Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 86.5 %

Procedure:
(+)-1-[(3-Chlorophenyl)phenylmethyl]piperazine (2.27 g, 7.90 mmol) prepared in the same manner as in Preparation Example 18 and N-cyclopropyl-6-chlorohexanesulfonamide (2.08 g, 8.69 mmol) were refluxed in N-ethyldiisopropylamine (10 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1)], to give (+)-N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (3.35 g) as a pale yellow oil (yield based on (+)-1-[(3-chlorophenyl)phenylmethyl]piperazine: 86.4%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O>O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:24])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 25 °C

Procedure:
To a suspension of 90 grams (0.352 moles) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide in 450 ml proprietory alcohol there is added a solution of 15.5 grams (0.3875 moles) of sodium hydroxide in 450 ml of water at a temperature of less than 20° C. 53.4 Grams (0.423 moles) of dimethyl sulphate is added while stirring, at 25° C. and the mixture is then allowed to stir for about 15 hours. It is cooled to 10° C. and filtered. The cake is washed with water, followed by a 50% alcohol/water wash, and dried. Yield is 90 grams (95%) m.p. 162.5°-164° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>O.CCOCC>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[N:19]1[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1ccc2nc(N3CCC4(CC3)OCCO4)ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 21.8 %

Procedure:
A mixture of 10 g (0.0613) of 2-chloroquinoline, 27 g (0.1886 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 13 g (0.0941) of K2CO3, and 75 ml of dimethylformamide is stirred at 100°-110° C. for 4 days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed copiously with water, then brine, dried over Na2SO4, and concentrated in vacuo to give a waxy solid. Trituration with ether furnishes 3.6 g (22%) of title compound: IR (KBr) 1620, 1610 and 1510 cm-1 ; NMR (CDCl3) δ7.92 (d, 1H), 7.78-7.50 (m, 3H), 7.30-7.22 (m, 1H), 7.04 (d, 1H), 4.02 (s, 4H), 3.94-3.86 (m, 4H), and 1.88-1.76 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=CC=1)[NH:7]C=[CH:5]2.C([O-])([O-])=O.[K+].[K+].IC.[CH3:19][N:20]1[C:24](=O)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH3:19][N:20]1[C:24]2[C:23](=[CH:5][C:4]([C:8]#[N:7])=[CH:3][CH:2]=2)[CH:22]=[CH:21]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-bromoindole (500 mg; 2.55 mmol) and cuprous cyanide (342 mg; 3.83 mmol) in NMP (10 mL) was heated under microwave irradiations to 100° C. for 30 minutes then at 200° C. for 30 minutes. The reaction mixture was partitioned with water and DCM and the organic layer was washed with brine and concentrated in vacuo to give a pink solid. Purification by silica column chromatography (DCM) gave a white solid. It was dissolved in DMF (5 mL) and K2CO3 (704 mg; 5.10 mmol) and iodomethane (543 mg; 3.83 mmol) were successively added. The reaction mixture was stirred at RT for 3 days and then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give a slightly yellow oil which crystallized upon standing to give the title compound as an off-white solid (80 mg, 70%). LC/MS (Method A): 156.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(N(C(C)C)C(C)C)C.Cl.[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][NH:29][C:11]([C:9]1[N:10]=[C:5]2[N:6]([N:7]=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:8]=1)=[O:13])[CH3:25]
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
2.86 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 2.72 ml of N-ethyldiisopropylamine were suspended in 30 ml of N,N-dimethylformamide; 2.63 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 1 hour. To the reaction mixture, 2.21 g of glycine ethyl ester hydrochloride was added, followed by stirring at room temperature for 5 hours. Water was added; the crystal precipitated was collected by filtration, washed with water and ether and dried to yield 2.93 g of the title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cccc(CNC2CCCCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CNC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
Under argon atmosphere, BBr3 (9.1 mL of 1M solution in CH2Cl2 9.1 mmol) was slowly added at 0° C. to a solution of N-(3-methoxybenzyl)-cyclohexylamine in CH2Cl2 (40 mL). After stirring 3 h at room temperature, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and evaporated to provide 314 mg of cyclohexylamine 22 (50% yield) which was used without further purification. 1H NMR (300 MHz, acetone-d6) δ 1.12-1.31 (m, 5H), 1.59 (m, 1H), 1.73 (m, 2H), 1.92 (m, 2H), 2.53 (m, 1H), 3.77 (s, 2H), 6.70 (dd, J=1.9 and 8.9 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.91 (s, 1H), 7.12 (t, J=7.8 Hz, 1H) ppm. N-(3-hydroxybenzyl)-piperidine 22b was obtained using the same procedure (25% overall yield). 1H NMR (300 MHz, acetone-d6) δ 1.50-2.30 (m, 6H), 2.80-3.50 (m, 4H), 4.18 (s, 2H), 6.94 (m, 1H), 7.24 (m, 2H), 7.34 (s, 1H), 8.91 (br s, 1H), 11.24 (br s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(Cl)(Cl)Cl>ClC=CCl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCN
Solvent: ClC(Cl)Cl
Solvent: ClC=CCl
Product: NCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 64698.7 %

