Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH3:10])=[O:18])[CH2:3]2
Reactant: COc1ccccc1C(=O)N=C=O
Reactant: N[C@@H]1CN2CCC1CC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1ccccc1C(=O)NC(=O)N[C@@H]1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])(=[O:4])=[O:3].C1N2CCN(CC2)C1.[C:22](Cl)(Cl)=[O:23]>C1(C)C(C)=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:22]=[O:23])(=[O:12])=[O:11])(=[O:3])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)(=O)c1sccc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)c1sccc1S(=O)(=O)N=C=O

Procedure:
A suspension of 3.3 g of the N-(n-butylamino carbonyl) derivative of (XXV) in 75 ml of xylene containing 0.5 g of DABCO was heated to 125°-130° and a solution of 1.8 ml of liquid phosgene in 2 ml of xylene was added. The mixture was heated at reflux for an additional 1.5 hour, cooled under nitrogen, and concentrated to dryness in vacuo. A sample of the crude product displayed a characteristic sulfonyl isocyanate band in the IR at 2200 cm-1.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (30.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (25.8 mg), tetrakis(triphenylphosphine)palladium(0) (7.13 mg) and potassium carbonate (17.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.1 mg).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=CC(O)=[CH:3][CH:2]=1.S(=[CH:12][N+:13]#[C-:14])(=O)=O.[CH2:15]([O:17][C:18](=[O:22])/[CH:19]=[CH:20]/[CH3:21])[CH3:16]>>[CH3:3][C:2]1[C:1]([CH3:8])=[CH:6][NH:13][CH:12]=1.[CH2:15]([O:17][C:18]([C:19]1[C:20]([CH3:21])=[CH:14][NH:13][CH:12]=1)=[O:22])[CH3:16]
Reactant: [C-]#[N+]C=S(=O)=O
Reactant: C/C=C/C(=O)OCC
Reactant: Cc1ccc(O)cc1
Product: CCOC(=O)c1c[nH]cc1C
Product: Cc1c[nH]cc1C

Procedure:
Based on D. O. Cheng, T. L. Bowman, E. LeGoff, J. Heterocyclic Chem. 13, 1145 (1976), 3,4-dimethylpyrrole was synthesized starting from p-toluol-sulfonylmethyliso-cyanide and crotonic-acid-ethyl-ester. The dimethyl compound was quickly obtained after reduction of the intermediary 3-(ethoxycarbonyl)-4-methylpyrrole, but at only 18% total yield. The material had a melting point of 25°-28° C. H-NMR (CDCl3): 2.04 (s, 6H), 6.50 (d, 2H), 7.33 (s br, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)Cl>CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][C:5]#[N:6]
Reactant: C1=COCCC1
Reactant: N#CC[C@@H](CO)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: N#CC[C@@H](COC1CCCCO1)c1ccccc1F
Reaction time: 0.08 h

