Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:18]=[C:19]2[CH2:20][CH2:21][N:22]([C:32]([NH:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH2:23][CH2:24]2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 5-isopropoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.18 g, 0.55 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (0.118 g, 0.55 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.22 g, 89.2%). 1H NMR (500 MHz, CDCl3): δ 8.46 (s, 1H), 8.25 (d, J=3.5 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.86 (d, J=3 Hz, 1H), 7.27 (m, 2H), 7.23 (m, 1H), 6.98 (d, J=7.5 Hz, 1H), 6.93 (m, 2H), 6.85 (d, J=9 Hz, 1H), 6.68 (s, 1H), 6.39 (s, 1H), 4.45 (m, 1H), 3.60 (m, 2H), 3.50 (m, 2H), 2.58 (m, 2H), 2.44 (m, 2H), 1.33 (d, J=6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 157.34, 155.19, 154.58, 150.73, 143.84, 141.11, 138.80, 137.68, 136.27, 135.56, 129.41, 128.34, 127.50, 124.80, 124.61, 123.60, 120.61, 118.36, 112.49, 71.68, 45.69, 44.71, 35.73, 29.15, 21.96; m/z (445.2, M+ H+); HPLC: 96.0%.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C=O)C>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[O:1][CH2:17][CH2:16]1
Reactant: BrCCBr
Reactant: Oc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
2,3-Dihydroxypyridine (2.22 g, 20.0 mmol) was dissolved in N,N′-dimethylformamide (100 mL), and added potassium carbonate (5.52 g, 40.0 mmol) at room temperature. 5 minutes after, 1,2-dibromoethane (2.6 mL, 30.0 mmol) was added at the same temperature, and stirred at 90° C. overnight. The reaction solution was reverted to room temperature, filtered, and the obtained filtrate was concentrated in vacuo. Then, the obtained residue was added ethyl acetate. The suspension was filtered, washed ethyl acetate, and concentrated in vacuo. The title compound (157 mg (yield 5.7%)) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[Br:17][C:18]1[CH:19]=[N:20][C:21](Cl)=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][C:21]1[N:22]=[CH:23][C:18]([Br:17])=[CH:19][N:20]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
3,5-Bis-trifluoromethyl-benzylamine (10 g) and 5-bromo-2-chloro-pyrimidine (12 g) are dissolved in 1,4-dioxane (50 ml) and thereto is added N,N-diisopropylethylamine (10.7 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (10.1 g). MS (m/z): 713 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:20][O:21][C:22](=[O:45])[CH2:23][CH:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][CH:3]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1
Reactant: Cc1nc(C(F)(F)F)ccc1Nc1ccc(Br)cn1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4C)nc3)cc2)CC1
Temperature: 80 °C

Procedure:
(5-Bromo-pyridin-2-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-amine (290 mg, 0.87 mmol) and {4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (312 mg, 0.87 mmol) were dissolved in anhydrous DME (3 mL) in a pressure vessel. PdCl2dppf (21 mg, 0.026 mmol) was added, followed by aqueous sodium carbonate (2M, 0.870 mL, 1.74 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and heated at 80° C. for 18 hours. The mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (7-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) ppm 1.08-1.21 (m, 2 H) 1.50 (td, J=12.44, 10.23 Hz, 2 H) 1.81 (m, 4 H) 2.25 (d, J=6.57 Hz, 2 H) 2.59 (s, 3 H) 3.60 (s, 3 H) 7.22 (d, J=8.59 Hz, 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.57 (d, J=8.34 Hz, 2 H) 7.66 (d, J=8.59 Hz, 1 H) 7.97 (dd, J=8.59, 2.53 Hz, 1 H) 8.48 (d, J=2.53 Hz, 1 H) 8.64 (s, 1 H) 8.66 (d, J=8.34 Hz, 1 H); MS (M+H)+ 484.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].C[Si](C)(C)N[Si](C)(C)C.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.C(Br)C#C.C1OC1C>CO.COCCOCCOC>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:22][C:20]#[CH:21])(=[O:7])[OH:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCP(O)O
Agent: C#CCBr
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: COCCOCCOC
Solvent: CO
Product: C#CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1,23 g (10 mmol) of 3-aminopropylphosphonous acid in 10.4 ml (50 mmol) of hexamethyldisilazane is heated to reflux under argon for 24 hours. 5 ml of diethylene glycol dimethyl ether are added to the clear solution obtained and the mixture is heated for additional 2 hours and then cooled to 0°. 8.5 ml (50 mmol) of N-ethyl-N,N-diisopropyl-amine are added, followed by slow addition of 3.8 ml (50 mmol) of propargyl bromide over a period of 40 minutes. The mixtureis stirred for 1 hour at 0° and 4 hours at room temperature, filtered and evaporated under high vacuum. The residue is dissolved in 10 ml of dichloromethane and extracted with 3×10 ml of 1N hydrochloric acid solution. The water layer is evaporated under high vacuum and the residue obtained dissolved in 4 ml of methanol at 0°. 20 ml of propylene oxide are added during a period of 1 hour, after which time a crude product precipitates. Chromatography (silicagel Merck 230-400 ASTM, methanol) followed by recrystallization (methanol/ether) yields 3-aminopropyl(propargyl)-phosphinic acid, m.p. 172°-173°.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:7][N:8]([CH:15]([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][OH:6].[N:18]#[C:19]Br>>[CH:15]([N:8]([CH2:7][C@H:4]1[CH2:5][O:6][C:19]([NH2:18])=[N:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: N#CBr
Reactant: CC(C)N(C[C@H](N)CO)c1ccccc1
Agent: Cl
Product: CC(C)N(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-(isopropyl-phenyl-amino)-propan-1-ol dihydrochloride was reacted with cyanogen bromide to give (S)-4-[(isopropyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine as light yellow amorphous solid. MS (ISP): 234.3 ([M+H]+)
Reaction SMILES: [ClH:1].N(C1C=C(C#N)SC=1)N.[C:11]([C:13]1[S:17][C:16]([N:18](C(OC(C)(C)C)=O)[NH:19]C(OC(C)(C)C)=O)=[CH:15][CH:14]=1)#[N:12]>>[Cl-:1].[C:11]([C:13]1[S:17][C:16]([NH2+:18][NH2:19])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C#N)s1
Reactant: Cl
Agent: N#Cc1cc(NN)cs1
Product: N#Cc1ccc([NH2+]N)s1
Product: [Cl-]
Yield: 78 %

