Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27]#[N:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:32][OH:33]>C(N(CC)CC)C>[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27](=[N:32][OH:33])[NH2:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: NO
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Yield: 52.2 %

Procedure:
To a 30 ml methanol solution of 1.5 g of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile were added 1.1 ml of triethylamine and 540 mg of hydroxylamine hydrochloride, followed by heating under reflux for 27 hours. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 850 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]#N)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:27][CH3:28])(=[O:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C.C(#N)C>C(Cl)(Cl)Cl.[Ag]F>[C:20]1([C:18]2([C:17]([O:27][CH3:28])=[O:26])[CH2:15][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: C[Si](C)(C)CN(CC#N)Cc1ccccc1
Agent: F[Ag]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A suspension of 53.4 g (0.23 mol) of N-benzyl-N-(cyanomethyl)-N-[(trimethylsilyl)methyl]amine (J. Org. Chem., 50, 4006 (1985)), 41.2 g (0.25 mol) of methyl atropate, 32.2 g (0.25 mol) of silver fluoride and 1 l of acetonitrile was stirred overnight at room temperature in the dark. The mixture was diluted with chloroform and filtered through celite. Concentration of the filtrate gave an oil which was chromatographed on silica gel, eluting with an 80:20 chloroform:ethyl acetate mixture, to give 27.9 g of methyl 3-phenyl-1-(phenylmethyl)-3-pyrrolidinecarboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.COCCOC.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>[Cl:22][C:4]1[C:3](=[CH:2][C:28]2[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=2)[CH:12]=[C:11]2[C:6](=[CH:7][CH:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)[CH:5]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: O=Cc1ccc(B(O)O)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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C1C=c2cc(Cl)c(=Cc3ccc(C=O)cc3)cc2OC1C(F)(F)F
Temperature: 50 °C
Yield: 47.1 %

