Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.[CH3:21][S:22]([O-:24])=[O:23].[Na+]>CO>[CH3:21][S:22]([C@@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:24])=[O:23]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of 0.494 g of (3S,4S)-4-acetoxy-3-phenoxyacetamido-2-oxoazetidine in 14 ml of 50% methanol is added 0.51 g of sodium methylsulfinate and the mixture is stirred at room temperature for 18 hours. The methanol is distilled off under reduced pressure to give 222 mg of (3R,4S)-4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:17])[O:8][C:9]32[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:5][CH:4]=1.[C:18]1([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:17])[O:8][C:9]32[CH2:14][CH2:13][N:12]([C:31]([NH:30][C:27]2[CH:26]=[N:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=2)=[O:32])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2cc(F)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 6-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (101 mg) as colorless crystals (melting point 222-224° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20]([O:28]C)=[N:21][C:22]([CH2:26][OH:27])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:28])[NH:21][C:22]([CH2:26][OH:27])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COc1nc(CO)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CO)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 80 °C
Yield: 39 %

Procedure:
To a stirred solution of 6-bromo-N-((6-(hydroxymethyl)-2-methoxy-4-methylpyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (500 mg, 1.086 mmol) in tetrahydrofuran (5 mL) was added 6 N HCl (15 mL, 15.00 mmol). The reaction was stirred under N2 with heating at 80° C. for 18 hr. The reaction was cooled to RT and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 4% MeOH in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum. Triturated with a small volume of water, filtered, washed with water and dried under vacuum to give the product 6-bromo-N-((6-(hydroxymethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (189 mg, 0.423 mmol, 39.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.30 (s, 1H), 8.27 (t, J=4.9 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.33 (s, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.05 (s, 1H), 5.38 (t, J=5.9 Hz, 1H), 4.74 (dt, J=6.7, 13.2 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 4.25 (d, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.13 (s, 3H), 1.39 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 446.1 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1(/[CH:14]=[C:15](\[CH2:19][C:20]([OH:22])=[O:21])/[C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:8]1([CH:14]=[C:15]2[CH2:19][C:20](=[O:21])[O:22][C:16]2=[O:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C/C(=C\c1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=Cc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.3 l (approx. 2.49 kg, approx. 24.4 mol) of acetic anhydride are added at 20° C. to a solution of 2.28 kg (11.1 mol) of (E)-phenylitaconic acid in 5.7 l of THF. The mixture is stirred for 5 hours at room temperature. After 1 hour there is a clear light yellow solution; after 3 hours the product begins to crystallize out. The THF is removed under vacuum, 5.0 l of methyl tert-butyl ether are added to the residue in order to complete the crystallization, and the product is filtered off with suction. It is washed with MTB ether, dried with suction and dried under vacuum at 40° C. Yield: 1.68 kg (8.94 mol, 81% of theory), m.p. 167°-170° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19](O)[C:20]([CH3:33])=[CH:21][CH2:22]C(C)C(C)(O[SiH3])C(C)(C)C)=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)(C(C)(C)C)([CH3:3])[CH3:2].C(O)(=O)[C:40]([CH3:43])([CH3:42])[CH3:41]>C(OCC)(OCC)(OCC)C.CCOCC>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:33])/[CH:21]([CH2:22][CH2:17][CH2:9][O:8][Si:1]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:3])[CH3:2])[CH2:10][C:11]([O:12][CH2:13][CH3:14])=[O:38])=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)([C:20]([CH3:21])([CH3:33])[CH3:19])([CH3:3])[CH3:2]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(O)C(C)=CCC(C)C(C)(O[SiH3])C(C)(C)C)C(=O)OC2