Procedure:
Following the same procedure as described for compound 13 (step 3, scheme 2, example 1c) except using 20 (692 mg, 2.04 mmol) instead of 12 to afford 21 (278 mg, 78%) as a brown solid. LRMS (ESI): calc. 139.0; found 140.1 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]2.CN(C)[CH:16]=[O:17]>CCCCCC>[CH3:12][C:8]1([CH3:13])[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([CH:16]=[O:17])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)CCC2(C)C
Reactant: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc2c(cc1C=O)C(C)(C)CC2
Temperature: 100 °C
Yield: 39.7 %

Procedure:
To a mixture of 10.60 g (60.0 mmol) of 5-methoxy-1,1-dimethylindane (see U.K. Patent Application No. GB 2,067,195 A for a method of obtaining this compound) and 6.5 g (90.0 mmol) of dimethylformamide was added 11.5 g (75.0 mmol) of phosphorous oxytrichloride. The mixture was heated at 100° C. for 5 h. The reaction mixture was cooled to ambient temperature and poured onto 100 g of ice. The aqueous residue was extracted with ether. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel (70 g) using a gradient from hexane to 2:98 (v/v) ether:hexane as eluent, There was obtained 4.86 g (23.8 mmol, 40%) of 1,1-dimethyl-5-methoxyindan-6-carboxaldehyde as a white solid after crystallization from hexane mp 51°-52° C.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5]([O:9][P:10](OCCCC)[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH3:8]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:5]([O:9][P:10]([Cl:2])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][CH3:8]
Reactant: ClP(Cl)Cl
Reactant: CCCCOP(OCCCC)OCCCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOP(Cl)OCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 194.9 %

