Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:14]=[C:15]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=1)=[O:17])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)(Cl)Cl>[C:40]([C:37]1[CH:36]=[C:15]([CH:14]=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH:28]([Cl:1])[C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH:20]=1)=[O:17])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)CC(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Reaction time: 18 h

Procedure:
N-chlorosuccinimide (16.3 g; 0.122 mole) was added with stirring to a solution of the compound (55.7 g; 0.1 mole) from (c) in chloroform (480 ml) and stirring continued for 18 hr. The volume of the mixture was reduced to approximately 100 ml and hexane (250 ml) added. The mixture was washed with water (2×100 ml) and the organic solution dried and evaporated to give a solid. This material was crystallized from dichloromethane (100 ml) and hexane (500 ml), to give the product (44.5 g; 83%) as a white solid, m.p. 185°-187° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1CCO[CH:27]1[C:31]1[N:32]=[CH:33][S:34][C:35]=1[Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>C1COCC1.Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:35]4[S:34][CH:33]=[N:32][C:31]=4[CH:27]=[O:26])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1scnc1C1OCCO1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ncsc1-c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Yield: 40.9 %

Procedure:
Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (0.876 g,2 mmol), 4-(1,3-dioxolan-2-yl)-5-tributylstannylthiazole (2.1 mmol), bis(triphenylphosphine) palladium (II) chloride (0.105 g, 0.15 mmol, 7.5 mol %) and silver oxide (0.463 g, 2 mmol) heated under reflux under nitrogen for 18 hr. The reaction mixture was then filtered through Harborlite® and the filtrate was concentrated. The product was purified on Bond Elut™ cartridge, eluting sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. The ketal (0.385 g, 0.824 mmol) was stirred at room temperature in a mixture of THF (10 ml) and 1N HCl (10 ml) for 2 hr. The suspension was basified with 2N NaOH (5 ml) and the THF was removed. The aqueous suspension was filtered and washed with water to give the product as a yellow solid (0.346 g);m/z 424.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])[C:10]1([CH3:23])[CH3:22])=O)(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])[C:10]1([CH3:23])[CH3:22]
Reactant: COC(=O)CCNC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCNC(=O)[C@H]1C[C@@H](N)C1(C)C
Yield: 100 %

Procedure:
A stirred solution of methyl 3-((1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxamido)propanoate (step 1, 0.336 g, 1.024 mmol) in TFA:DCM (1:4) (4 ml) at 0° C.-room temperature for about 1 hour and after completion of the reaction, the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.87 ml, 6.29 mmol) then the resulting solution as such used for the next reaction. Wt: 0.233 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12](Br)[CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]([CH3:13])[N:25]([C@@H:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH3:24])[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1C(C)Br
Reactant: COc1ccc([C@@H](C)N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Temperature: 67 °C
Yield: 52.6 %

Procedure:
Add solid methyl 5-bromo-2-(1-bromoethyl)benzoate (1724 g, 5.35 mol) to a solution of commercially available (R)-1-(4-methoxyphenyl)ethanamine (BePharm, WZG111219-071; 974 g, 6.44 mol) and triethylamine (1710 mL, 12.26 mol) in methanol (12 L). Heat the mixture for 10 hours at 67° C. then evaporate to dryness under reduced pressure. Partition the residue with ethyl acetate (5 L) and aqueous 1 N HCl (10 L), separate the phases, wash the organic phase again with aqueous 1 N HCl (5 L), saturated sodium bicarbonate, saturated aqueous sodium chloride, then dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve the dark red oil in methyl-tert-butyl ether (750 mL) and add petroleum ether (3 L) with vigorous stirring. Filter the solids, wash with methyl-tert-butyl ether/petroleum ether (1:8), petroleum ether, dry in open air to give the title compound as an off-white solid (1014 g, 52%). ES/MS m/z: 360 (M+H).
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: COC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-bromopropionate (60.12 g, 0.36 mol) is added to a mixture of 4-nitrophenol (25 g, 0.18 mol) and potassium carbonate (49.75 g, 0.36 mol) in acetonitrile. The reaction mixture is refluxed for 18 hours, cooled and poured into water. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white powder, mp 79°-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17](Br)=[CH:16][C:15]([F:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]3)=[CH:16][C:15]([F:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncc(F)cc2Br)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2ncc(F)cc2N2CCC(CO)CC2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 3-(3-bromo-5-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (58) (660 mg, 2 mmol, Preparation 17) and piperidin-4-yl-methanol (35) (230 mg, 2 mmol) in DMSO (20 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (EtOAc:PE=3:1) on silica gel to give (76) (490 mg, 1.34 mmol, yield 67%). ESI-MS (M+1): 366 calc. for C19H28FN3O3 365.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[S:13]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=2)[CH:8]=[O:9])=[CH:14]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccnc(Br)c1
Agent: OBO
Product: O=Cc1ccnc(-c2ccsc2)c1

