Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([N:11]([C:55]2[N:60]=[C:59](Cl)[N:58]=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH:67]3[CH2:72][C:71]([CH3:74])([CH3:73])[N:70]([O:75][CH3:76])[C:69]([CH3:78])([CH3:77])[CH2:68]3)[N:56]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH3:52])[C:45]([CH3:54])([CH3:53])[CH2:44]2)[C:19]2[N:24]=[C:23](Cl)[N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH3:40])[C:33]([CH3:42])([CH3:41])[CH2:32]3)[N:20]=2)[CH2:5][C:4]1([CH3:80])[CH3:79].[CH2:81]([CH2:83][NH2:84])[OH:82]>>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([N:11]([C:55]2[N:60]=[C:59]([NH:84][CH2:83][CH2:81][OH:82])[N:58]=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH:67]3[CH2:72][C:71]([CH3:74])([CH3:73])[N:70]([O:75][CH3:76])[C:69]([CH3:78])([CH3:77])[CH2:68]3)[N:56]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH3:52])[C:45]([CH3:54])([CH3:53])[CH2:44]2)[C:19]2[N:24]=[C:23]([NH:84][CH2:83][CH2:81][OH:82])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH3:40])[C:33]([CH3:42])([CH3:41])[CH2:32]3)[N:20]=2)[CH2:5][C:4]1([CH3:80])[CH3:79]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(N(CCCCCCN(c3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(CCCCCl)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCCSc1ccc(O)cc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 47.9 g (0.250 mole) of p-mercaptophenol, 51.4 g (0.250 mole) of 4-(5-chlorovaleryl)morpholine, 52 ml of 5N sodium hydroxide and 600 ml of water was heated to boiling and then stirred at 50° C. for one hour; and, thereafter, stirred at room temperature for 15 hours. The white, crystalline intermediate precipitated during this period. The dried, crude intermediate was recrystallized from benzene to give the intermediate, 4-[5-(4-hydroxyphenylthio)valeryl]morpholine, as white crystals, mp 112°-113° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: BrCCCBr
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCBr)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H) (5.0 g, 0.028 mole), 1,3-dibromopropane (5.7 mL, 0.056 mole) and sodium hydride (1.2 g, 0.028 mole) were stirred in 50 mL of DMF at room temperature overnight under Argon. The reaction mixture was quenched with water (150 mL), extracted with ethyl acetate, then washed with 1 N HCl and brine. The extract was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound, 5-(3-Bromo-propoxy)-6-methoxy-indan-1-one. MS m/z 297 (M+H)+.
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[N+:7]([C:10]1[CH:31]=[CH:30][C:13]([O:14][C:15]2[C:16]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[CH:12][CH:11]=1)([O-])=O>[Fe].O1CCCC1>[C:24]1([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([O:14][C:13]4[CH:30]=[CH:31][C:10]([NH2:7])=[CH:11][CH:12]=4)[C:16]=3[CH:23]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 ml of ethanol and 2 ml of water to 110 mg of 4-(4-nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 80–85° C. for 2.5 hours. After returning the mixture to room temperature, 20 ml of tetrahydrofuran was added, and the mixture was stirred for 5 minutes and filtered with celite, after which 100 ml of ethyl acetate and 50 ml of water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with plug cotton and concentrated to dryness to obtain 90 mg of the title compound.
Reaction SMILES: CN([CH2:4][CH2:5][CH2:6]N1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH2:25]([N:31]=[C:32]=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[N-]=C=[O:36]>C(O)(C)C>[CH2:25]([NH:31][C:32](=[O:36])[O:33][CH:5]([CH3:6])[CH3:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Reactant: CCCCCCN=C=O
Reactant: [N-]=C=O
Solvent: CC(C)O
Product: CCCCCCNC(=O)OC(C)C
Temperature: 60 °C

Procedure:
In a 250 ml round-bottomed flask, 0.02 g of Desmorapid Z, 34.0 g of n-hexyl isocyanate were initially introduced and heated to 60° C. Thereafter, 16.0 g of isopropanol were added dropwise and the mixture was further kept at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, cooling was effected and the product was obtained as a clear liquid.