Procedure:
17.0 g (0.125 mole) of phosphorus trichloride is added dropwise at 5° to 10° C., with vigorous stirring, to a mixture of 62.5 g (0.25 mole) of tri-n-butylphosphite and 5.0 g of benzyltriethylammonium chloride (water content 7%). After completion of the addition, the reaction mixture is heated to room temperature and stirred for a further 8 hours at this temperature. After separation of the benzyltriethylammonium chloride by filtration there is obtained, by distillation of the filtrate under reduced pressure, 51.8 g (65% of theory, relative to phosphorus trichloride) of di-n-butylchlorophosphite, b.p. 96° to 98° C./10 Torr.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10]C(C#N)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[OH-:14].[Na+].N.[CH2:17]([OH:20])[CH2:18]O>O>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:18]([C:17]([OH:20])=[O:14])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(CO)c1ccc(C#N)cc1
Reactant: [OH-]
Reactant: OCCO
Agent: N
Agent: [Na+]
Solvent: O
Product: CC(C)(CO)c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
p-(1,1-Dimethyl-2-hydroxyethyl)cyanobenzene, 75 g, 0.43 mole, was dissolved in a solution of ethylene glycol, 150 mL, and water, 50 mL, at 80° C. in a 2-L flask. The above solution was then heated on an oil bath with good stirring to 135°-140° C. A solution of 50% aqueous NaOH, 140 mL, in 150 mL water was added dropwise at such a rate that a gentle reflux was maintained, and the resulting clear solution was allowed to reflux until no more ammonia could be detected The solution was then diluted while still hot with 500 mL water and then allowed to cool to room temperature. The cooled solution was extracted twice with 100 mL portions of ether and the ether layers discarded. The aqueous layer was heated on a steam bath to expel any trapped ether, cooled to 0° C. and acidified with conc. HCl. The precipitated hydroxyacid was filtered, washed with 150 mL ice-cold water and dried in a vacuum oven at 50° C. The crude yield was 80 g (96%), mp=154°-156° C. The material was recrystallized once from water/methanol (3/1 vol.) ca. 1100 mL and three more times from boiling water. The final mp=156°-157° C. vs. 158°-159° C. (Heck et al., above).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][C:11](=O)[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1.[N+:23](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:24].CC(C)([O-])C.[K+].O>COCCOC>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:24]#[N:23])[CH2:10][CH2:9][N:8]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1Cc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl 2-(4-chlorobenzyl)-4-oxopiperidine-1-carboxylate (8.737 g, 26.98 mmol) in DME (200 mL) under nitrogen was added simultaneously 1-(isocyanomethyl-sulfonyl)-4-methylbenzene (7.90 g, 40.47 mmol) in 200 mL DME and potassium tert-butoxide (81 mL, 80.94 mmol) over 1 hour so that the temperature never rose above 0° C. The solution was stirred at −20° C. for 2 h and then let to warm to room temperature overnight. Water (200 mL) was added to the orange reaction mixture and the solution was stirred for 20 min and then extracted with 3× diethyl ether and 3× EtOAc. The organic phases were combined and dried over Na2SO4 and evaporated to give a brown residue. Further purification was done on Biotage (340 g column, 3 runs, heptane/EtOAc, gradient 20-60% EtOAc) to give tert-butyl 2-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylate (5.54 g, 61%). 1H NMR (400 MHz, cdcl3) δ, 1.21-1.50 (m, 9H), 1.58-2.14 (m, 4H), 2.55-3.27 (m, 4H), 4.06-4.25 (m, 1H), 4.34-4.60 (m, 1H), 7.02-7.34 (m, 4H). MS m/z 235, 237 (M-C5H8O2+H)+
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[C:12]3[C:24](=[O:38])[N:25](CC4C=CC(OC)=CC=4OC)[CH2:26][C:11]=3[C:10]=2[F:39])[CH2:6][CH2:5][O:4][CH2:3]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:1][C@@H:2]1[C@H:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=34)[C:12]3[C:24](=[O:38])[NH:25][CH2:26][C:11]=3[C:10]=2[F:39])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cnn3ccccc23)c2c(c1F)CNC2=O
Temperature: 60 °C
Yield: 44.2 %

Procedure:
To a 25 mL round bottom flask with a stir bar was added 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-2-(2,4-dimethoxybenzyl)-7-fluoro-4-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (85 mg, 0.160 mmol) in TFA (5 mL). The mixture was heated at 60° C. for 1.5 h and then cooled to RT. The mixture was concentrated and purified via preparative HPLC to give a TFA salt of the title compound as a white solid (27 mg, 44.2%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.85 (m, 1H), 2.12-2.14 (m, 1H), 3.65-3.73 (m, 2H), 3.81-3.82 (m, 1H), 3.93-3.95 (m, 1H), 4.01-4.03 (m, 1H), 4.43 (s, 2H), 4.53-4.55 (m, 1H), 7.04 (t, J=6.83 Hz, 1H), 7.13 (d, J=4.88 Hz, 1H), 7.49 (t, J=8.05 Hz, 1H), 7.94 (br s, 1H), 8.36-8.42 (m, 2H), 8.78 (d, J=6.83 Hz, 1H), 9.33 (s, 1H). [M+H] calc'd for C19H19FN6O2, 383. found, 383.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]=[CH:10][C:9]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(O)ccc1C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(OCc2ccccc2)ccc1C(=O)OCC

Procedure:
A solution of 5.3 g (12.3 mmol) of N-(2,4-dimethoxy-benzyl),N-(2-ethoxycarbonyl-5-hydroxy-benzyl)glycine ethyl ester, 1.8 mL (15.4 mmol) benzylbromide, and 4.4 g (13.5 mmol) cesium carbonate in 35 mL of anhydrous DMF was stirred for 18 hours. The reaction mixture was partitioned between diethyl ether and water, and the organic fraction washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered through a pad of silica gel, and concentrated under reduced pressure to 6.4 g of the title compound. MS (ESI+) 522.5 e/z (M+1)
Reaction SMILES: [C:1]([NH:4][C:5]1([C:13]#[N:14])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2].[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C.[Pt]=O>[C:1]([NH:4][C:5]1([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(C#N)CC2CCC1CC2
Reactant: CC(=O)O
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1(NC(C)=O)CC2CCC1CC2

