Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
To a solution of 2,6-dichloro-5-fluoro-nicotinic acid (1.11 g, 5.29 mmol) in 20 mL of THF at 0° C., was added BH3.THF (1M, 8 mL, 8 mmol) and the mixture was stirred at room temperature for 5 h. K2CO3 (4 g) was added and the mixture was stirred for 2 h, filtered and concentrated. The residue was purified by flash chromatography (eluent: 10 to 50% ethyl acetate+0.1% triethylamine in hexane) to afford 55a as a white solid (0.57 g, 55% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].C1([C:14]([PH3+])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=CC=CC=2)C=CC=CC=1.C1(C([N:37]2[CH:41]=[C:40]([C:42]3[C:43]4[CH:50]=[CH:49][N:48]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:44]=4[N:45]=[CH:46][N:47]=3)[CH:39]=[N:38]2)CC=O)CCCC1>C1COCC1>[CH:26]1([CH:21]([N:37]2[CH:41]=[C:40]([C:42]3[C:43]4[CH:50]=[CH:49][N:48]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:44]=4[N:45]=[CH:46][N:47]=3)[CH:39]=[N:38]2)[CH2:14][CH:15]=[CH2:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in THF (0.207 mL) in THF (2.0 mL) at 0° C. was added triphenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture was warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the addition of saturated ammonium chloride solution and the product was then extracted with ether. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) afforded the product (40 mg, 44%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[CH:9]=[C:10]([C:14](=O)[CH3:15])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1)[CH3:15]
Reactant: CC(=O)c1cccc(F)c1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=NCCCCl)c1cccc(F)c1
Reaction time: 8 h

Procedure:
In step 8-1, 3-chloropropan-1-amine hydrochloride (4.1 g, 32 mmol) was added to a suspension of 1-(3-fluorophenyl)ethanone (4.4 g, 32 mmol) and sodium carbonate (3.7 g, 35 mmol) in water (15 mL). The reaction mixture was stirred overnight and the resulting solution was then extracted with ethyl acetate (3×150 mL). The organic layer was dried with sodium sulfate, and the ethyl acetate removed to yield 3-chloro-N-(1-(3-fluorophenyl)ethylidene)propan-1-amine (8-1) as a light yellow oil. m/z=214.0 [M+1].
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH3:25][N:26]([CH3:28])[NH2:27].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][N:26]([CH3:28])[NH:27][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C:4]2[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:6][O:7][C:3]=2[CH2:2][OH:1])=[N:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added N,N-dimethylhydrazine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (49 mg, 62%) as a white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: CN(C)C=O.Cl.[CH3:7][C:8]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:9]=1[NH2:10].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:7][C:8]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][C:9]=1[NH:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5 mL of N,N-dimethylformamide containing 0.50 g of 2-methyl-5-phenoxyaniline hydrochloride, 0.91 mL of triethylamine and 0.27 mL of benzoyl chloride were added sequentially while ice-cooled sequentially and stirred at room temperature for 3 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.42 g of N-(2-methyl-5-phenoxyphenyl)benzamide as white solid.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[CH2:17](I)[CH3:18]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]1=2)[CH3:18]
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (60% dispersion in oil; 400 mg) and was then stirred with ethyl iodide (10% v/v solution in DMF; 4 ml) to give the title compound (758 mg), m.p. 203°-204.5°.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C1(C)C=CC=CC=1.O.CCOC(C)=O.O.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>[Br:8][C:9]1[N:10]=[CH:11][C:12]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:14]=1
Reactant: Brc1ncccn1
Reactant: OB(O)c1ccc(Br)nc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(-c2ncccn2)cn1
Temperature: 25 °C

Procedure:
A mixture of 2-bromopyrimidine (0.43 g, 2.70 mmol), 2-bromopyridine-5-boronic acid (0.55 g, 2.72 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.259 mmol), cesium carbonate (1.15 g, 3.03 mmol) was stirred in MeOH/toluene/water (15 ml, 1/1/1) at reflux temperature overnight. The reaction was cooled to room temperature and diluted with EtOAc (200 ml) and water (50 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding a residue which was purified on silica gel eluting with 25% v/v EtOAc/hexanes yielding product 76 as white solid. (0.55 g, 85%) ESMS (MH, 236).
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:25]3[N:26]=[CH:27][C:28]([C:29]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)=[O:30])=[C:24]3[N:23]=[CH:22][CH:21]=2)[CH:15]=1)S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH2:1]([NH:3][C:14]1[CH:15]=[C:16]([C:20]2[N:25]3[N:26]=[CH:27][C:28]([C:29]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)=[O:30])=[C:24]3[N:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCN(c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1)S(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCNc1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1
Temperature: 25 °C