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:10][CH2:9][N:8](C(O)=O)[CH2:7]1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:14].[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]2[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Clc1ccc(Nc2ccccc2)cc1Cl
Reactant: O=C1CCN(C(=O)O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(N(c2ccccc2)C2CCNC2)cc1Cl
Temperature: 25 °C

Procedure:
An acetic acid solution (15 ml) containing 3-oxopyrrolidine-1-carboxylic acid text-butyl ester (0.67 g) and (3,4-dichlorophenyl)phenylamine (0.94 g) was stirred at room temperature over night. To the mixture was added 1.5 g of sodium triacetoxyborohydride, followed by stirring at room temperature for 8 hours. Dichloromethane was added to the reaction solution and washed with water, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1). The solvent was distilled off from the purified product under reduced pressure, and the residue was dissolved in 1 N hydrochloric acid-ethanol and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 50 mg of brown amorphous solid (3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine dihydrochloride.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[OH:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Compound 1 (770 mg, 1.87 mmol) obtained in Reference Example 1 was dissolved in 15 ml of methylene chloride. To the solution was added 5.6 ml (5.6 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give 550 mg (yield 77%) of Compound 53 as a yellow solid, which was then triturated with ether to give a yellow powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:27][B-:28]([F:31])([F:30])[F:29].[CH2:32]([O+](CC)CC)C>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:27][B-:28]([F:31])([F:30])[F:29].[C:8]1([P+:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:32])[O:26]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCO)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1CCC(=C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g of (5-hydroxy-2-oxopentyl)triphenylphosphorane was dissolved in 20 ml of methylene chloride under a nitrogen atmosphere, cooled in dry ice/acetone bath and 15 ml of triethyloxonium tetrafluoroborate as a 1 M solution in methylene chloride was added. The reaction mixture was stirred at about -78° C. for 0.5 hour and allowed to warm to room temperature over about 2 hours, decanted into ice water and stirred vigorously with the addition of an additional 30 ml of methylene chloride. The extraction was repeated twice, the extracts combined, dried over sodium sulfate, the solvent removed under nitrogen gas followed by warming to 40° C. for 2 hours at 0.5 mm. Crystallization from ethyl acetate gave 700 mg of the desired product, m.p. 118.5°-122.5° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]([O-])=[O:14].[Na+].[C:17]([O:21][C:22](NN1CCC(CCO)CC1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.CCOCC>[C:17]([O:21][C:22]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH:13]=[O:14])[CH2:8][CH2:7]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)NN1CCC(CCO)CC1
Reactant: CC(=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 3 h

Procedure:
A solution of CH2Cl2 (200 mL) was treated with pyridiniumchlorochromate (PCC) (6.7 g, 0.031 mol) for five minutes. Solid NaOAc (2.55 g, 0.031 mol) and 4Å molecular sieves were added, followed by a solution of 4-1 (4.75 g, 0.02 mol) in CH2Cl2 (50 mL). The reaction was stirred for 3 h, diluted with 400 mL of Et2O, and filtered through a pad of silica gel. The silica gel was washed with 1 L of Et2O and 0.5 L of 1:1 Et2O/CHCl3. The organic solutions were combined, concentrated to give a greenish oil which was filtered through another pad of silica gel, eluting with 1.2 L of Et2O. The filtrate was concentrated to give 4-2 as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 4.08 (bd, 2H), 2.7 (bt, 2H), 2.37 (dd, 2H), 2.03 (m, 1H), 1.7 (bd, 2H), 1.42 (s, 9H), 1.2 (m, 2H). ##STR32## Methyl 2-(S)-benzyloxycarbonylamino-3-aminopropionate hydrochloride (5-2)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][OH:26])([CH3:24])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[O:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][C:21]([CH3:24])([CH:25]=[O:26])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCC(C)(CO)CC2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCC(C)(C=O)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 40 %

Procedure:
A solution of oxalyl chloride (0.176 mL, 2.015 mmol) in DCM (8 mL) was cooled to −70° C. and treated with anhydrous DMSO (0.238 mL, 3.36 mmol). The resultant solution was stirred at −70° C. for 20 min and then treated with (1-(4-chloro-3-methoxyphenyl)-4-methylpiperidin-4-yl)methanol in DCM (3 mL) and stirred for 40 min. Triethylamine (0.702 mL, 5.04 mmol) was added to the reaction. Upon completion of addition, the mixture was stirred at −70° C. for 30 min and then warmed to RT. The mixture was diluted with DCM, washed with sat NaHCO3, brine, dried (Na2SO4) and concentrated to yield a residue. The residue was purified by flash chromatography on 12 g cartridge to give 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carbaldehyde (180 mg, 0.672 mmol, 40% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ ppm 9.50 (1 H, s), 7.18 (1 H, d, J=8.57 Hz), 6.47 (1 H, s), 6.43 (1 H, dd, J=8.57, 1.98 Hz), 3.82-3.89 (3 H, m), 3.27-3.36 (2 H, m), 2.93-3.03 (2 H, m), 2.03-2.12 (2 H, m), 1.57-1.67 (2 H, m), 1.11 (3 H, s).