Reactant: CC(C)(C)C(=O)O
Agent: CCOC(C)(OCC)OCC
Solvent: CCOCC
Product: CCOC(=O)CC(CCCO[Si](C)(C)C(C)(C)C)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 2 h
Yield: 276.5 %

Procedure:
7-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-tert-butyldimethyl-silyloxy-6-hydroxy-5-methylhept-4-ene (4.74 g) was dissolved in triethyl orthoacetate (76 ml) and pivalic acid (171mg) was added. The solution was placed in an oil bath preheated to 130° C., and stirred for 21/2 hrs. ter cooling, the reaction was diluted with ether, washed with 1N NaHSO4 (3X), saturated sodium bicarbonate, brine, and dried. The solvent was evaporated and the resulting oil chromatographed on silica gel (20% ethyl acetate in hexanes) to give ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-(3-tert-butyldimethylsilyloxypropyl)-4-methylhex-4-enoate (2.94 g), a compound of Formula 802.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[N:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[F:27])[N:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2cn(C)c3cccc(F)c23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)O)cc2Cl)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In THF (19 ml) was dissolved ethyl (5-chloro-2-fluoro-4-((4-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (762 mg, 1.87 mmol). To the resulting solution was added 0.25N NaOH (11.2 ml, 2.81 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1N HCl (3.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (5-chloro-2-fluoro-4-((4-fluoro-1-methyl-3-indolylcarbonyl)amino)phenyl)acetic acid (698 mg, 99%) as a purple solid.
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>O1CCCC1.O>[NH2:2][CH2:1][C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2
Reactant: N#CC12CCN(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCC12CCN(CC1)CC2
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
4- Cyanoquinuclidine (0.31 g, 0.0028 moles) was reduced with lithium aluminium hydride (0.45 g, 0.012 moles) in tetrahydrofuran (20 ml) at ambient temperature for 18 hours. Diethyl ether (20 mls) was added followed by water (1.8 ml) and 10%w/v aqueous sodium hydroxide (0.68 ml) and the mixture stirred for 30 minutes. The mixture was then filtered and the filtrate concentrated in vacuo to give the title compound 0.3 g (94%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:55]=[CH:54][C:53](Br)=[CH:52][C:29]=1[C:30]([NH:32][C:33]1[CH:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.O>[CH2:20]([O:27][C:28]1[CH:55]=[CH:54][C:53]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[CH:52][C:29]=1[C:30]([NH:32][C:33]1[CH:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: C1CSCCN1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCSCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Thiomorpholine (0.14 mL), cesium carbonate (0.58 g), tris(dibenzylideneacetone)dipalladium(0) (8.2 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (21 mg), and palladium(II) acetate (4.0 mg) were added to a toluene (5.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.50 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then thiomorpholine (0.045 mL), cesium carbonate (0.15 g), tris(dibenzylideneacetone)dipalladium(0) (8.2 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (21 mg), and palladium(II) acetate (4.0 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.36 g of tert-butyl 2-(2-(benzyloxy)-5-(thiomorpholin-4-yl)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C=C(CNC(C)=O)C(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
A solution of 0.42 g (1.57 mmol) of the amine obtained in Step C in 5 ml of anhydrous pyridine is cooled to 0° C.; 0.18 ml (1.97 mmol) of acetic anhydride is then added to the medium. After 30 minutes of stirring under argon, the medium is diluted with dichloromethane and then adjusted to an acid pH with 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained, after evaporation of the solvent in vacuo, is purified on a silica column (eluant:AcOEt/PE:70/30) to yield the title amide in the form of a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[CH:13]=[N:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1

