.774 g, 1.95 mmol), phthalimide potassium (0.542 g, 2.93 mmol) as starting materials, preparation following the method as described in Example 1(d) afforded white solid 0.693 g, yield: 79.3%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[CH2:1]([O:8][C:9]([N:11]([CH3:18])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(((benzyloxy)carbonyl)(methyl)amino)acetate (2.66 mg, 10.6 mmol, prepared the previous step) in MeOH (24 mL) and THF (5 mL) and treated with a solution of LiOH (12 mL, 54 mmol, 4.52 M in water). After stirring at room temperature for 3 hours, the pH was adjusted to ˜5 by the addition of aqueous HCl. After extraction with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated in vacuo to yield the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4ccc(OC)c(OC)c4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.6 using 1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound. [α]2D0=+15.1 (c=0.83, chloroform).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(F)cc2N1

Procedure:
The title compound was prepared from {4-fluoro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M4) (94 mg, 0.21 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (55 mg).