Procedure:
26.4 g (0.3 mol) of 1,4-diaminobutane was dissolved in 100 ml of 1,2-dichloroethene and stirred together with 6.3 g (0.03 mmol) of 4-chlorophenylsulfonyl chloride at room temperature for 4 hours. After addition of chloroform, the reaction solution was filtered through celite, and the filtrate was washed with water three times and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent to give 5.1 g of the title compound in a yield of 65%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH3:22])[C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH3:22])[C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8])(=[O:25])[CH3:24]
Reactant: CC(COCCO)C(=O)c1ccc(Cc2cccnc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOCC(C)C(=O)c1ccc(Cc2cccnc2)cc1

Procedure:
In 3 ml of pyridine was dissolved 2.0 g of 3-[p-[3-(2-hydroxyethyl)oxy-2-methylpropionyl]benzyl]pyridine, and 0.76 ml of acetic anhydride was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 12 hours. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 16 ml of ethyl acetate. The resulting solution was washed with 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain crude oily 3-[p-[3-(2-acetoxyethyl)oxy-2-methylpropionyl]benzyl]pyridine. This was dissolved in 17 ml of ethanol.
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=O)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])=[CH:22][CH:21]=1)[CH3:8])(C)(C)C.Cl>O1CCOCC1>[ClH:15].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]=[C:17]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[NH:29][C:28]4=[O:33])=[CH:24][CH:25]=3)[N:7]([CH3:8])[C:9]=2[CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 183.2 %

Procedure:
N-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-chlorophenyl]-N-methylcarbamic acid t-butyl ester (3.16 g) (obtained in Example 3-1) was dissolved in dioxane (30 ml). To the solution was added 4N hydrochloric acid in dioxane (30 ml) and the resulting mixture was stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture was filtered and the crystals were washed with ethyl acetate and dried in vacuo to afford the title compound (2.44 g). softening point: 301-303° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34](Cl)=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=1>CCCCCCC.C(OCC)(=O)C>[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([C:38]([F:39])([F:41])[F:40])[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-chloro-3-trifluoromethyl-benzoic acid methyl ester (commercially available) after a reaction time of 6 h and using a gradient of n-heptane:Ethyl acetate (100:0 to 60:40). White solid (32%). MS (Turbo Spray): m/z=493.3 [M+H].
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7].C(Cl)(Cl)Cl.[OH-:14].[Na+]>CC(C)=O>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][C:2]([CH3:9])([CH3:8])[NH:1][C:2]([CH3:9])([CH3:8])[C:3]1=[O:14]
Reactant: [OH-]
Reactant: CC(C)(N)CNCCO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
To a solution of 2-((2-amino-2-methylpropyl)amino)ethanol (12 g, 91 mmol) in 90 mL of acetone was added chloroform (10.9 mL, 136 mmol) and the solution was cooled to 0° C. with an external ice bath. A solution of NaOH (50% by weight, 43.6 g, 545 mmol) was added slowly to the cold solution over several minutes and the resultant solution was stirred at 0° C. for 2 hours then allowed to warm to room temperature and stirred for an additional 18 hr. The crude reaction mixture was filtered to remove solids, washing with acetone, and the solution was concentrated to 20 g of a clear oil. A portion of the crude material was purified by a bulb-to-bulb distillation under reduced pressure to give 1.45 g of a clear oil, which was used directly in the next step without further purification. LRMS (ESI/APCI) m/z 201 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][CH:28]([F:37])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[F:36])[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([F:36])=[C:29]([CH:28]([F:37])[F:27])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1ccc(F)c(C(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)F)c1
Yield: 18.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(difluoromethyl)-4-fluoroaniline (Intermediate-28, 0.065 g, 0.403 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.32 (s, 3H), 3.94 (s, 3H), 7.05-7.41 (m, 3H), 7.50 (s, 2H), 7.68-7.88 (m, 4H), 8.11 (m, 1H), 10.27 (s, 1H), 12.53 (s, 1H); MS (m/z): 503.10 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]2)=[CH:6][C:5]=1[F:21])([OH:3])=[O:2].N1C=CC=CC=1.S(Cl)(Cl)=O.O[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>C(OCC)C>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([O:2][C:1]([C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]3)=[CH:6][C:5]=2[F:21])=[O:3])=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: CCCCCC1COB(c2ccc(C(=O)O)c(F)c2)OC1
Reactant: N#Cc1ccc(O)cc1F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC1COB(c2ccc(C(=O)Oc3ccc(C#N)c(F)c3)c(F)c2)OC1
Reaction time: 1 h