Procedure:
To a solution of β(R)-(hydroxymethyl)-β-(2-fluorophenyl)-propionitrile (210 g, 1.18 mol) in Et2O (200 ml), is added 3,4-dihydro-2H-pyran (225 ml, 2.68 mol) at ambient temperature. The mixture is stirred for 5 minutes and POCl3 (5 mL) is added dropwise. The reaction mixture is stirred for 30 minutes at ambient temperature and then refluxed for 2 hours. The resulting solution is allowed to cool and the solvent is removed in vacuo. The residue is then chromatographed (EtOAc/hexane, 1:4) to give β(R)-[[(tetrahydropyran-2-yl)oxy]methyl]-β-(2-fluorophenyl)-propionitrile as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1.[B-]C#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:43]2[CH:46]=[CH:47][C:40]([C:39]([F:49])([F:48])[F:38])=[CH:41][CH:42]=2)[CH2:7][CH2:6]1)[CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
Tert-butyl (S)-4-[2-(N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamino)-ethyl]piperazine-1-carboxylate prepared in Example 173 (400 mg, 0.94 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). After stirring for 5 minutes at room temperature, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). To the solution, 4-(trifluoromethyl)benzaldehyde (0.4 ml, 2.83 mmol), sodium cyanotrihydroborate (178 mg, 2.83 mmol) and acetic acid (0.2 ml) were added followed by stirring at room temperature for 30 minutes. To the solution, a saturated sodium hydrogencarbonate solution and methylene chloride were added followed by stirring, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford (S)-N-methyl-N-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]ethylamine (307 mg, yield 68%) as a white powder.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[C:8]([CH:13]([O:21][C:22](=[O:24])[CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1>C(O)(C(F)(F)F)=O.O>[CH3:12][C:11]1[C:4]([OH:3])=[C:5]([CH2:6][OH:7])[C:8]([CH:13]([O:21][C:22](=[O:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][N:10]=1
Reactant: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c2c1COC(C)(C)O2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c(O)c1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.24 g (0.66 mmoles) of (+)-2,2,8-trimethyl-5-(4-chloro-α-acetoxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 10 ml round bottomed flask and dissolved in 3.3 ml of TFA/H2O (10:1). The reaction is allowed to stir at room temperature for 1.5 hours, the solvent is then removed by rotary evaporation. 1 ml of methanolic ammonia is added to the crude product (the excess of TFA being neutralized), then evaporated to dryness under high vacuum. The crude product was shown to contain 90% of the desired diol-acetate by HPLC along with 4.4% of unreacted starting material.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:13]=[CH:12][C:9](C=O)=[C:8](O)[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CCCC)C1C=[C:26]([OH:30])C=CC=1)CCC.P(Cl)(Cl)(Cl)=[O:36].NC1C=C(O)C=CC=1>CN(C)C=O>[CH2:15]([N:5]([C:6]1[C:7]([OH:36])=[C:8]([CH:9]=[CH:12][CH:13]=1)[CH:26]=[O:30])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1cccc(O)c1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(O)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
Firstly, the starting compound N,N-dibutyl-4-amino-2-hydroxy-benzaldehyde had to be prepared by Vilsmeyer formylation of N,N-dibutyl-3-amino-phenol. The Vilsmeyer reagent was prepared by slow addition of 4.7 ml (0.0497 mol) of phosphorus oxychloride to 15 ml (0.189 mol) of N,N-dimethyl formamide with stirring for 15 minutes at room temperature. Stirring was continued for 30 more minutes before this Vilsmeyer reagent was used. 11 g (0.497 mol) N,N-dibutyl-3-amino-phenol, prepared by alkylation of 3-aminophenol after the procedure described in EP 0356173 was dissolved in 13 ml N,N-dimethyl formamide. This solution was added dropwise at room temperature to the Vilsmeyer reagent described above. The solution was stirred for 3 h, heated to 50° C. for 10 minutes. The solution was cooled to room temperature and stirred for another 2 h. Then, the reaction mixture was poured onto 70 g ice and stirred for 1 h. The aequous layer was extracted three times with 100 ml chloroform. The combined organic layers were evaporated in vacuo. The raw product was purified by column chromatography (450 g silicagel, eluent hexane/ethyl acetate 15:1, vol. ratio). 3.2 g (26%) N,N-Dibutylamino-2-hydroxy-benzaldehyde was obtained as an orange oily compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Br:12]Br>C(O)(=O)C.C(OCC)C>[Br:12][C:8]1[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(CC)c1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cc(Br)cc(CC)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of 2,6-diethylaniline (10.0 g, 67.0 mmol) in acetic acid (50 mL) at ambient temperature was added bromine (10.4 mL, 201 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was diluted with diethyl ether (200 mL) and washed with 5% sodium bisulfite (4×50 mL) and brine. The organic phase was dried with sodium sulfate and the solvents were removed in vacuo. The residue was chromatographed on silica gel, eluting with 9:1 hexane-ethyl acetate to give the title compound (3.28 g, 21 % yield).
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH:3]=[CH2:4].[C:7]([OH:10])(=[O:9])[CH3:8].B(O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:7]([O:10][CH2:4][CH:3]=[C:2]([CH3:5])[CH3:1])(=[O:9])[CH3:8]
Reactant: C=CC(C)(C)O
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC=C(C)C
Reaction time: 4 h