Procedure:
A 10.7 g portion of N-ethyl-N-[3-[3-(2-furanylcarbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]-4-methylbenzenesulfonamide was added to a mixture of 90 ml of water and 210 ml of concentrated sulfuric acid. This mixture was heated to 140°-145° C., allowed to cool slowly to room temperature, then cooled to -10° C., poured onto ice, made basic with 550 ml of concentrated ammonium hydroxide and cooled to 0° C. This mixture was extracted with dichloromethane. The extract was passed through hydrous magnesium silicate and washed with 200 ml of dichloromethane. The dichloromethane filtrate and wash was combined with 300 ml of hexane, concentrated to 300 ml, diluted to 800 ml with hexane, treated with charcoal, clarified and cooled to -10° C. This material was filtered, the filtrate concentrated to turbidity and cooled at -10° C. The precipitate was collected, washed with hexane and dried at 60° C. in vacuo, giving 2.3 g of the desired product, mp 142°-143° C.
Reaction SMILES: [Br:1][C:2]1[C:7](C=O)=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O:19][CH3:20])([O:17][CH3:18])OC>CO>[CH3:20][O:19][CH:14]([O:17][CH3:18])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=1
Reactant: COc1cc(Br)c(C=O)cc1OC
Reactant: COC(OC)OC
Solvent: CO
Product: COc1cc(Br)c(C(OC)OC)cc1OC
Temperature: 25 °C

Procedure:
6-Bromo-3,4-dimethoxybenzaldehyde (470 g) is suspended in methanol (600 ml), and thereto are added trimethyl orthoformate (1025 ml) and IRA-120 (H+ -type, 10 g), and the mixture is refluxed for one hour. The mixture is cooled to room temperature, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ether, washed, dried, evaporated to remove the ether, and distilled under reduced pressure to give 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal (522 g) as a main distillate (133-138° C./1 Torr).
Reaction SMILES: [CH:1]1([N:7]([CH3:24])[C:8]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:15]([NH2:17])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>N1C=CC=CC=1>[CH:1]1([N:7]([CH3:24])[C:8]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[C:15]([NH:17][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)c1ccc2c(c1)nc(N)n2CCCO)C1CCCCC1
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCOC(=O)c1cccs1)C1CCCCC1
Reaction time: 6 h
Yield: 43.2 %

Procedure:
To a stirred solution of the above amino benzimidazole (0.7 g, 2.1 mmol) in pyridine (10 mL) was added 2-thiophenecarbonyl chloride (0.68 mL, 6.4 mmol). The reaction was complete in 6 h. The pyridine was evaporated and the resulting orange solid was purified by flash chromatography with 1% MeOH/dichloromethane to give thiophene-2-carboxylic acid 3-{5-(cyclohexyl-methyl-carbamoyl)-2-[(thiophene-2-carbonyl)-amino]-benzoimidazol-1-yl}-propyl ester (0.50 g, 43%), m.p. 92-94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Cu](I)I>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (145 mg, 0.232 mmol), copper iodide (2.213 mg, 0.012 mmol) and TEA (162 μL, 1.162 mmol) in THF (8 ml) was added trimethylsilylacetylene (43 μL, 0.302 mmol) and the reaction mixture was degassed for 5 minutes with nitrogen. The resulting mixture was heated with stirring at 60° C. for 4 hours under nitrogen. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(trimethylsilyl)ethynyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (121 mg, 0.189 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.41-7.48 (m, 1H), 7.36 (t, 1H), 7.25 (s, 1H), 7.09 (t, 1H), 6.79 (s, 1H), 5.46 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), 0.08-0.31 (m, 9H), −0.12 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16](=[N:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:17][CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30]>C(Cl)Cl>[CH2:21]([N:20]([S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])[C:16](=[N:15][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:17][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN=C(SCC)N(CCCCCCC)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.8 g (0.018 mole) of triethylamine was added to 4.5 g (0.015 mole) N,N'-diheptyl-S-ethyl-isothiourea in 50 ml methylene chloride in a stirred round bottom flask. A solution of propanesulfonyl chloride (0.018 mole, 2.6 g) in 8 ml methylene chloride was added dropwise to the above solution at 0° C. The mixture was stirred 1.5 hours at room temperature then at 30°-35° C. for 1.5 hours. The cooled solution was washed twice with 20 ml water, once with 25 ml saturated sodium bicarbonate solution and twice more with 20 ml of water. The organic phase was dried over magnesium sulfate and evaporated invacuo to yield the product as a yellow oil. nD30 1.4805. Yield was 5.2 g (85.4% of theory). The structure was confirmed by IR spectrum. Compound No. 203 in Table I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[CH:30](=O)C.[Na]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH3:30])[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: CC=O
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Product: CCN1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (338 mg, 1.00 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3 was stirred for 10 minutes, then extracted with DCM and treated with acetaldehyde (88 mg, 2.0 mmol) and sodium triacethoxyborohydride (318 mg, 1.5 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (200 mg) as a yellow oil. The ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (210 mg) as a white solid (hydrochloride salt). The resulting acid was suspended in DCM (7 ml), TEA (0.13 ml, 0.93 mmol) was added, and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-ethyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (180 mg) as a light yellow solid. The compound was dissolved in DCM (6 ml) and treated with 1 M HCl in diethyl ether (6 ml, 6 mmol) as described in Example 2, Step D, giving a light yellow solid (114 mg, hydrochloride salt)
Reaction SMILES: [F-].[K+].P(C(C(F)(F)F)(F)F)(C(C(F)(F)F)(F)F)C(C(F)(F)F)(F)F.[CH2:25]([O:28][CH2:29][CH2:30][OH:31])[CH:26]=[CH2:27].[F:32][C:33]([P:39](=[O:54])(C(F)(F)C(F)(F)F)[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])([F:38])[C:34]([F:37])([F:36])[F:35]>>[F:38][C:33]([P:39]([C:40]([F:45])([F:46])[C:41]([F:43])([F:44])[F:42])(=[O:54])[O:31][CH2:30][CH2:29][O:28][CH2:25][CH:26]=[CH2:27])([F:32])[C:34]([F:37])([F:36])[F:35]
Reactant: C=CCOCCO
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: C=CCOCCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Potassium fluoride (0.277 g; 4.8 mmol) is suspended in tris(pentafluoro-ethyl)phosphine oxide, (C2F5)3P═O, (16.783 g; 41.5 mmol) in a 100 ml glass flask, cooled (0° C.), and 2-allyloxyethanol (4.188 g; 41.0 mmol) is added. The two-phase reaction suspension is stirred at 0° C. for 3 h and at room temperature for 20 h. After recondensation in vacuo (10−3 mbar) at 50° C. (decomposition is observed from 40° C.) and subsequent fractional distillation under reduced pressure (b.p.: 40 to 42° C. at 3.8·10−3 mbar), 2-(allyloxy)-ethyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH2CH2OCH2—CH═CH2, can be isolated as clear and colourless liquid (7.083 g; 18.3 mmol) in a yield of 45% and a purity of 96%. The product is stored at −20° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1.[BH4-].[Na+]>C(O)(C)(C)C.CO.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH2:15][OH:16])=[CH:12][C:11]=2[CH:18]=1
Reactant: O=C(O)c1cc2cc(-c3ccccn3)ccc2o1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)(C)O
Product: OCc1cc2cc(-c3ccccn3)ccc2o1
Temperature: 50 °C
Yield: 61.8 %