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (2.0 g, 5.0 mmol) and Pd(PPh3)4 (174 mg, 0.15 mmole) were mixed in DME (50 mL) and the mixture was heated at 50° C. for 10 min. The solution of 4-formylphenylboronic acid (1.12 g, 7.5 mmole) in EtOH/DME (1:1, 4 mL) was added to above mixture and followed by adding 2 M Na2CO3 (5 mL, 10 mmole). The mixture then was heated to 90° C. for overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford the crude product, which was purified by Biotage chromatography eluted with 5 to 10% EtOAc in hexane to give 1 g the desired product as a yellow solid (47%), which had suitable purity to use without fuirther purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous dichloromethane (100 ml). The resulting solution was then treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The mixture was stirred at room temperature. When LCMS showed completion of the reaction, the mixture was treated with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (1-3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2ccccc2F)(c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (3 drops) is added to a solution of 4,4-bis(2-fluorophenyl)cyclohexenone (4.3 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (5.8 cc) in dry dichloromethane (30 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after the temperature has been allowed to return to 25° C. N-Butoxymethyl-N-(trimethylsilylmethyl)benzylamine (2.5 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for 3 hours under reflux. The reaction mixture is treated with potassium carbonate (3 g) and stirred for 15 minutes. After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 4 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 20-cc fractions. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(2-fluorophenyl)perhydro-4-isoindolone (2.28 g). M.p. 138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[F:11].C([Mg]Br)(C)C.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[C:3]([F:11])[C:4]=1[O:9][CH3:10]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(Cl)ccc(Br)c1F
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (2.6 g, 10.86 mmol) in tetrahydrofuran (30 mL) cooled to −10° C. was added isopropylmagnesium bromide (4.49 mL, 13.03 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0° C. and stirred for 1 h. The reaction mixture was cooled to −10° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.215 mL, 10.86 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirring continued for 16 h. The reaction was quenched with 5% aqueous sodium hydroxide and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.15 g, 7.50 mmol, 69% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 7.13 (m, 1H), 3.96 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [I:1][CH:2]([OH:5])[C:3]#[CH:4].[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1.O>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH:2]([I:1])[C:3]#[CH:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(O)I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(I)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 500 mL 4-neck round bottom flask, equipped with a magnetic stirrer and an addition funnel, in an ice bath were placed iodopropargyl alcohol (10 g, 54.9 mmol) in THF (20 mL) and sodium hydroxide (3.4 g, 84.6 mmol) in water (20 mL) To the above cold mixture was added a solution of p-toluenesulfonyl chloride (10.4 g, 54.95 mmol) in THF (20 mL) from an addition funnel. The reaction mixture was stirred for 2 hrs. below 5° C. The reaction mixture was then poured into ice water and the precipitate was collected by suction-filtration and washed with water. After drying under vacuum, the precipitate afforded 17.2 g (yield: 93.4%) of iodopropargyl 4-methylbenzenesulfonate as an off-white solid, mp=75°-78° C. An NMR spectrum showed the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=O)[CH3:15].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:14]([C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH3:15]
Reactant: CCc1cnccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 15.6 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.41 g of 3-ethylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 2.5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 7 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.10 g of 2-(3-ethylpyridin-4-yl-)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 217).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[C:13]([N:34]4[CH2:35][CH2:36][C:31]([F:37])([F:30])[CH2:32][CH2:33]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: FC1(F)CCNCC1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C=C(N2CCC(F)(F)CC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.65 mmol), 4,4-difluoropiperidine hydrochloride (0.800 g, 5.1 mmol) and K2CO3 (0.73 g, 5.3 mmol) in toluene/DMF (2:1; 15 ml) according to method 8a described above.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O1CCOCC1>[O:1]([CH:8]([C:9]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccccc1)c1nnc(N)s1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A 1,000 milliliter, 3-neck flask equipped with a Claisen adaptor, paddle stirrer, thermometer, addition funnel and condenser, was charged with 100 grams (0.602 moles) of 2-phenoxypropanoic acid, (54.8 grams, 0.602 mole) of thiosemicarbazide and 300 ml. of dioxane. The slurry was heated to 85° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 was slowly added (for 70 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 105 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous residue to which 400 ml of water was added and the residue emulsified. A 50 percent solution of NaOH was added until the pH of the solution was 10, and a solid precipitate formed. The solid precipitate was filtered off, washed with water, air dried, then dried in a vacuum oven at 60° C. to a granular grey solid which was recrystallized from H2O/ethanol mixture, filtered and then dried in a vacuum oven at 60° C. to white needles of 5-(1-phenoxyethyl)-2-amino- 1,3,4-thiadiazole. (Melting point 157°-167° C.).
Reaction SMILES: [CH2:1]1[CH2:31][O:30][C:3]2([CH2:20][CH2:19][C:18]3[C@@:5]([OH:29])([CH2:6][CH2:7][C@@H:8]4[C:17]=3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:28])[CH2:4]2)[O:2]1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]1[CH2:31][O:30][C:3]2([CH2:20][CH2:19][C:18]3[C@@:5]([OH:29])([CH2:6][CH2:7][C@@H:8]4[C:17]=3[C@@H:16]([C:21]3[CH:26]=[CH:25][C:24]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)=[CH:23][CH:22]=3)[CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:28])[CH2:4]2)[O:2]1
Reactant: c1c[nH]cn1
Reactant: C[C@]12C[C@H](c3ccc(I)cc3)C3=C4CCC5(C[C@]4(O)CC[C@H]3[C@@H]1CCC2=O)OCCO5
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@]12C[C@H](c3ccc(-n4ccnc4)cc3)C3=C4CCC5(C[C@]4(O)CC[C@H]3[C@@H]1CCC2=O)OCCO5
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of compound 3 (9.7 g, 18 mmol), imidazole (1.4 g, 20 mmol), cuprous iodide (346 mg, 1.8 mmol), N, N-dimethyl glycine (374 mg, 3.6 mmol) and potassium carbonate (5 g, 36 mmol) in anhydrous DMSO (10 mL) was degassed three times applying vacuum and nitrogen and was immersed in to a preheated oil bath at 110° C. The reaction mixture was heated for 60 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and filtered through a Celite pad. The filtrate was transferred to a reparatory funnel and was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford the crude product, which on purification by chromatography on SiO2 column eluting with 30% acetone in dichloromethane gave 7.6 g (91%) of required product 4 as a pale yellow solid.
Reaction SMILES: [C:1]1([P:7]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:8]2[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=2[CH:10]=[N:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:33]1([P:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][NH:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[NH:11][CH2:10][C:9]2[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=2[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C(=NC1CCCCC1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(P(c2ccccc2)c2ccccc2CNC2CCCCC2NCc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of N1,N2-bis(2-(diphenylphosphino)benzylidene)cyclohexane-1,2-diamine (2.18 g, 2.83 mmol) (prepared according to the literature procedure: Laue, S.; Greiner, L.; Woltinger, J.; Liese, A. Adv. Synth. Catal. 2001, 343, 711) and sodium borohydride (NaBH4) (0.64 g, 17 mmol) in ethanol (30 ml) was refluxed with stirring for 6 hours. The resulting solution was cooled to room temperature and water (15 ml) was added to destroy excess NaBH4. The mixture was extracted with dichloromethane and the combined extracts were washed with saturated aqueous ammonium chloride solution [NH4Cl] and then water. The organic layer was dried over magnesium sulfate and then filtered through silica gel. The filtrate was then evaporated to dryness to obtain a yellow solid. Yield: 2.0 g (91%). 1H NMR (400 MHz, CD2Cl2): δ 7.58-6.80 (m, 20H, Ph-H), 3.86 (d, 4H, NCH2), 3.65 (br, 2H, NH), 2.21 (s, 24H, CH3), 1.80 (m, 8H, cyclohexane-H). 31P{1H} NMR (162 MHz, CD2Cl2): δ−13.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of postassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>C1COCC1.C(O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:2]=[C:3]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:5])[N:13]=2)[CH:16]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccccc1)c1cn2cc([N+](=O)[O-])ccc2n1
Temperature: 160 °C
Yield: 87.5 %

Procedure:
To a solution of 0.48 g of 3-bromo-1-phenylpropane-1,2-dione in a mixture of 3 mL of THF and 0.5 mL of ethanol is added 0.25 g of 2-amino-5-nitropyridine. The reaction mixture is heated for 15 minutes at 160° C. in a microwave machine. The solid formed is separated out, taken up in 3 mL of ethanol and refluxed for 6 hours. After evaporating off the solvent, the residue is taken up in ethyl acetate and diluted with sodium hydroxide solution. The organic phase is washed with water, dried and then evaporated to give 0.42 g of (6-nitroimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone in the form of a brown solid, which is used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[OH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)[O:12][CH2:11][C:10]1([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=1)[CH3:15]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCO)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
(3RS,4RS)-4-[4-(t-butyl dimethylsilyloxy)-1-butyl 3-(7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (680 mg, 1.28 mmol) was dissolved in tetrahydrofuran (10 ml), and cooled to 0° C. To this solution was added tetrabutylammonium fluoride (2.6 ml, 2.56 mmol), and the reaction mixture was stirred at room temperature for 6 hours The solvent was removed by evaporation under vacuum, and the residue was dissolved in ethyl acetate, which was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate in n-hexane to afford 487 mg of the title compound as a colorless oil. (yield: 92.4%)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/S(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].CCO>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:23][NH:22][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step.