Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[CH2:38]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:39]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
70 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea are suspended in 3 mL of a 3N solution of HCl in dioxane. The medium is stirred at ambient temperature for 48 hours. The solvent is evaporated off under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on a 4 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. The fractions containing the expected product are concentrated and the solid obtained is triturated in isopropyl ether. After filtration and rinsing of the solid, 26.2 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea hydrochloride are isolated in the form of a sand-colored solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm) after addition of a drop of TFA-d1 (CF3COOD-d1): 1.15 (t, J=7.0 Hz, 6H); 1.39 (m, 1H); from 1.57 to 1.76 (m, 3H); 1.83 (m, 2H); 2.22 (m, 2H); 2.93 (m, 2H); 3.25 (m, 2H); 3.37 (q, J=7.0 Hz, 4H); 3.51 (m, 2H); 4.21 (t, J=6.0 Hz, 2H); 7.34 (d, J=7.5 Hz, 1H); 7.56 (d, J=11.0 Hz, 1H); 8.00 (s, 1H).
Reaction SMILES: ClC1C=CC=CC=1O[C:5]1[C:10]2[N:11]=[CH:12][S:13][C:9]=2[CH:8]=[C:7]([O:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:6]=1.ClC1[S:28][C:29]2[CH:35]=[C:34](OCCN(CC)CC)[CH:33]=[CH:32][C:30]=2N=1.[Cl:44]C1C=CC(O)=CC=1.CC(C)([O-])C.[K+]>>[Cl:44][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[S:28][C:12]1[S:13][C:9]2[CH:8]=[C:7]([O:14][CH2:15][CH2:16][N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH:6]=[CH:5][C:10]=2[N:11]=1
Reactant: CCN(CC)CCOc1cc(Oc2ccccc2Cl)c2ncsc2c1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCN(CC)CCOc1ccc2nc(Cl)sc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCN(CC)CCOc1ccc2nc(Sc3ccccc3Cl)sc2c1

Procedure:
2-(4-(Chlorophenoxy)-6-(2-diethylamino-ethoxy)-benzothiazole, from 2-chloro-6-(2-diethylamino-ethoxy)-benzothiazole and 4-chlorophenol in the presence of potassium tert. butoxide, Yield: 63.7% of theory, Melting point: 60-62° C., 1H-NMR spectrum (200 MHz, DMSO-d6, signals at ppm): 0.98 (t, 6H); 2.55 (q, 4H); 2.78 (t, 2H); 4.04 (t, 2H); 7.02 (dd, 1H); 7.41-7.64 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-:19].[Na+]>[Fe]>[F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:19])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=Cc1cccc(SC(F)(F)F)c1)[N+](=O)[O-]
Reactant: [OH-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: CC(=O)Cc1cccc(SC(F)(F)F)c1
Reaction time: 7 h
Yield: 60.5 %

Procedure:
13.2 g. (50 mmols) of 1-(3'-trifluoromethylthiophenyl)-2-nitro-propene, 19.6 g. (0.35 g. atom) of iron powder and 0.25 g. of ferric chloride are introduced into a 250 ml. three-necked flask equipped with a mechanical stirrer, a condenser and a dropping funnel, and this mixture is heated on an oil bath at 80°-90°C. 13.5 ml. of concentrated hydrochloric acid are added dropwise, via the dropping funnel, with stirring, over the course of 7 hours, while the temperature is kept at 90°C. The reaction mixture is allowed to cool and rendered alkaline with sodium hydroxide solution. The ketone is then steam distilled. The distillate is extracted twice in succession with 100 ml. of diethyl ether each time. The two ether extracts are combined, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate in vacuo on a water bath, and the residue is rectified. 7.1 g. (60.5% yield) of 1-(3'-trifluoromethylthiophenyl)-2-propanone are thus obtained as a colourless oil, b.p. 138°-146°C./25-30 mm. Hg., nD23 ° = 1.489.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C([O-])(=O)C.