Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1>N1C=CC=CC=1>[C:1]([N:14]1[CH2:15][CH2:16][C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][C@@H:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CC(CCO)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1C[C@H](CCO)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0°, 9.4 ml acetic anhydride is added to a stirred solution of 13.5 g of ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate in 75 ml pyridine. After stirring at room temperature for 30 minutes the solution is concentrated in vacuo and ethyl acetate (300 ml) is added; the solution is washed twice with 2N hydrochloric acid, once with water and once with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 100 ml ethanol, 5 g of powdered potassium carbonate is added and the mixture stirred 1 hour at room temperature. The solution is filtered, concentrated in vacuo and purified by flash chromatography using methylene chloride/methanol (95:5) to yield trans ethyl 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])[S:17]2)[C@@H:13](O)[C@@H:12]1[O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:46])CC>C(Cl)Cl>[C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])[S:17]2)[C@@H:13]([F:46])[C@@H:12]1[O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](OC(=O)c3ccccc3)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OC(=O)c3ccccc3)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (-(3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate (0.49 g, 0.88 mmol) in anhydrous DCM (3 mL), at −40° C. under N2, was added DAST (1.0 g, 6.2 mmol). After addition the mixture was stirred at room temperature overnight. After the reaction mixture was again cooled at −40° C., it was diluted with DCM (20 mL), and then quenched by adding satd. aqueous NaHCO3 dropwise. The organic layer was collected, and the aqueous was extracted with DCM (2×15 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:5 to 2:7), affording (-(3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (0.14 g, impure, ˜28%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (50 mg, 0.123 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (42 mg, 0.369 mmol), and DIEA (46 mg, 0.369 mmol) in anhydrous DMA (1 mL) was heated in a sealed vessel at 100° C. for 15 h. The reaction was allowed to cool to rt and then was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (12 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.98-8.10 (m, 2H), 7.64 (d, J=1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.31 (m, 1H), 7.18 (dd, J=1.6, 8.2 Hz, 1H), 5.46 (s, 2H), 4.79 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65-1.67 (m, 2H), 1.12-1.34 (m, 4H). LCMS (ESI) m/z 458 and 460 (M+H)+.
Reaction SMILES: [Br:1][C:2](=[CH2:8])[CH2:3][Si](C)(C)C.[F:9][C:10]([F:19])([F:18])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[C:11]([OH:17])([C:10]([F:9])([F:18])[F:19])[CH2:3][C:2]([Br:1])=[CH2:8])[CH3:16]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(Br)C[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(Br)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a chilled (−78° C.) solution of 5.2 mL (30.18 mmol) of 2-bromoallyltrimethylsilane and 5.3 g (31.16 mmol) of ethyl trifluoropyruvate in 75 mL of dichloromethane was added 30 mL (30 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane over a 10 minute period. The cold bath was then removed and the mixture was warmed to room temperature. After 3 hours, the mixture was cautiously added to 100 mL of saturated aqueous ammonium chloride and filtered through diatomaceous earth washing with dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford 6.7 g (76%) of 4-bromo-2-hydroxy-2-trifluoromethylpent-4-enoic acid ethyl ester as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 88.3 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.8 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which 3.21 ml of 30% aqueous hydrogen peroxide and 0.262 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 1.32 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 88%) as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:26]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCC1
Yield: 69 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 13.5 g (0.0576 mol) of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester (commercially available) dissolved in 350 ml of toluene, 8.0 g (0.063 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.91 g (0.023 mol) of HNa (60% dispersion in mineral oil). The yield was 13.1 g (69%) of the title product as an oil mixture of diastereomers, structure confirmed by 1H-NMR; The two diastereomers I-5a and I-5b were separated after several crystallizations.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:43]=[C:34]1[C:35]2[C:36](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:38])[N:33]1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])=[CH:10][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of tert-butyl (2S)-3-[4-(3-hydroxypropoxy)phenyl]-2-[(phenylmethoxy)carbonylamino]propanoate (0.215 g, 0.5 mmol), as prepared in the preceding step, N-hydroxyphthalimide ((0.098 g, 0.6 mmol), and triphenylphosphine (0.157 g, 0.6 mmol) in anhydrous tetrahydrofuran (10 mL) was treated with diethyl azodicarboxylate (0.095 g, 0.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was placed on a silica gel column (10 g Waters Sep-Pak) and eluted with 20% ethyl acetate and 80% hexane. The pure fractions were combined and evaporated to give the title compound (0.280 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ7.84 (dd, J=5.6,3.0 Hz, 2H), 7.75 (dd, J=5.6, 3.0 Hz, 2H), 7.28-7.34 (m, 5H), 7.03 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 5.22 (br d, J=8.2 Hz, 1H), 5.09 (d, J=2.5 Hz, 2H), 4.48 (m, 1 H), 4.41 (t, J=6.3 Hz, 2H), 4.20 (t, J=6.2 Hz, 2H), 3.01 (br d, J=5.9 Hz, 2H), 2.23 (p, J=6.2 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:22])[C@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@]12CCc3c(Cl)cccc3[C@H]1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@]12CCc3c(Cl)cccc3[C@H]1CNC2
Temperature: 160 °C
Yield: 83.3 %

