Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[S:34])N)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.S>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:32]([C:29]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:16]([CH3:17])[CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:31]=2[CH:30]=1)=[S:34]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NCc1cccc(F)c1
Agent: S
Solvent: CCO
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=S)NCc3cccc(F)c3)cc21
Temperature: 20 °C
Reaction time: 20 h

Procedure:
3-Fluorobenzylamine (2.3 cc) is added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.70 g) in absolute ethanol (50 cc). The mixture is saturated with hydrogen sulphide and brought to 110° C. for 20 hours. After cooling to 20° C., the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is purified by chromatography on a column (height: 22 cm; diameter: 4.2 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with pure ethyl acetate (400 cc) and then with a 90:10 (by volume) mixture (400 cc) of ethyl acetate and methanol and collecting 80-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-(3-fluorobenzyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.3 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: O/[N:2]=[CH:3]\[C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:3]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc2cc(/C=N\O)oc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2cc(C#N)oc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
E/Z-Methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate (438 mg, 2.0 mmol) is suspended in CH2Cl2 (8 ml) in a dry flask under nitrogen. Pyridine (0.65 ml, 8.0 mmol) is added via syringe, and the mixture is cooled to 0° C. Trifluoroacetic anhydride (0.56 ml, 4.0 mmol) is added drop-wise, and the reaction is stirred overnight, allowing the ice bath to expire. The reaction is carefully quenched with saturated NaHCO3 (10 ml). The layers are separated and the organic layer is dried (K2CO3), filtered, and concentrated to a pink solid. The crude material is chromatographed over 25 g slurry-packed silica gel, eluting with 25% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 315 mg (78%) of methyl 2-cyano-1-benzofuran-6-carboxylate as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[CH2:9]([N:16]1[C:20]([NH2:21])=[CH:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]=[C:43]=[O:44]>C(Cl)Cl>[CH2:9]([N:16]1[C:20]([NH:21][C:4](=[O:5])[C:3]([NH:2][C:43]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[O:44])([CH3:8])[CH3:7])=[CH:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(-c2ccccc2)nn1Cc1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Reactant: CC(C)(N)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)Nc1ccccc1Cl)C(=O)Nc1cc(-c2ccccc2)nn1Cc1ccccc1
Reaction time: 2 h

Procedure:
2-Amino-2-methyl-propionyl chloride hydrochloride (150 mg, 1.2 mmol) and 2-benzyl-5-phenyl-2H-pyrazol-3-ylamine (200 mg, 0.8 mmol) were stirred in DCM (5 mL) containing triethyl amine (100 μL, 0.8 mmol). After two hours, 2-chlorophenyl isocyanate (220 mg, 0.9 mmol) and triethyl amine (100 μL, 0.8 mmol) were added. Purification by silica gel chromatography gave the title compound. 1H NMR (400 MHz, DMSO-D6) δ 1.44 (s, 6H) 5.23 (s, 2H) 6.54 (s, 1H) 6.92 (s, 1H) 7.17 (s, 4H) 7.24 (s, 3H) 7.36 (s, 3H) 7.55 (s, 1H) 7.74 (s, 2H) 8.04 (s, 1H) 8.15 (s, 1H) 9.81 (s, 1H). m/z 488.0 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[CH2:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>[OH-].[Na+].O1CCOCC1>[CH2:14]([S:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in 1N aqueous sodium hydroxide (10 ml)-dioxane (3 ml), and dioxane (7 ml) solution of benzylsulfonylchloride (1.91 g, 10 mmole) was added dropwise to the solution while cooling with ice and stirring while keeping pH value thereof to between 10 and 11 using 1N aqueous sodium hydroxide. After completion of the addition, the mixture was further stirred for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 1.5 with 1N aqueous hydrochloric acid while cooling with ice and stirring to precipitate N-benzylsulfonyl-L-alanyl-L-proline in a crystalline form[yield: 1.78 g, 52.3%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[N+:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:12])=[O:13])[CH:15]=1)([O-:4])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cc1cccc2c1c([N+](=O)[O-])cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To acetic anhydride (5 mL) at 0° C. was added 90% nitric acid (0.183 mL, 3.90 mmol) and the resulting mixture was aged for 10 min, then added dropwise to a solution of tert-butyl [1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step B (1.00 g, 2.69 mmol) in acetic anhydride (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 6 h, then aged at −20° C. for 16 h, then quenched with H2O and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=361 (M-C4H7).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:46]2[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=2)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 83.2 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (500 mg, 0.9 mmol), 4-methylsulfonyl phenylboronic acid (540 mg, 2.7 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 40% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (405 mg, 83%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O5S2 [M+H]+ 541.64, observed 541.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:17][C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C=O
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1C