Procedure:
2-(thiophen-3-yl)isonicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and thiophen-3-ylboronic acid (89 mg, 101.8 mg theoretical, 87.4%). LC-MS m/z 190.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([CH:14]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].O.O.O.[F-].C([NH3+])(C)(C)C.O>O1CCCC1>[CH2:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[C:6]([C@@H:14]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C(CO[Si](C)(C)C(C)(C)C)N(CC)CC)cccc2cc1C
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c([C@H](CO)N(CC)CC)cccc2cc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
0.40 g (1.0 mmol) of (+)-2-ethyl-3-methyl-8-(1-diethylamino-2-[tert-butyldimethylsilyloxy]ethyl)-quinoline and 5 ml of tetrahydrofuran are introduced into a 50 ml round-bottomed flask. This solution is cooled to 0° C. on an ice bath and a solution of 0.40 g (1.52 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 45° C. for 3 hours. 50 ml of water are added and the resulting mixture is extracted with ethyl acetate (3×50 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a column of silica (elution solvent: 5% methanol in dichloromethane). 0.25 g (yield: 87.4%) of (+)-2-ethyl-3-methyl-8-(1(R)-diethylamino-2-hydroxyethyl)quinoline is obtained in the form of an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH:13](N(C)C)N(C)C)[CH3:12]>C1C=CC=CC=1>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CC(=O)c1cccnc1
Solvent: c1ccccc1
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
A mixture of 0.02 mole of 3-acetylpyridine and 0.022 mole of tris(dimethylamino)methane in benzene was refluxed for 5 hours, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [C:1]1([SiH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]1[CH:16]([CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:15]1>C1(C)C=CC=CC=1.C(O)C.O.[Rh](Cl)(Cl)Cl>[C:8]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[O:14][CH2:15]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[O:14][CH2:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CCCC1CO1
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Agent: Cl[Rh](Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc([Si](CCCCC2CO2)(CCCCC2CO2)c2ccccc2)cc1
Yield: 78.8 %

Procedure:
27.6 g of diphenylsilane (0.15 mole) were dispersed in 100 g toluene with 0.02 g rhodiumtrichloride hydrate (as a solution in 0.5 cc ethanol) then the solution was brought to 100° C. when 32 g 1,2-epoxy-5-hexene (0.32 mole) were added dropwise. A two hour hold at 100°-110° followed, which consumed all SiH per IR analysis. Solvent was distilled off leaving 45 g residue as a mobile, 15 cstk viscosity fluid product, nD25 =1.5532. Infrared analysis was consistent with the proposed structure, with evidence of siloxane by products also present.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([F:19])[CH:11]=1)#[N:9].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:44][C@H:45]1[NH:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]1>C1COCC1.O.C(OCC)(=O)C>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:50]2[CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46][C@H:45]2[CH3:44])=[O:16])=[C:12]([F:19])[CH:11]=1)#[N:9]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(C#N)cc1F
Reaction time: 0.25 h