[Na+].CC(O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (D11) (44 mg) and ethyl 4-piperidinecarboxylate (89 mg) in methanol (10.00 mL) stirred at room temperature was added sodium acetate (55 mg) and AcOH (0.033 mL). The reaction mixture was stirred at room temperature for 10 min. And the solvent was removed by evaporation. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (72.3 mg) was added. Stirring continued for 2 h. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford ethyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D12) (60.1 mg). MS (ES): C28H34ClN3O3S requires 527. found 528.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12]Cl)=[C:4]([CH3:14])[N:3]=1.[CH:15]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[C:18]([CH3:19])[C:16]=1[OH:17].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:17][C:16]2[CH:15]=[C:22]([CH:23]([CH3:24])[CH3:25])[CH:21]=[CH:20][C:18]=2[CH3:19])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: Cc1nc(Cl)c2ccccc2c1CCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 1-chloro-4-chloromethyl-3-methyl-isoquinoline (150 mg, 0.66 mmol) is added to a mixture of carvacrol (199 mg, 1.33 mmol) and CsCO3 (645 mg, 1.98 mmol) in DMF (8 ml). After stirring overnight at room temperature, water is added and the mixture is extracted with ether. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is chromatographed on silica gel to give 220 mg of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline. A mixture of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline (220 mg, 0.65 mmol), 5-isopropylindazole-4-boronic acid (173 mg, 0.85 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), and Na2CO3 (1.3 ml of 2M in H2O) in dioxane (8 ml) The mixture is heated for 18 h at 100° C. After cooling to room temperature, water is added and the resulting mixture is extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 133 mg of 1-(5-isopropyl-1H-indazol-4-yl)-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline
Reaction SMILES: [F:1][C:2]1[C:3]([F:18])=[C:4](F)[C:5]([F:16])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1CCN2C(=NCCC2)CC1.Cl.[N+:31]([CH3:34])([O-:33])=[O:32]>>[F:16][C:5]1[C:4]([CH2:34][N+:31]([O-:33])=[O:32])=[C:3]([F:18])[C:2]([F:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(F)c(F)c(C[N+](=O)[O-])c(F)c1C(=O)OC
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
200 g of dimethyl tetrafluorophthalate was dissolved in 400 ml of nitromethane (Ishikawa, Suzuki & Tanabe: Nippon Kagaku Kaishi, 1976, 200) and the solution was cooled on an ice-salt bath. At an internal temperature of 15°-20° C. 171 g of 1,8-diazabicyclo[5,4,0]-7-undecene was added dropwise over a period of 30 minutes. After completion of the dropwise addition, the mixture was further stirred at an internal temperature of 10° C. for 30 minutes, then, the mixture was poured into a mixture of 1.5 liters of 1N hydrochloric acid and 1 liter of ice.
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[C:14]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][C:24]([CH3:28])=[N:25][CH:26]=3)[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[N:20]=2)[N:18]=1>C(#N)C>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][N:21]1[C:22]2=[N:23][C:24]([CH3:28])=[N:25][CH:26]=[C:27]2[C:19]([C:17]2[N:18]=[C:2]([I:3])[C:14]3[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:15]=3[N:16]=2)=[N:20]1
Reactant: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1ncc2c(-c3nc(I)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3.770 g (14.08 mmol) of diiodomethane and 411 mg (3.51 mmol) of isopentyl nitrite were added to 70 mg (0.17 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one. The mixture was stirred for 8 h at 85° C. After cooling, it was diluted with acetonitrile and the mixture was purified by preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 35 mg (24% of theor.) of the target compound was obtained.
