Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+]>C1COCC1>[CH3:10][S:11]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 29 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirred solution of 4-piperidone hydrate hydrochloride (40.00 g, 0.260 mol) and THF (320 ml) was added CH3SO2Cl (31.0 ml, 0.402 mol) and 15% aq. NaOH (156 ml) such that the temperature of the reaction mixture was maintained at 26-32° C. After this addition, the reaction mixture was stirred at RT for 2 hours and transferred to a separatory funnel. The organic layer was collected and the aqueous layer was extracted with THF (2×250 ml). The combined organic layers were dried over Na2SO4. After filtration, the concentrated residue was washed with hexane to give the product (46.0 g, 100%). 1H NMR (CDCl3) δ 3.59 (t, J=6.00 Hz, 4H), 2.89 (s, 15 3H), 2.59 (t, J=5.6 Hz, 4H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]#[N:26])=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1.C([BH3-])#N.[Na+]>O.C(O)C.C(O)(=O)C>[Br:34][C:30]1[CH:29]=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([NH:14][CH2:3][CH2:4][CH2:5][N:6]4[CH2:10][CH2:9][CH2:8][CH2:7]4)[CH:16]=3)[N:21]=[CH:20][C:19]=2[C:25]#[N:26])[CH:33]=[CH:32][CH:31]=1
Reactant: COC(CCN1CCCC1)OC
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2ccc(NCCCN3CCCC3)cc2c1Nc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Dissolved 0.64 g (3.69 mmol) 3-(pyrrolidin-1-yl)propionaldehyde dimethyl acetal in 10 ml water and acidified to pH 1 with concentrated HCl. Heated to 40° C. for 90 minutes, removed heat and neutralized with sodium bicarbonate. Dissolved 500 mg (1.47 mmol) 6-amino-4-(3-bromo-phenylamino)-quinoline-3-carbonitrile in 100 ml ethanol and added acetic acid until pH was 3 to 4. Added the deprotected aldehyde to the amine solution and stirred at 25° C. for 0.5 hour. Gradually added 94 mg (1.47 mmol) sodium cyanoborohydride and stirred overnight. Stripped solvent, partitioned between chloroform and water. Washed organic layer with brine and dried with sodium sulfate. Stripped solvent and filtered through a pad of silica gel, first with 10% methanol/chloroform, then 20% methanol/chloroform/1% ammonium hydroxide. Stripped solvent and dried in vacuo, giving 143 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=450, 452.1.
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl>C1COCC1>[CH:1]1([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(OC2CCCCCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(OC2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Dissolve 4-cycloheptyloxy-benzonitrile (2 g, 9.29 mmol) in anhydrous THF (20 mL) and cool to 0° C. Add borane dimethylsulfide complex (2.8 mL, 27.9 mmol, 10-12 M solution), stir at 0° C. for 0.5 h and then heat at reflux for 1 h. Cool the mixture to 0° C., add methanol (5 mL) and stir for 15 min. Add 2M aqueous HCl (15 mL) and stir for 30 min at room temperature. Concentrate the mixture in vacuo and purify the residue by chromatography on silica gel (45 g RediSep column) eluting with a gradient of dichloromethane in chloroform/methanol/concentrated ammonium hydroxide (80:18:2) over 30 min (80 ml/min) to provide the title compound as a colorless oil (1.87 g, 97%). MS (APCI) m/z: 220 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[Cl-].[NH4+].Cl.C([N:16]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O.C(OCC)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:16])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
5-Bromonicotinic acid (5.05 g), ammonium chloride (2.10 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (7.30 g), 1-hydroxy-1H-benzotriazole monohydrate (3.90 g) and triethylamine (5.5 ml) were suspended in DMF (40 ml) and the mixture was stirred at room temperature for 16 hrs. Ethyl acetate and water were added to the reaction mixture and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was concentrated by drying and recrystallized from ethyl acetate to give the title compound (2.33 g) as colorless needle crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2[S:13][C:14]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])[CH:6]=[CH:5][N:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH:8]=2)=[O:10])[S:13][C:14]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(Cn2ccnc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
Compound 107 (150 mg, 0.387 mmol) was dissolved in DMF (2 ml), and imidazole (129 mg, 1.89 mmol) was added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 108 (120 mg, 74%).
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]([O:14][CH:15]([O:22][CH2:23][CH3:24])[CH2:16][C:17](OCC)=[O:18])[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:22][CH2:23][CH3:24])[CH2:16][CH2:17][OH:18])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CCO)OCC
Temperature: 10 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
In the following, tetrahydrofuran (THF) to be used was dehydrated on molecular sieves of 4 angstrom overnight. Inside of a 5 L four-neck flask was substituted with nitrogen gas and 2.2 kg of THF was placed therein, followed by cooling to 10° C. or lower. Then, 50 g of lithium aluminum hydride was placed therein and 250 g of ethyl 3,3-diethoxypropionate was added dropwise so that inner temperature did not exceed 10° C. After completion of the dropwise addition, temperature was elevated to 20° C. and reaction was carried out for 1 hour. After the reaction, 420 g of distilled water was added and the whole was stirred for 2 hours, then filtration was performed through No. 2 filtration paper, and subsequently a cake was washed with 1.1 kg of THF. The filtrate was concentrated at 40° C. to obtain 213 g of crude 3,3-diethoxy-1-propanol (hereinafter 33DEP).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23](C=O)=[CH:24][C:19]3=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:50])C=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([OH:50])=[CH:24][C:19]3=[C:18]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:17]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C=O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 46.6 %