Procedure:
Triethylamine (803 μL, 5.76 mmol) was added to a mixture of 4-cyano-2-fluorobenzoic acid (247 mg, 1.50 mmol, Alfa Aesar) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (522 mg, 1.37 mmol) in THF (11 mL). After stirring for 15 min, tert-butyl (3R)-3-methylpiperazine-1-carboxylate (0.25 g, 1.2 mmol, Aldrich) was added. The mixture was stirred for 3 h. Ethyl acetate and water were added, shaken and the layers separated. The organic layer was washed with water, 0.1N NaOH, and brine; dried over sodium sulfate, decanted and concentrated to afford product which was used without further purification (450 mg, 100%). 1H NMR (400 MHz, CDCl3, rotamers): δ 7.57-7.40 (m, 3H), 4.98-2.63 (m, 7H), 1.47 (s, 9H), 1.28 (d, 1.8H), 1.19 (br s, 1.2H); LCMS (M-tBu+2H)+: 292.1.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[Cl:22])[CH2:6][CH2:5]1)(=O)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C.Cl[SiH](Cl)Cl>C(Cl)Cl>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=1[C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH:1]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:2])[CH2:5][CH2:6]1)=[O:23]
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: Nc1ccccc1
Agent: Cl[SiH](Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Nc1ccccc1)[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Trans-N-(4-acetylcyclohexyl)-2-chloro-5-(trifluoromethyl)-benzamide (200 mg, 0.57 mmol) and aniline (54 mg, 0.57 mmol) in DCM (10 mL) is added DMF (0.1 mL) followed by trichlorosilane (78 mg, 0.57 mmol). After stirring at room temperature for 1 hour, further trichlorosilane (5×78 mg, 5×0.57 mmol) is added at 1 hour intervals for the next 5 hours. Further DMF (0.1 mL) was then added and the mixture is stirred at room temperature overnight. The colourless solid that is formed is recovered by filtration, washed successively with water and then EtOAc and dried. [MH+425.38]. The racemic mixture was separated by supercritical fluid chromatography on chiral stationary phase analogously to that reported for Example 1.37.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1cccs1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)ccc1-c1cccs1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-5-(thiophen-2-yl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (65 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate (5 ml) was added and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residual aqueous layer was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the object product (20 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])([O-:15])=[O:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 3.00 gm (0.019 mole) of 2-quinolinecarboxaldehyde, 3.44 gm (0.019 mole) of m-nitrobenzhydrazide and 100 ml of ethanol is refluxed for 9 hrs. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected. The crude product is recrystallized from tetrahydrofuran to yield 3.04 gm (50%) of the title compound, having a melting point of 217°-218° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([O-])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.N1C=CC=CC=1>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([O:17][CH3:18])[C:14]([Cl:25])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Reaction time: 2 h

Procedure:
Sodium N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycinate (0.92 g, 3 mMol) is suspended in dry CH2Cl2 (25 ml) and cooled in an ice-water bath. Oxalyl chloride (0.38 g, 3 mMol) and 2 drops of pyridine are added. The resulting mixture is stirred in the cold for 2 hours, and then filtered. The filtrate, which contains N-(p-nitrobenzyloxycarbonyl)-α-methoxyglycyl chloride, is used directly in the next step.
Reaction SMILES: C(O[BH3-])(=O)C.[Na+].[CH:7](=O)[CH:8]([CH3:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:20]2[CH2:23][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH2:21]2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[N:20]2[CH2:21][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][N:38]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH2:23]2)=[CH:17][CH:18]=1
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CC(C)C=O
Agent: O=C([O-])O
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)CN1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 105.2 %

Procedure:
32 mg of sodium acetoxyborohydride and then 22 mg of isobutyraldehyde are successively added, at a temperature close to 20° C., to a solution of 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine in 2 cm3 of 1,2-dichloroethane. After stirring for 4 hours at a temperature close to 20° C., 3 cm3 of dichloromethane and 2 cm3 of a saturated aqueous sodium bicarbonate solution are added to the reaction medium. After separating after settling out, the organic [lacuna] is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 63 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 0.92 (d, J=7 Hz, 6H), 1.82 (mt, 1H) 2.14 (d, J=8 Hz, 2H), 2.54 (t, J=5.5 Hz, 4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.[ClH:28].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:51][O:52][CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][C:56]1=[O:61].C(OCC)(=O)C.Cl>>[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:58]3[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][O:52][CH3:51])[C:56](=[O:61])[CH2:57]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: COCCN1CCNCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: COCCN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1=O
Yield: 12 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (50.0 mg, 0.189 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.0415 mL, 0.378 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.7 mg, 0.265 mmol), 1-hydroxybenzotriazole monohydrate (33.2 mg, 0.246 mmol) and 1-(2-methoxyethyl)piperazin-2-one (44.8 mg, 0.284 mmol) in a similar manner to Step 7 of Example 1, was treated with hydrogen chloride-ethyl acetate solution (4 mol/L, 0.236 mL) to obtain Compound 134 (10.0 mg, 12%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c1) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]1[O:19][C@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:20][C@H:18]1[CH2:17][O:19]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1cc(Br)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Br)cc(OC[C@H]2CO2)c1F
Temperature: 25 °C
Yield: 97 %

Procedure:
To an acetone solution (0.1 M, 240 mL) of commercially available 5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K2CO3 (9.92 g, 71.77 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.20 g, 23.93 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to RT, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (15% ethyl acetate/hexanes) gave the product as a white solid in 97% yield (6.19 g).