Reaction SMILES: Br[CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>C(O)(=O)C>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:16])[CH3:3].[C:14]([O:17][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3])(=[O:16])[CH3:15]
Reactant: CC(Br)c1ccc2ccccc2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)c1ccc2ccccc2c1
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1-bromoethyl)naphthalene, prepared as described above, with sodium acetate in acetic acid to afford 2-(1-acetoxyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[S:10]1[C:9]2[C:4](=[O:3])[NH:5][CH2:6][CH2:7][C:8]=2[CH:12]=[CH:11]1
Reactant: CCOC(=O)NCCc1ccsc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccsc21
Temperature: 110 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
Using an analogous procedure and workup as described in Example 1, (2-thiophen-3-yl-ethyl)-carbamic acid ethyl ester (I-5c: 1.1 g, 5.527 mmol) in POCl3 (10 mL) was reacted with P2O5 (1.6 g, 11.05 mmol). The resulting mixture was stirred at 110° C. for 3 hours to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 280 mg of the product (33.13% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:6]=1[NH2:7].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28].O>ClCCl>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:6]=1[NH:7][C:25](=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 17.8 mmol) in dichloromethane (50 mL) and Et3N (10.3 mL, 71.2 mmol) was added butyryl chloride (1.9 g, 17.8 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then poured into water. The aqueous phase was separated and the organic layer was washed with water (50 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was washed with ether to give N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was used in the next step without further purification.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.C(O)(C(F)(F)F)=O.[NH:16]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=[N:17]1>CC#N>[I:8][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:16][NH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccn[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
NIS (8.83 g, 39.2 mmol) and TFA (0.825 mL, 10.70 mmol) were added to a stirred solution of ethyl 1H-pyrazole-5-carboxylate (5 g, 35.7 mmol) in CH3CN (120 mL) under Ar. The reaction mixture was stirred for 6 hr at rt, concentrated, diluted with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 10-50%) to afford the title product (8.31 g, 31.2 mmol, 88% yield) as a white solid. tR: 3.47 min (HPLC 1); tR: 0.72 min (LC-MS 2); ESI-MS: 267 [M+H]+ (LC-MS 2); Rf=0.55 (hexane/EtOAc 1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)(=O)CCCCC(O)=O.[H][H]>[Ni].O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Agent: O=C(O)CCCCC(=O)O
Solvent: O
Product: Nc1ccc(N)c(N)c1

Procedure:
91 Parts of finely ground 2,4-dinitro-aniline together with 73 parts of adipic acid, 10 parts of a commercial-type nickel catalyst and 400 parts by volume of water were charged into a hydrogenation autoclave. After the autoclave had been sealed, hydrogenation was effected in the usual manner at a temperature ranging from 60 to 100° C., while keeping the hydrogen pressure constant for about half an hour after the end of hydrogenation. For evidencing 1,2,4-triamino-benzene obtained, residual hydrogen was released, and the mixture was freed from the catalyst by filtration through a pressure filter under 20 atmsg. nitrogen and the filtrate passed into another flask flushed with nitrogen. The urea compound was prepared as described in Example 1. 62 Grams of a compound having a melting point higher than 335° C. were obtained. The following table shows accordance of the analytical data with the calculated values of the formula
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][Cl:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:20]1C3.C(O)C.Cl>C(Cl)(Cl)Cl>[ClH:17].[NH2:20][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18]
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