Procedure:
The title compound was synthesized according to the method described for Example A1 except reacting oxindole (67 mg, 0.216 mmol) with 1H-indazole-6-carbaldehyde (73 mg, 0.238 mmol) to obtain 32 mg, 51%. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.89 (s, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11N3O+H]+ 262.10.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:51])(O)[CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:37][CH:36]=1.[S:52]1C=CC=C1CC(O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([CH3:51])([SH:52])[CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:37][CH:36]=1
Reactant: CC(O)(CCN1CCCCC1)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: CC(S)(CCN1CCCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl azodicarboxylate (80 mL, 0.40 mmol) was added to an efficiently stirred solution of triphenylphosphine (105 mg, 0.40 mmol) in 1 mL of THF at 0° C. The mixture was stirred at 0° C. for 30 min during which time a white precipitate formed. A mixture of compound 54 (0.20 mmol, 59 mg) and 28.2 μL (0.4 mmol) of thiolacetic acid in 0.5 mL of THF was added dropwise, and the mixture was stirred at 0° C. for 1 h and then at 25° C. for 2 h. The solution was concentrated. Ether (5 mL) was added, and the ether solution was acidified with 10% HCl. The water layer was extracted with ether and neutralized with saturated NaHCO3. The resulting solution was extracted with CH2Cl2, and the organic layer was washed with brine, dried, and concentrated to give 50 mg of the crude product. To the solution of the crude thioester (crude, 50 mg, 0.15 mmol) in 5 mL of THF was added portionwise LiAlH4(18 mg, 0.45 mmol). The mixture was stirred at room temperature for 2 h then a saturated solution of Rochelle salt (1.8 mL) was added followed by extraction with EtOAc. The organic phase was washed with brine, dried, and concentrated. Flash chromatography of the residue afforded the title compound (17 mg, 26% overall for the two steps): [α]D +40.0 ((c 1.40, CHCl3);1H NMR (CDCl3) d 0.92-1.08 (m, 1H), 1.10-1.30 (m, 2H), 1.32-1.64 (m, 2H), 1.64-1.90 (m, 4H), 1.93-2.18 (m, 2H), 2.22-2.50 (m, 5H), 2.95 (d, 1H, J=10.8 Hz), 3.06 (d, 1H, J=10.5 Hz), 7.05-7.15 (m, 2H), 7.20-7.32 (m, 2H); 13C NMR (CDCl3) 24.8, 30.7, 31.4, 35.1, 41.0, 46.7, 48.3, 56.4, 61.7, 128.9, 129.2, 132.1, 143.6; MS m/z 44 (26), 250 (100), 282 (M+, 2); Anal. (C15H22ClNS) Calcd: C 63.47, H 7.81, N 4.93; Found: C 63.85, H 7.89, N 4.76.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:26])[CH:14]=[C:15]([C:22](OC)=[O:23])[NH:16]2.C(N(CC)CC)C.Cl>O.C(OCC)(=O)C.CO>[ClH:10].[Cl:10][C:11]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:26])[CH:14]=[C:15]([C:22](=[O:23])[NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[NH:16]2
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-aminoethyl)morpholine (10 ml) was added methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1 g) followed by triethylamine (1 ml) and the solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (5×50 ml), the combined organic layers were washed with water (2×50 ml), brine (2×50 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure to yield a crude product (0.4 g). The aqueous layer yielded a further 0.9 g of crude product after standing overnight. The combined crude product was treated with methanol (5 ml) and hydrogen chloride in ethyl acetate (5 ml of 5M), to give a white crystalline product which was recrystallised from ethanol-water to yield 5,7-dichloro-2-[2-(4-morpholinyl)ethyl]carbamoyl-4-oxo-1,4-dihydroquinoline hydrochloride (0.63 g), m.p.