Procedure:
To a solution of the compound of step 2 (0.395 g, 0.71 mmol) in 7.1 ml of DCM was added 77% 3-chloro-perbenzoic acid (0.239 g, 1.06 mmol) in small portions and the solution was stirred at room temperature for 2.75 h. Then DCM (15 ml) and a saturated solution of sodium hydrogencarbonate (15 ml) were added and the aqueous phase was separated and extracted with DCM (15 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The obtained oil was dissolved in 14 ml of MOH and stirred in the presence of potassium carbonate (0.147 g, 1.06 mmol) at room temperature for 15 min. Then water was added (15 ml) and the mixture was acidified to pH 5 by dropwise addition of a 1 M aqueous solution of potassium hydrogensulfate. The solution was then extracted twice with 15 ml each of EA and the combined organic phases were washed with brine (15 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (DCM/EA, 80:20, then 60:40, then 40:60) to give 0.180 g of the title compound as a yellow solid melting at 165° C.
Reaction SMILES: [OH-].[Na+].C1COCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])=[CH2:30])=[CH:25][C:24]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([NH:40][CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[O:39])=[N:36][CH:37]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])=[CH2:30])=[CH:25][C:24]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:39])=[N:36][CH:37]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: C=C(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)c1ccc(CNc2ccc(-c3ccc(F)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous NaOH solution (0.32 mL, 0.97 mmol) was added to a THF (1.0 mL) and MeOH (1.5 mL) solution of ethyl 3-(5-(2-(((4′-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(prop-1-en-2-yl)phenyl)picolinamido)propanoate (87 mg, 0.16 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was acidified with 1N aqueous HCl and extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][N:17]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COc1ccc(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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(Cl)nc2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A flask was charged with 4-methoxyphenylboronic acid (1.0 g, 6.8 mmol), 5-bromo-2-chloropyridine (1.0 g, 5.2 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), potassium carbonate (1.08 g, 7.8 mmol), 1,4-dioxane (40 mL) and water (4 mL). The mixture was stirred at 100° C. under Argon for 20 h, and evaporated to afford a crude product. The crude product was purified by chromatography on silica gel (petroleum ether:ethyl acetate=40:1) to give the title compound (1.0 g, 88% yield) as white solids. MS: m/z 220.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCCN2)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)c(F)c2)cc1

Procedure:
The title compound, white solid, m.p. 127° C. and MS: m/e=338.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[N+:22]([O-])=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:8]=1[NH2:22])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)CNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.2 %