Procedure:
The procedure is as in Example 1, but starting from 2-acetylamino-2-cyano-bicyclo[2.2.2]octane (5.8 g) in acetic acid (100 cc) and acetic anhydride (5.6 cc) in the presence of Adams platinum oxide (0.6 g); chromatographing the residue from the evaporation on a column 5.5 cm in diameter containing silica gel (200 g), eluting with a mixture of ethyl acetate and ethanol (75/25 by volume) and collecting fractions of 50 cc. The fractions between 800 and 1750 cc are concentrated to dryness; 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.2]octane (5.45 g) is thus obtained in the form of a pale yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]1=[O:34]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C:29]([CH3:33])([CH3:32])[C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:34])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1C(=O)NC(C)(C)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)c(C)c1
Yield: 16.5 %

Procedure:
Using (4-bromo-2-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (30 mg) was obtained.
Reaction SMILES: [OH:1][C:2](C(F)(F)F)=O.[NH2:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][C@@:24]([CH3:31])(OC)[C:25]([F:28])([F:27])[F:26])[C:20]([N+:32]([O-:34])=[O:33])=[C:19]([F:35])[CH:18]=2)[CH2:12][S@:11](=[O:36])[CH2:10]1.[C:37]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH:44]=O)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][C@H:24]([CH2:31][O:1][CH3:2])[C:25]([F:26])([F:28])[F:27])[C:20]([N+:32]([O-:34])=[O:33])=[C:19]([F:35])[CH:18]=2)[CH2:12][S@:11](=[O:36])[CH2:10]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1cccc(C=O)c1
Reactant: CO[C@](C)(Oc1cc(C[C@@H]2C[S@](=O)C[C@H](N)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 1h, starting from (1S,3R,4S,5S)-3-amino-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxy-methyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol TFA salt (310 mg, 0.7 mmol) and 3-tert-butyl-benzaldehyde and was obtained after purification by flash-chromatography (hexane-(EtOAc-MeOH 9:1) gradient) as a light yellow foam: TLC (EtOAc-MeOH 9:1) Rf=0.38; HPLC RtH1=1.05 min; ESIMS [M+H]+=591; 1H NMR (600 MHz, CDCl3): δ 7.36 (s, 1H), 7.28 (s, 1H), 7.23 (m, 2H), 7.13 (d, 1H), 7.11 (d, 1H), 5.66 (m, 1H), 5.16 (d, 1H), 3.83-3.79 (m, 2H), 3.69 (dd, 1H), 3.63 (d, 1H), 3.55 (m, 1H), 3.30 (s, 3H), 3.14 (m, 2H), 3.00 (d, 1H), 2.55 (m, 1H), 2.5-2.4 (m, 3H), 1.95 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26].Cl>C(=O)([O-])O.[Na+].O1CCCC1>[CH2:28]([O:27][C:25]([S:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([NH:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])=[O:26])[CH:29]([CH3:31])[CH3:30]
Reactant: Cc1c(NC(=O)C(CS)Cc2ccccc2)cccc1C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(CSC(=O)OCC(C)C)Cc2ccccc2)cccc1C(=O)O
Yield: 36 %

Procedure:
3-[(2-Mercaptomethyl-3-phenylpropionyl)amino]-2-methylbenzoic acid (compound of Example 7) (0.66 g) is dissolved in a mixture of saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran (1 ml), and to the mixture is added a solution of isobutyl chloroformate (0.33 g) in tetrahydrofuran (5 ml) with stirring under ice cooling, and the mixture is stirred under ice cooling for 30 minutes and further at room temperature for one hour. The reaction mixture is acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (0.31 g). m.p.: 165°-167° C. (amorphous) IR (KBr; cm-1): 1700, 1650
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:32]C(=O)OC(C)(C)C)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]([CH2:28][CH3:29])[S:26](=[O:31])(=[O:30])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]=1[F:40]>O1CCOCC1.C(Cl)Cl.CO>[NH2:32][C@H:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([F:40])[CH:5]=1)[C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]([CH2:28][CH3:29])[S:26](=[O:30])(=[O:31])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CCC1c2c(ncnc2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)c(F)c3)NC(=O)OC(C)(C)C)CC2)CS1(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCC1c2c(ncnc2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)c(F)c3)CC2)CS1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
HCl in dioxane (4M, 2 mL) was added to a solution of tert-butyl (2R)-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.005 g, 0.009 mmol) in DCM (2 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 5 hours. The solvent was removed to afford (2R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as the HCl salt (4 mg, 97%). LCMS: 482.1 [M+H+] (APCI+).