>280° C. δ (360 MHz, D2O) 3.48 (6H, CH2N and morpholinyl-3,5-H), 3.86 (2H, t, CONHCH2), 4.00 (4H, bs, morpholinyl-2.6-H), 6.63 (1H, s, 3-H), 7.33 (1H, d, 6-H) and 7.54 (1H, d, 8-H), (Found: C, 46.36: H, 4.57: N, 10.12; Cl, 24.80%. C16H17Cl2N3O3.HCl.H2O requires C, 46.23; H, 4.61, N, 10.11; Cl, 25.59%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add 6-bromohexanoic acid (4.1 g, 21.1 mmol) into 100 mL absolute methanol solution and then slowly drop 30 mL thionyl chloride into the solution with an ice bath. Stir the solution at room temperature overnight, concentrate the solution and add chloroform to dissolve. After suction filtration, take and concentrate the filtrate to get the product methyl 6-bromohexanoate (4.4 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]#[N:10])[S:5][CH:6]=1.[K].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[NH2:30][C:31]1[C:36]2[CH:37]=[C:38](Br)[S:39][C:35]=2[C:34]([C:41]([NH2:43])=[O:42])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[NH2:30][C:31]1[C:36]2[CH:37]=[C:38]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][C:9]#[N:10])[S:5][CH:6]=3)[S:39][C:35]=2[C:34]([C:41]([NH2:43])=[O:42])=[CH:33][N:32]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: N#CC=Cc1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#CC=Cc1cc(-c2cc3c(N)ncc(C(N)=O)c3s2)cs1
Temperature: 100 °C

Procedure:
A mixture of 3-(4-bromo-thiophen-2-yl)-acrylonitrile 76 (0.33 g, 1.55 mmol), potassium acatete (0.47 g, 4.74 mmol), bis(pinacolato)diboron (0.84 g, 3.3 mmol), Pd(PPh3)4 (0.12 g, 0.1 mmol), and DMF (11 mL) was heated at 100° C. under nitrogen for 1 h. 4-Amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 (0.28 g, 1.0 mmol), 2 M aqueous Na2CO3 solution (3.6 mL), and Pd(PPh3)4 (0.12 g, 0.1 mmol) were added. The reaction mixture was then heated at 100° C. under nitrogen until completion of the reaction (approx. 1 h), cooled to room temperature and concentrated in vacuo to approx. half volume. The mixture was diluted with water (20 mL) and the precipitate of 77 that formed was collected by filtration, washed with MeOH, and dried. 4-amino-2-[5-(cyanovinyl)-thiophen-3-yl]-thieno[3,2-c]pyridine-7-carboxylic acid amide 77 was then dissolved in pyridine (5 mL) and EtOH (1 mL). To the resulting solution was added NaBH4 (0.16 g, 4.1 mmol). The solution was then heated at 100° C. until completion of the reaction (approx. 2 h) and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: 80% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2). The major fractions were combined and concentrated to give 78 (0.12 g) as a pale-yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (s, 1H), 7.90 (br.s, 1H), 7.86 (s, 1H), 7.65 (d, J=1.4 Hz, 1H), 7.31 (s, 1H), 7.26 (br s, 1H), 7.12 (s, 2H), 3.17 (t, 2H), 2.92 (t, 2H). MS (EI) m/z (M+H+) 329 and (M+Na+) 351.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1cnc(C(F)(F)F)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 5-(azidomethyl)-2-(trifluoromethyl)pyrimidine (Description 120; 660 mg, 3.26 mmol) in anhydrous THF (10 ml) was added triphenylphosphine (1.71 g, 6.52 mmol) and water (0.059 ml, 3.26 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was evaporated and the residue purified by column chromatography on silica elution with 5% MeOH in DCM+0.5% NH4OH to give the title compound (320 mg, 55%) as a pale yellow solid.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH2:23][CH:22](Br)[CH:21]([Br:25])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2-].[Na+].C(O[Na])(C)(C)C>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:23][CH:22]=[C:21]([Br:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:8])[CH3:2]
Reactant: CC(C)(C)[Si](OC1=CC(Br)C(Br)C1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC=C(Br)C1
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
To a solution mixture of 4.5 g of 3,4-dibromocyclopenten-1-yl (t-butyldiphenylsilyl) ether and 50 ml of tetrahydrofuran were added at room temperature 910 mg of sodium amide and 3.25 g of t-butoxysodium, and the resulting mixture was stirred for 3.5 hours. The reaction liquid obtained was after-treated and purified in the same manner as in (1) of the intermediate preparation example 1 to obtain 2.53 g of (RS)-3-bromo-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 68%