Procedure:
To a tetrahydrofuran solution (5 mL) of 2-(4-neopentylamino-3-nitrophenyl)benzoxazole (see Working Example 81-1) (242 mg, 0.744 mmol) was added 10% palladium-carbon (40 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 15 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (196 mg, 89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: ClCc1ccnc(-c2ccccc2)c1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (612 mg) and 4-chloromethyl-2-phenylpyridine (204 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: CN(CCO)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (1.10 g) in chloroform (10 mL) was stirred in an ice bath, during which N-methylethanolamine (5 mL) was slowly added dropwise thereto. The mixture was returned to room temperature and stirred for about 2.5 hours. The reaction solution was quenched with concentrated hydrochloric acid with stirring again in an ice bath. The mixed solution was poured into 6 M hydrochloric acid (10 mL) as such, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide as a colorless oil (1.339 g, quant.).
Reaction SMILES: [C:1]1(=[O:12])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13]C1CC(C(C)C)CCC1=O>>[Br:13][CH:2]1[CH2:3][CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[C:1]1=[O:12]
Reactant: O=C1CCCCC12CCCCC2
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: O=C1C(Br)CCCC12CCCCC2

Procedure:
The bromination of spiro[5.5]undecan-1-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:35]/[P:44](=[O:51])([O:45][CH2:46][CH3:47])[O:48][CH2:49][CH3:50])=[CH:24][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cn1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1)OCC
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a mixture of 3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.28 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-{3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridin-3-yl)methoxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.38 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[C:3]1=[O:19].[N+:21]([O-])([OH:23])=[O:22].N>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=2)[C:3]1=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)cc2)C1=O
Agent: N
Agent: O=S(=O)(O)O
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c([N+](=O)[O-])c2)C1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3.8 g of 5,5-dimethyl-3-{4-[(trifluoro-methyl)thio]phenyl}imidazolidine-2,4-dione obtained in stage a) below in 7 mL of concentrated sulphuric acid is added dropwise at −5° C. a mixture of nitric acid (0.75 mL) in 3 mL of concentrated sulphuric acid. After stirring for 4 hours at 0° C. (ice bath) the mixture is poured onto 150 g of ice and the pH is raised to 10 by addition of concentrated aqueous ammonia. The aqueous phase is then extracted with twice 150 mL of ethyl acetate and the combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 1.8 g of 5,5-dimethyl-3-{3-nitro-4-[(trifluoromethyl)thio]phenyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH:15]=[CH:14][C@@H:13]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:12][C@@H:10]1[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([CH2:16][OH:17])[O:12][C@@H:10]1[CH3:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)C=C[C@H]1NC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1O[C@H](CO)CC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 19 h
Yield: 79.7 %

Procedure:
The compound (960 mg, 2.68 mmol) obtained in Step 5 above was dissolved in ethyl acetate (5 ml) and ethanol (5 ml), platinum (IV) oxide (18 mg, 0.08 mmol) was added and the resulting mixture was stirred for 19 hours under hydrogen atmosphere. The catalyst was removed by filtration through celite, then the solvent in the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1→2:3 (v/v)] to give 524 mg (79%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: O=[N+]([O-])c1cc(Cl)ccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc([N+](=O)[O-])c3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 4-chloro-2-nitropyridine (2.53 g, 16 mmol, 2 eq.) in 50 ml of DMF was added cesium carbonate (7.8 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=19:1 to 4:1) to give desired product as light yellow oil. MS (ESI) m/z=743 [2M−H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=O)=[O:4]>P(Cl)(Cl)(Cl)=O>[F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][C:7]1[N:15]2[C:11]([S:12][CH:13]=[CH:14]2)=[CH:10][N:9]=1)=[O:4]
Reactant: O=C(CNC(=O)C(F)(F)F)NCc1nccs1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NCc1ncc2sccn12)C(F)(F)F
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 60.7 %

Procedure:
To 1.98 g of the above-obtained 2-[(N-trifluoroacetylglycyl)amino]methylthiazole was added 20 ml of phosphorus oxychloride, and the mixture was heated and stirred at 100° C. for 4.5 hours. The reaction solution was cooled to room temperature, and concentrated to dryness under reduced pressure. The residue was dissolved in 30 ml of methylene chloride. To this solution was added 50 ml of water with ice- cooling. The pH of the mixture was adjusted to 8 by adding potassium carbonate little by little with ice-cooling, and the mixture was stirred for one hour. The crystals precipitated were collected by filtration, washed with cold water and a small amount of cold methylene chloride, and dried under reduced pressure to give 1.12 g (yield 60%) of 5-(trifluoro- acetylamino)methylimidazo[5,1-b]thiazole as light yellow crystals.