Procedure:
To a solution of cis-2-benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.882 mmol, 0.275 g) in toluene (2 ml) was added 1-chloroethyl chloroformate (6.17 mmol, 0.883 g) and the reaction mixture was heated at 160° C. for 15 min in a microwave reactor. MeOH (2 ml) was added and the mixture further irradiated at 160° C. for 5 mins. The mixture was concentrated in vacuo and then diluted with water and extracted with DCM (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo to afford a residue that was purified by silica column chromatography (eluting with DCM—20% MeOH in DCM) to afford cis-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (163 mg), m/z=222.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][CH:17]=1>C(OCC)C>[N:16]1([C:2]2[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: c1ccc2[nH]cnc2c1
Solvent: CCOCC
Product: CCOC(=O)c1oc(-n2cnc3ccccc32)nc1C(F)(F)F
Temperature: 25 °C
Yield: 41 %

Procedure:
A reaction vessel was charged with 5 g (21 mmol) ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 4.96 g (42 mmol) benzimidazole. This mixture without solvent was heated at a temperature of about 100°-110° C. for 30 hours. The mixture was cooled to room temperature. This mixture was slurried in ethyl ether, washed with 5% hydrochloric acid, and then washed with large amounts of water, at which time a white precipitate began to form. A yellow filtrate was separated from 2.1 g of the precipitate (m.p. 133°-135° C.). The filtrate was concentrated under reduced pressure to provide 2.80 g of an off-white solid material (m.p. 132°-134° C.). This solid material and the white precipitate were combined and recrystallized from ethanol-water solution to give 4.03 g of an off-white solid product (m.p. 132°-134° C.) identified in Table I.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[NH2:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:35][OH:36])[C:24]([N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[C:25]([F:26])[C:20]=2[O:19][N:18]=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:16][C:17]1[C:21]2[CH:22]=[C:23]([CH2:35][OH:36])[C:24]([N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[C:25]([F:26])[C:20]=2[O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CN(c2c(CO)cc3c(N)noc3c2F)C[C@H](C)O1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2c(CO)cc3c(NCc4ccccc4)noc3c2F)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To an ice cooled solution of benzaldehyde (0.08 mL, 2.54 mmol) in TFA (5 mL) was added triethylsilane (0.4 mL, 2.5 mmol) followed by {3-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzisoxazol-5-yl}methanol (Intermediate 7, 250 mg, 0.84 mmol), and slowly allowed to reach room temperature and stirred for 12 hour. The reaction mixture was concentrated and the residue thus obtained was purified column chromatography using EtOAc in petether to give the title compound as solid. Yield: 70 mg (21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1B(O)O.Br[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:19]1[S:23][C:22]([N:24]([CH3:35])[CH:25]2[CH2:30][C:29]([CH3:31])([CH3:32])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)=[N:21][N:20]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1c(B(O)O)c(=O)n(C)c2ccccc12
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: C1COCCO1
Solvent: O
Product: COc1c(-c2nnc(N(C)C3CC(C)(C)NC(C)(C)C3)s2)c(=O)n(C)c2ccccc12
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A degassed reaction mixture of (4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (500 mg, 2.15 mmol), 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (858 mg, 2.57 mmol), tetrakis(triphenylphosphine)palladium(0) (248 mg, 0.215 mmol) and Na2CO3 (682 mg, 6.44 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated via microwave irradiation at 100° C. for 1 h. After cooling to room temperature, the mixture was filtered through celite, washed with MeOH then the filtrate was concentrated. The residue was purified by silica gel chromatography (2%˜10% 2M NH3 in MeOH/DCM) to give 4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one (240 mg, MS: 442.1 [M+H+].) (4 mg, MS: 442.0 [M+H+], LCMS Rt=1.25 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.55 (s, 1H), 8.14 (dd, J=8.08, 1.52 Hz, 1H), 7.72-7.81 (m, 1H), 7.61-7.69 (m, 1H), 7.33-7.45 (m, 1H), 4.61 (br. s., 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.11 (s, 3H), 1.95 (d, J=12.13 Hz, 2H), 1.79 (br. s., 2H), 1.50 (s, 6H), 1.39 (br. s., 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]1>C1COCC1.O>[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]1
Reactant: N#CCCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To anhydrous THF (70 mL) was added LiAlH4 (5.37 g, 142 mmol) in one portion. The mixture was stirred at 0° C. for 20 min, and a solution of 4-morpholinobutanenitrile (7.26 g, 47 mmol) in anhydrous THF (40 mL) was added dropwise. Upon the end of addition the mixture was refluxed for 4 h, then cooled to 0° C., diluted with water (20 mL) and filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16](=[O:22])[N:15]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:14]1[C:32]3[CH:33]=[C:34]4[O:42][CH2:41][O:40][C:35]4=[CH:36][C:37]=3[C:38](=[O:39])[C:13]2=1>CS(C)=O.C(Cl)(Cl)Cl>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16](=[O:22])[N:15]([CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:14]1[C:32]3[CH:33]=[C:34]4[O:42][CH2:41][O:40][C:35]4=[CH:36][C:37]=3[C:38](=[O:39])[C:13]2=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN=[N+]=[N-])C(=O)c1cc2c(cc1-3)OCO2
Temperature: 100 °C
Yield: 29.9 %