Procedure:
To a solution of 5-pyridin-2yl-benzofuran-2-carboxylic acid (770 mg, 2.9 mmol) in 28 mL t-butanol and 2.5 mL methanol was added NaBH4 (275 mg, 7.2 mmol). The mixture was heated at 50° C. under argon overnight, allowed to cool, poured into brine, extracted with ethyl acetate, washed with brine, dried (MgSO4), and evaporated. Purification by chromatography gave 404 mg of (5-pyridin-2-yl-benzofuran-2-yl)-methanol. MS: (M+H)+=226.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:23])[CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:23])[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: CN(CCCN1C(=O)c2ccccc2C1=O)CCOc1cc(F)cc(F)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(CCCN)CCOc1cc(F)cc(F)c1
Yield: 99.7 %

Procedure:
A mixture of 2-(3-([2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino)-propyl)-isoindole-1,3-dione (1 g, 2.67 mmol), hydrazine hydrate (0.8 ml) and ethanol (20 ml) was heated under reflux for 2 hours. The solvent was concentrated and the residue was suspended in diethyl ether. The solid formed was filetered off and washed with ether. The filtrated was concentrated to dryness to give N1-[2-(3,5-difluoro-phenoxy)-ethyl]-N1-methyl-propane-1,3-diamine (0.65 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([N+:29]([O-:31])=[O:30])([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)[CH3:7].[OH-].[Li+].O>CO.O1CCCC1>[N+:29]([C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([F:26])([F:27])[F:28])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:7])[CH2:5][CH2:4][C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester (0.098 g, 0.22 mmol) in methanol (1.00 mL, Fisher) and tetrahydrofuran (1.00 mL, Acros) was added 2 M lithium hydroxide in water (1.00 mL, 2.00 mmol). The mixture was stirred at room temperature. After 2 hours, the mixture was concentrated under vacuum. The resulting product was diluted in methylene chloride and washed with 1N HCl. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the product in 99 mg yield (100%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1.Cl[C:16]([S:18]Cl)=[O:17].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[O:13][C:16](=[O:17])[S:18][N:14]=2)[CH:3]=1
Reactant: NC(=O)c1cc(Br)c2ccccc2c1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1oc(-c2cc(Br)c3ccccc3c2)ns1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromonaphthalene-2-carboxylic amide (1.10 g) in toluene (11.0 mL) was added chlorocarbonylsulfenyl chloride (0.73 mL), and the mixture was stirred at 100° C. for 18 hours. To the reaction solution was added water (50 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water and hexane to give 5-(4-bromonaphthalene-2-yl)-[1,3,4]oxathiazole-2-one (1.13 g). This compound (1.13 g) was dissolved in dichlorobenzene (18 mL). To the solution was added ethyl propiolate (1.52 mL), and the mixture was stirred at 160° C. for 18 hours. The reaction solution was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (0.66 g).