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH:12](C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 5-bromosalicylaldehyde (10 g, 50 mmol), diethyl bromomalonate (13.1 g, 55 mmol), potassium carbonate (6.9 g, 50 mmol), and 2-butanone (80 mL) was stirred at 90° C. for 16 h. The solvent was removed under reduced pressure at 45° C., and the residue was acidified with 1M HCl, extracted, washed, dried, and evaporated. The residue was purified by chromatography to give 3.6 g of ethyl 5-bromo-benzofuran-2-carboxylate, mp. 59-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:42])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (96 mg) in tetrahydrofuran (10 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.33 ml), followed by stirring at room temperature for 2.5 hrs. A solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 0.800 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to provide the titled compound (64.5 mg, 48%) as pale yellow powder.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18]C)=O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(O)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:16](=[O:18])[C:7]3[N:8]=[N:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:6]=3[NH:30]2)=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1nnc2ccccc2c1O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: O=c1c2nnc3ccccc3c2[nH]n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (326 g, 200 ml) was added dropwise under inert atmosphere to methyl 4-hydroxycinnoline-3-carboxylate (10.0 g, 49 mmol). The mixture was heated to reflux for 2.5 h, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (100 ml) was added to the residue and removed under vacuum. This procedure was repeated with further toluene (100 ml). A brown semi-solid material was obtained and taken up in ethanol (200 ml). 4-Nitrophenylhydrazine (5.99 g, 39.2 mmol) was added portionwise. The mixture was stirred at room temperature overnight. The mixture was heated to 40-45° C. for 1 h and cooled to room temperature. The solids were collected by filtration, triturated with ethanol (100 ml) and dried under vacuum. The title compound was isolated as a brown solid (8.42 g, 27.4 mmol, 70%). LCMS: m/z 308 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=C([O:30][C:31]([F:34])([F:33])[F:32])C=CC=1C=O>>[CH3:19][O:18][C:5]1[CH:4]=[C:3]([O:30][C:31]([F:34])([F:33])[F:32])[CH:2]=[CH:7][C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(OC(F)(F)F)ccc1C=O
Product: COc1cc(OC(F)(F)F)ccc1C(O)C#Cc1ccccc1
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-4-trifluoromethoxy-benzaldehyde was reacted to give the title compound as a pale yellow oil (650 mg, 100%). LCMS (Method B): RT=4.13 min, [M−H2O+H]+=305.
Reaction SMILES: [OH-].[Na+].Cl[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([Cl:15])[CH:9]=1)=[CH:5]C=O.ClCCl>O.O1CCOCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]#[CH:5])=[CH:9][C:10]=1[Cl:15]
Reactant: O=CC=C(Cl)c1ccc(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(Br)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
40 g of sodium hydroxide are dissolved, under an inert atmosphere, in 230 ml of water, 120 ml of 1,4-dioxane are added and the reaction mixture is heated to 80° C. 17.5 g of 3-chloro-3-(4-bromo-3-chlorophenyl)propenal dissolved in 400 ml of 1,4-dioxane are added and the reaction mixture is stirred for 30 minutes at 80° C. The reaction mixture is allowed to cool to room temperature and 2300 ml of dichloromethane are then added. The phases are separated after settling has taken place and the organic phase is washed with water and dried over magnesium sulphate. The compound dissolved in a dichloromethane/1,4-dioxane mixture is used in its current form in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:3]=1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([NH:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[CH:5][C:6]=1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 3-{2-amino-3-(aminomethyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.9 g, 4.055 mmol) and triethylamine (1.13 mL, 8.109 mmol) in tetrahydrofuran (40.0 mL) was added acetic anhydride (0.457 mL, 4.865 mmol). The mixture was stirred at 0° C. for 4 hrs. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (yellow solid) was purified by recrystallization from ethyl acetate/diisopropyl ether to give tert-butyl 3-{3-(acetylamino-methyl)-2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.13 g, yield; 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH3:20].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][NH2:20])=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Solvent: O
Solvent: CO
Product: NCCOC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
A mixture of 28.2 g (0.1 mole) of 2-[bis(p-fluorophenyl)methoxy]ethyl chloride and 17 g (1 mole) of ammonia in 187.5 ml of methanol is shaken in an autoclave for a period of 6 hours at 135° C. The reaction mixture is poured into water and extracted with diethyl ether. The extract is acidified with 2N hydrochloric acid. The acid aqueous layer is separated off, made alkaline with 2N sodium hydroxide and extracted with diethyl ether. The extract is dried over potassium carbonate and the ether is distilled off. The residue is distilled, yielding 15.4 g of 2-[bis(p-fluorophenyl)-methoxy]ethylamine, boiling point 130° C./0.2 mm.Hg. The base is dissolved in diethyl ether and an ethereal solution of maleic acid is added. The precipitate is filtered off and crystallised from a mixture of ethanol and diethyl ether. 2-[Bis(p-fluorophenyl)methoxy]ethylamine hydrogen maleate is obtained. Its melting point is 126°-127° C.