Procedure:
Sodium azide (0.021 g, 0.22 mmol) and compound 19 (0.128 g, 0.22 mmol) were diluted with DMSO (4 mL), and the mixture was heated at 100° C. for 2 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×60 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl2, to yield the product 21 as a solid (0.036 g, 60%). The solid was used for next step without further purification. ESIMS m/z 548 (MH+); HRESIMS m/z 548.2141 (MH+), calcd for C28H30N5O7 548.2145.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:30][CH3:31]>>[CH2:30]([N:21]1[CH:22]=[CH:23][C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:24])[C:11]2[N:25]([CH3:28])[C:26](=[O:27])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)=[N:20]1)[CH3:31]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CCI
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, with the compound from Example 72, 3-(4-fluorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and iodoethane.
Reaction SMILES: [F:1][C:2]([CH3:10])([CH3:9])[CH:3]([OH:8])[C:4]([O:6][CH3:7])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15](S(C)(=O)=O)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:8][CH:3]([C:2]([F:1])([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[N:14]=1
Reactant: COC(=O)C(O)C(C)(C)F
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)F
Temperature: 20 °C
Reaction time: 5 h

Procedure:
4 g (26.6 mmol) Methyl 3-fluoro-2-hydroxy-3-methylbutanoate and 5.81 g (26.6 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine were dissolved in 75 ml dimethylformamide at 20° C. and treated with 1.84 g (13.3 mmol) potassium carbonate. The suspension was stirred for 5 hours at 20° C. and heated for one hour at 60° C. The reaction mixture was then poured into 150 ml ice-water and extracted with three lots of 75 ml ethyl acetate. The combined ethyl acetate phase was washed with water, dried over magnesium sulphate, filtered and evaporated. The solid residue was purified by silica gel column chromatography using hexane/ethyl acetate as eluent.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2ccccc2)CC1

Procedure:
The title compound was prepared according to Example 1 from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-1,2,3,6-tetrahydropyridine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield as a white foam. FDMS m/e=348 (M+ of free base). α[D]589 =-17.09 (c=0.49, methanol).