Procedure:
A mixture comprising 0.004 mole of 2-(4-carboxy-3-flurophenyl)-5-pentyl-1,3,2-dioxaborinane, 0.32 ml of pyridine, 0.32 ml of thionyl chloride in 50 ml of anhydrous diethyl ether is stirred for 1 hour. Then 0.004 mole of 4-hydroxy-2-fluorobenzonitrile and 1 ml of pyridine are added. The mixture is allowed to stand overnight and then filtered. The residue obtained after distilling off the solvent is crystallized from a mixture of hexane and ethyl alcohol. The yield of the compound (VIs) is 60%. M.p. 63° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][C:42]([F:45])([F:44])[F:43])[CH:35]=2)O1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:59].Cl>>[ClH:1].[ClH:59].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([O:41][C:42]([F:43])([F:45])[F:44])[CH:35]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2ccc(O)c(OC(F)(F)F)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(O)c(OC(F)(F)F)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (55 mg, 0.15 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenol (68 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (71 mg, 79%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.04-7.97 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 5.70-5.60 (m, 1H), 3.07 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.50-2.40 (m, 2H), 2.08-1.97 (m, 3H), 1.74-1.62 (m, 2H), 1.39-1.27 (m, 2H). ESI MS m/z 503 [M+H]+; HPLC>99% (AUC), tR=9.80 min.
Reaction SMILES: C(OC([C:8]1([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25].FC(F)(F)C(O)=O>ClCCl>[NH2:14][CH:8]1[CH2:9][CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)C1(N)CCNCC1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of 4-amino-piperidine-4-carboxylic acid tert-butyl ester (2.50 g; 12.5 mmol) and Huenigs base (3.2 mL) in dichloromethane (15 mL) is added acetyl chloride (1.1 mL; 15.0 mmol) under ice-cooling. The mixture is stirred overnight at ambient temperature. The solvent is evaporated and the obtained crude is partitioned between ethyl acetate and 1M aqueous HCl. Drying and evaporation of the solvent gave an orange oil which is dissolved in dichloromethane (38 mL). Trifluoroacetic acid (19 mL) is added and the mixture is stirred for 20 min at ambient temperature. The volatiles are completely evaporated at 35° C. bath temperature and the obtained residue is dissolved in a mixture of dichloromethane/methanol (95:5 v/v). Solid sodium carbonate is added and the suspension is stirred at ambient temperature overnight. Filtration and evaporation of the solvent gave 0.98 g of the title compound as slightly brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=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>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1Cl
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1 Step 2, 15.0 g, 57.9 mmol) in toluene (120 mL) and water (30 mL) under nitrogen was added 2-chlorophenylboronic acid (19.9 g, 127.4 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (3.34 g, 2.8 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. LC/MS (Method B): 291.0 (M+H)+. 1H NMR (CDCl3, 400 MHz) δ 8.21 (1H, s), 8.01 (1H, d), 7.48 (1H, m), 7.34 (2H, m), 7.26 (2H, m), 4.33 (1H, d), 4.20 (1H, d), 3.94 (3H, s), 3.27 (3H, s).
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[S:7][C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[CH:9]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cnc2sc(Br)cc12
Temperature: 80 °C

Procedure:
The product from Example 14 (0.75 g) was added to glacial acetic acid (10 ml) and heated with stirring until it dissolved. Bromine (0.75 ml) was then added and the mixture immediately set solid. More acetic acid was added and the mixture broken up. It was then heated at 80° C. for 6½ hours, cooled and poured into ice-water. The solid was filtered and washed with water followed by dichloromethane and dried to give the title product, m.p. 304° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1([C:17]([C:16]2[N:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=23)=[O:19])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), morpholine (174 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (400 mg, yield 100.0%) as a yellow solid.