78 g of 1-(4-benzyloxyphenyl)-2-chloroethanone and 63 g of hexamine are dissolved in 2.2 liters of chloroform, and the mixture is stirred at room temperature overnight. The mixture is condensed to a volume of 1.1 liters, and refluxed for 3 hours. After cooling, the precipitated crystals are collected by filtration, washed and then dried. The colorless crystals thus obtained are added to a mixture of 750 ml of ethanol and 120 ml of conc. hydrochloric acid, and the mixture is refluxed for 50 minutes. After cooling, the precipitated crystals are collected by filtration, washed and then dried. 55.6 g of 2-amino-1-(4-benzyloxyphenyl)ethanone hydrochloride are obtained as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (100 mg, 0.497 mmol) in dichloromethane (1 ml) at 0° C. was treated in a dropwise manner with a solution of phosphorus tribromide (0.3 ml, 1M, 0.3 mmol) in dichloromethane at 0° C. for 1 hour. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. Reaction was quenched with sat'd NaHCO3 solution until reaction was no longer yellow-orange in color. Reaction was extracted with dichloromethane and organic layer was dried over anhydrous magnesium sulphate and concentrated in vacuo. The crude residue was purified by chromatography on Biotage column (12+M), eluting with ethyl acetate in heptane 0-30% (10CV), 30% (2CV) to yield the title compound (56 mg, 43%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.46 (s, 2H) 7.80 (s, 1H) 7.84 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][OH:12].NN>C1COCC1.CO.[Ni]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH2:11][OH:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1CO
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Br)c1CO
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a warm solution of (2-bromo-6-nitro-phenyl)-methanol (751 mg, 3.24 mmol), and a catalytic amount of Raney (Ni) in THF/MeOH (10 ml/10 ml) was added H2NNH2 (0.2 ml, 6.37 mmol). With stirring, the solution was heated under reflux for an hour and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The concentrated filtrate was purified by flash chromatography to give (2-amino-6-bromo-phenyl)-methanol (549 mg, 84%). MS: 202.1 (M+H)+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH2:30][F:31])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OCF
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Yield: 65.7 %

Procedure:
37.4 mg of N-iodosuccinimide was added little by little to a solution containing 47.8 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine obtained in Example 111 and 4.0 ml of N,N-dimethylformamide under stirring in an ice-bath, followed by stirring overnight as it was. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was successively washed with an aqueous sodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 43.9 mg of the target compound.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][OH:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH3:25][S:26]([O:17][CH2:16][CH2:15][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:28])=[O:27]
Reactant: OCCN1c2ccccc2Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reaction time: 3 h
Yield: 235.7 %

Procedure:
To a solution of 2-(10H-phenoxazin-10-yl)-1-ethanol (4.6 g, 20.28 mmol) in dichloromethane (20 ml) was added triethylamine (1.06 g, 10.56 mmol) under an atmosphere of nitrogen at 25° C. Methanesulfonyl chloride (0.90 g, 7.92 mmol) was added to the above reaction mixture at 0° C. and stirring was continued for further 3 h at 25° C. Water (50 ml) was added, and aqueous phase extracted with chloroform (2×25 ml). The combined organic phases were washed with water (25 ml), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was triturated with petroleum ether to afford the title compound (5.7 g, 92%) as a solid. mp: 81-83° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([F:18])[CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.C(OCC)C>[F:18][C:10]1[CH:9]=[C:8]([NH2:7])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: CC(C)(C)OC(=O)Nc1cc(F)cc2ccccc12
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(F)cc2ccccc12
Yield: 32.8 %

Procedure:
A third intermediate compound, 1-(3-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A solution of (3-fluoro-naphthalen-1-yl)-carbamic acid tert-butyl ester (4.78 g, 18.30 mmol) in dichloromethane (30 mL) and trifluoroacetic acid (10 mL) was refluxed for 2 hours. The mixture was diluted with diethyl ether and the solid that precipitated out was collected by vacuum filtration as the TFA salt (2.137 g). The filtrate was neutralized with 2N KOH and extracted with dichloromethane. The extracts were dried over anhydrous Na2SO4, filtered and concentrated to a brown residue. The residue was purified by column chromatography (5:1, hexanes/ethyl acetate) to afford 3-fluoro-naphthalen-1-ylamine (0.967 g, 33%). The TFA salt (2.137 g) was stirred in a heterogeneous solution of 2N KOH (10 mL) in dichloromethane (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford an additional amount of 3-fluoro-naphthalen-1-ylamine (1.193 g, 40%). 1H NMR (400 MHz, CDCl3) δ 7.78–7.64 (m, 2H), 7.48–7.42 (m, 1H), 7.41–7.34 (m, 1H), 6.90 (d, 1H), 6.54 (d, 1H), 4.30 (br s, 2H).