Procedure:
A mixture of 3-methyl-3-hydroxybut-1-ene (32 g.), acetic acid (150 ml.) and boric acid (30 g.) was stirred at 105° for 4 hours. The cooled reaction mixture was diluted with water, neutralised with solid sodium carbonate and extracted with ether (3 × 50 ml.) The combined ethereal extracts were brine washed, dried and the solvent removed giving a pale yellow oil (30 g.) Distillation gave 3,3-dimethylallyl acetate as a colourless oil (22 g.) b.p. 44°-45°/14 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[O:25][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].C(OCC)(=O)C>CO>[ClH:27].[CH3:26][O:25][C@H:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (800 mg, 2.2 mmol) was dissolved in methanol (40 mL). A 4 N hydrochloric acid/ethyl acetate solution (30 mL) was added, and the mixture was stirred at room temperature for one hour. Concentration under reduced pressure gave 691 mg of the title compound as a colorless oily substance (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCSc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOCCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-propoxyethylthio)phenyl borate (172 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed at 100° C. for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and. recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 105) (220 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1oc2cc(Cl)ccc2c2ccncc12
Temperature: 60 °C
Yield: 72.4 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (0.3 g, 1.192 mmol) in anhydrous DMSO (1 mL) was added Cs2CO3 (0.388 g, 1.192 mmol) and the mixture was subjected to microwave heating for 2 h at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water (1×15 mL) and brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 8-chloro-5H-chromeno[3,4-c]pyridin-5-one (0.2 g, 0.863 mmol, 72% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J=0.40 Hz, 1H), 8.98 (d, J=5.60 Hz, 1H), 8.01 (d, J=8.80 Hz, 1H), 7.88 (q, J=0.40 Hz, 1H), 7.44 (d, J=2.00 Hz, 1H), 7.39 (q, J=2.00 Hz, 1H); LCMS (ESI) m/e 232.6 [(M+H)+, calcd for C12H7ClNO2 232.0]; LCMS retention time (Method D): tR=0.81 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH2:15][O:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCO)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (1.92 g) in a mixture of triethylamine (1.15 ml) and methylene chloride (40 ml) was added methanesulfonyl chloride (0.592 ml) at −78° C., and the mixture was stirred for 1 hour. After completion of the reaction, aqueous sodium hydrogencarbonate was added and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (2.38 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:24])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1.C1(C(N)C2CCCCC2)CCCCC1.[CH3:39][OH:40]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:4]2[C:3](=[O:24])[C:2]3[C:39]([OH:40])=[C:9]4[C:10](=[O:15])[N:11]([CH3:14])[CH2:12][CH2:13][N:8]4[C:7]=3[CH:6]=[N:5]2)=[CH:18][CH:19]=1
Reactant: CO
Reactant: CN1CCN(c2cnn(Cc3ccc(F)cc3)c(=O)c2Br)CC1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)ncc32)C1=O
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-2-(4-fluorobenzyl)-5-(4-methyl-3-oxopiperazin-1-yl)pyridazin-3(2H)-one (0.2 g, 0.51 mmol), dicyclohexylmethylamine (0.15 g, 0.76 mmol), and bis-(tri-t-butylphosphine)palladium (0) (52 mg, 0.10 mmol) in anhydrous methanol (5 mL) was heated in a stainless steel pressure vessel under an atmosphere of carbon monoxide (250 psi) in an oil bath at 90° C. overnight. The resultant mixture was diluted with methanol, filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residual oil was triturated with methanol. The white solid precipitated was filtered to provide the titled dione.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[C:26]2[S:43][C:42]([NH2:44])=[N:41][C:27]=2[N:28]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[N:30]=1>CN1C(=O)CCC1>[NH2:44][C:42]1[S:43][C:26]2[C:25]([NH:1][C@H:2]3[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)=[N:30][C:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[F:40])=[N:28][C:27]=2[N:41]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Nc2nc(SCc3cccc(F)c3F)nc3nc(N)sc23)C1

Procedure:
(3R,4R)-3-Amino-4-hydroxy-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.73 g), diisopropylethylamine (1.0 ml) and the product of example 4 step b), were stirred in NMP (10 ml) at 100° C. for 28 hrs. The cooled mixture was poured onto water and the solid produced collected, washed with water and air dried. The crude material was purified (SiO2, ethyl acetate as eluant) to give the subtitle compound as a colourless solid (0.58 g).
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C>[CH:1]1([C@@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 109 mg) in ethyl acetate (EtOAc, 5.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(+)-DuanPhos](BF4) (5.5 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 20 bar pressure. The reaction mixture was stirred at room temperature under this hydrogen pressure for 19 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 97.9% ee (98.95% of the first peak, (S)-22; 1.05% of the second peak, (R)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with ethyl acetate (EtOAc, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (98 mg) was analyzed by chiral HPLC analysis and result showed a 97.9% of enantiomeric excess favoring the first peak (98.95% of the first peak, (S)-22; 1.05% of the second peak, (R)-22).