Procedure:
Using General Procedure B: Reaction of 3-methyl-2-aminomethylpyridine and 3-methyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave bis-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. 1H NMR (CDCl3) δ 2.33 s, 6H), 4.06 (s, 4H), 7.08 (dd, 2H, J=9, 6 Hz), 7.42 (dd, 2H, J=9, 3 Hz), 8.41 (d, 2H, J=3 Hz).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[O:19][CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)[Cl:22].N>C(OCC)(=O)C>[ClH:22].[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[O:19][CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Reactant: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1NC(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A mixture of N-benzoyl 2-methoxy-4-nitroaniline (2.63 g, 9.66 mmol) and tin (II) chloride (10.9 g, 48.3 .mmol) were heated in ethyl acetate (200 ml) at reflux for 4 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature and concentrated aqueous ammonia (20 ml) was added. The reaction was filtered, the solid material was washed with ethyl acetate (3×30 ml) and then the combined organic layers were evaporated in vacuo. The orange solid was dissolved in ethyl acetate (45 ml) and a 1.0 N solution of hydrogen chloride in diethyl ether (25 ml) was added, causing precipitation of a white solid. Recrystallisation of this solid from methanol/ethyl acetate, yielded N-benzoyl 2-methoxy-4-aminoaniline hydrochloride (1.06 g, 39% yield) as a white crystalline solid:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1ccc(-c2cc(-c3ccccc3)ncn2)cc1
Yield: 38 %

Procedure:
First, 5.02 g of 4,6-dichloropyrimidine, 8.29 g of phenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, there were further put 2.08 g of phenylboronic acid, 1.79 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile into the flask, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained solution of the extract was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent, so that a pyrimidine derivative Hdppm (yellow white powder, 38% in yield) was obtained. Note that for the irradiation with microwaves, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme (a-1) of Step 1 is shown below.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[N:21]([C:2]1[C:3](=[O:4])[NH:5][C:6]2[C:7]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N+:22]=[N-:23]
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=Nc1c(-c2ccccc2Cl)c2ccccc2[nH]c1=O

Procedure:
To a warm solution of 5.0 g. of 2-bromo-2'-(2-chlorobenzoyl)acetanilide in 100 ml. of methanol was added 1.8 g. of sodium azide. The solution was heated to reflux for 15 minutes. On addition of 0.77 ml. of a 35 percent solution of benzyltrimethylammonium hydroxide in methanol, and standing at room temperature overnight, 1.8 g. of pure (tlc) 3-azido-4-(2-chlorophenyl)carbostyril crystallized and was collected and washed with methanol. On recrystallization from dimethylformamide-methanol, pale yellow needles were obtained, having a melting point of 152°-155° dec.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH3:14])[N:10]=[C:9]1[NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][C:21]=3[C:8]1=[N:7]2.Cl.[CH3:24][N:25]([CH2:27][CH2:28]Cl)[CH3:26]>CS(C)=O>[CH3:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH3:14])[N:10]=[C:9]1[N:15]([CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])[C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][C:21]=3[C:8]1=[N:7]2
Reactant: CN(C)CCCl
Reactant: Cc1cc2nc3[nH]c4ccc(Br)cc4c3nc2cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2nc3c4cc(Br)ccc4n(CCN(C)C)c3nc2cc1C
Temperature: 35 °C
Reaction time: 4 h

Procedure:
To a suspension of 5.38 g sodium hydride (0.22 mole) in 600 ml dry dimethylsulphoxide maintained at 35° C. 32.6 g 2,3-dimethyl-9-bromo-6H-indolo(2,3-b)quinoxaline (0.10 mol) is added under nitrogen and with good stirring. 30 minutes after completed addition 15.9 g N,N-dimethylamino-2-chloroethane-HCl (0.11 mole) are added at 35° C. The mixture is stirred at 35° C. for four hours and then the solvent is distilled off in vacuum at room temperature. The residue is dissolved after soaking out with water in methylacetate and slowly cooled to -30° C. whereby the base crystallizes out. Yield 22 g, 55%, mp. 146°-147° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH:41]([C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:41][C:43]1[CH:57]=[CH:56][C:46]([O:47][C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=2)=[C:45]([CH3:58])[CH:44]=1
Reactant: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=Cc1ccc(Oc2ccc(C#N)cn2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Suspend (methoxymethyl)triphenylphosphonium chloride (1.14 g, 3.34 mmol) in THF (11 mL) under N2 and cool the mixture at 0° C., add slowly 0.5M KHMDS in toluene (6.7 mL, 3.34 mmol) and stir at 0° C. for 30 min. Cool the mixture at −78° C. and add a solution of aldehyde from step 1 above (663 mg, 2.78 mmol) in THF (2 mL). Warm the mixture slowly to room temperatures and stir for 1 h. Add water and extract the aqueous layer with Et2O. Dry the organic layer over MgSO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: gradient from EtOAc/hexane 10/90 to 20/80) to get the title compound (530 mg, 76%). Electrospray MS M+1 ion=267. 1H-NMR (CDCl3, 300 MHz, mixture of isomers): 8.47-8.45 (m, 2H), 7.92-7.86 (m, 2H), 7.50-7.45 (m, 1H), 7.15-6.93 (m, 5H), 6.14 (d, 1H, J=7.1 Hz), 5.79 (d, 1H, J=13.2 Hz), 5.20 (d, 1H, J=7.1 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17](O)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5 H); 3.43-3.28 (m, 4 H) and 2.00-1.81 (m, 4 H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([C:17]#[N:18])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:19])[CH:11]=[CH:10]3)=[N+:2]=[N-:3].S(=O)(=O)(O)[OH:22].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([C:17](=[O:22])[NH2:18])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:19])[CH:11]=[CH:10]3)=[N+:2]=[N-:3]
Reactant: N#Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: [N-]=[N+]=NCC1Cc2cc(C(N)=O)c3[nH]c(=O)ccc3c2O1
Yield: 6.4 %

Procedure:
2-Azidomethyl-5-cyano-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (3.4 g) was suspended in 95% ethanol (85 ml). Concentrated sulfuric acid (32 ml) was added to the mixture, and the mixture was refluxed for 5 hours while heating. 30% potassium carbonate was added to the reaction mixture to turn the pH of the mixture alkaline. Extraction was performed using a solvent mixture of chloroform-methanol (8:1), and the extract was dried. The solvent was distilled off, and the resultant residue was washed with chloroform to obtain 0.232 g of 2-azidomethyl-5-carbamoyl -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as a pale brown solid (6.4%, mp.: 220°-223° C. (dec.)). The chloroform used to wash the above-described residue was dried to solidity under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent=chloroform) to obtain 1.64 g of 2-azidomethyl-5-ethoxycarbonyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (41.1%). The purified product was recrystallized from acetone to obtain colorless needles (mp.: 173° C.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:22][S:23]([O:14][CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reaction time: 0.17 h

Procedure:
1-Boc-3-hydroxypiperidine (0.5 g, 2.49 mmol) was dissolved in tetrahydrofuran (5 ml), triethylamine (0.75 g, 7.46 mmol) was added and the mixture was cooled. Methanesulfonic acid chloride (0.23 ml, 3 mmol) was added, the mixture was stirred in an ice bath for 10 min, saturated sodium bicarbonate solution (10 ml) was then added, as well as ethyl acetate (10 ml). Phase separation, the aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. Yield: 0.54 g (77%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH2:46][C:47]1[S:51][C:50]([CH:52]=[O:53])=[N:49][CH:48]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:52]([C:50]2[S:51][C:47]([CH2:46][O:45][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)=[CH:48][N:49]=2)=[O:53])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (525 mg) in ethanol (3 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (259 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (28.3 mg) and triethylamine (57 μL), and the mixture was stirred with heating under reflux for 1.5 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (416 mg, yield 56%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).