Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:24]([OH:26])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:24]=[O:26])[C:9]1=[O:16]
Reactant: Cc1cc(O)cc(=O)n1-c1ccccc1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(O)c(C=O)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1-(2-Chlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one obtained in Step A (9.25 g) was added to a solution of sodium hydroxide′ (54.9 g) in water/ethanol (1:2, 157 mL) at room temperature, and the mixture was heated at 70° C. Chloroform (34.8 mL) was slowly added to the reaction mixture at 70° C., and the mixture was stirred for 2 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from diethyl ether to give the title compound (3.95 g).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OCCOC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A solution of 2-cyclohexyloxyethanol (4.56 g, 32 mmol) and triethylamine (22 mL, 160 mmol) in dichloromethane (225 mL) was stirred under nitrogen. A saturated solution of 4-bromobenzenesulfonyl chloride (9.0 g, 35 mmol) in dichloromethane was added dropwise at 0° C., and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was then washed with 1N aqueous hydrochloric acid (2×200 mL) and the organic layer separated. The organic layer was washed sequentially with water (200 mL) and brine (200 mL), dried (MgSO4) and then concentrated in vacuo to give a white solid. The crude solid was dissolved in the minimum amount of dichloromethane and purified by passing through a plug of silica, which was eluted with ethyl acetate:hexane (50:50), ethyl acetate (100%) and finally methanol:ethyl acetate (10:90). The title compound was obtained as a yellow oil (4.3 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].C(OC(=O)C)(=O)C.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([CH:33]=O)[N:32]=1>O.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:33][C:31]1[N:32]=[C:28]([CH3:27])[S:29][CH:30]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Reactant: Cc1nc(C=O)cs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C=Cc2nc3ccccc3c(=O)n2-c2ccccc2Cl)cs1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (10 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-2-methyl-3H-quinazolin-4-one (0.135 g, 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed for 3 hours, and was then allowed to cool to ambient temperature. Once the reaction had cooled to abient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, dried over sodium sulfate and then concentrated to yield a waxy tan solid. This residue was triturated with ether, filtered and dried to afford 0.139 g (73%) of 3-(2-chloro-phenyl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:34]=[C:33]([CH:35]=O)[S:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:34]=[C:33]([CH2:35][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[S:32][CH:31]=3)[S:29][C:20]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C=O)c4)sc23)c(Cl)cc1Cl
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(CN5CCN(C)CC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
1-Methylpiperazine (70 μL, 0.63 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(5-formylthien-3-yl)thieno[3,2-b]pyridine-6-carbonitrile (225 mg, 0.49 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (520 mg, 2.45 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane. The fractions containing product are combined and concentrated in vacuo. The residue is washed with diethyl ether to provide 133 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2{5-[(4-methylpiperazin-1-yl)methyl]thien-3-y}thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 224-226° C.; 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.25-2.55 (m, 8H), 3.68 (s, 2H), 3.85 (s, 3H), 7.35 (s, 1H), 7.37 (s, 1H), 7.74 (s, 1H), 7.75 (s, 1H), 7.82 (s, 1H), 8.58 (s, 1H), 9.68 (s, 1H); MS 523.1, 544.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.I[CH:14]([CH2:16][CH3:17])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:14]([CH2:16][CH3:17])[CH3:15])[CH:6]=1
Reactant: CCC(C)I
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(CC(=O)OC)c1
Temperature: 65 °C

Procedure:
To 3-hydroxyphenyl acetic acid methyl ester (27.3 g, 165 mmol) in acetone (200 mL) was added 2-iodobutane (55 mL, 478 mmol) and potassium carbonate (83 g, 601 mmol). The mixture was heated at 65° C. for 48 hrs and filtered through a Celite® pad. The filtrate was concentrated in vacuo and the residue was diluted with dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×100 mL). The combined extracts were washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl)-acetic acid methyl ester. To a solution of (3-sec-butoxy-phenyl)-acetic acid methyl ester in methanol (200 mL) was added 10N sodium hydroxide solution (50 mL). The reaction mixture was stirred at 60° C. for 4 hrs. The solvent was evaporated and the mixture was acidified to pH=3 by addition of 6N hydrogen chloride solution. The aqueous phase was extracted with dichloromethane (3×100 m]L). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl) acetic acid (25 g, 73% yield) as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]=1.O(OC(C)=O)[O:23][C:24]([CH3:26])=O.C(N(CC)CC)C.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:24](=[O:23])[CH3:26])=[CH:17][CH:18]=2)[CH2:9][CH2:10][CH:11]=1
Reactant: CC(=O)OOOC(C)=O
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(N)cc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC1=CCCN(Cc2ccc(NC(C)=O)cc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
17.5 mg of 3-[1-(4-amino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.06 mM). And then 6 μl of (AcO)2O (0.07 mM), 0.01 ml of triethylamine (0.08 mM) and 1.0 mg of DMAP (0.008 mM) were added thereto and the mixture was stirred for 3 hrs at 0° C. The reaction was stopped by adding methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with ethylacetate as an eluant to give 46 mg of 3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (i) (yield: 44%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:19])[CH3:2].C=O.[C:23](=O)([O-])O.[Na+]>C(O)=O>[CH2:1]([C:3]1([CH3:20])[N:15]([CH3:23])[C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:19])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5.5 g of the 7,9-diethyl-3,6,7,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 2) obtained in Example 2 were added 1.8 g of formic acid and 6.3 g of 37% formalin; the mixture was stirred at room temperature for one hour and then refluxed by heating for 5 hours. After cooling the reaction mixture, its pH was adjusted to a value of 8 by addition of a 5% aqueous solution of sodium hydrogen carbonate; the solution was then extracted with ethyl acetate. The extract was dried over potassium carbonate and the solvent was then removed. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give 5.58 g of Compound 64, mp 190° - 195° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:41])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:35][CH2:34]4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].[O:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57](O)=[O:58])[CH2:52][CH2:51]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[Si:43]([O:42][C@H:3]1[C@H:2]([NH:1][C:57](=[O:58])[CH2:56][N:53]2[CH2:54][CH2:55][O:50][CH2:51][CH2:52]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH:33]4[CH2:34][CH2:35]4)[CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:20]4=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]4[N:18]=3)[C:9]=2[Cl:41])[CH2:4]1)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CN5CCOCC5)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.6 %

Procedure:
A mixture of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171E, 40 mg, 0.057 mmol), 2-morpholinoacetic acid (9.96 mg, 0.069 mmol) and HATU (26.1 mg, 0.069 mmol) in DMF (1 mL) was stirred at room temperature for 6 h. The reaction mixture was diluted with dichloromethane and was filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-50% ethyl acetate/hexanes). (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-morpholinoacetamide (46 mg) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].[OH-].[Na+].Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][S:18]([C:15]1[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=1)(=[O:19])=[O:20]
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Reactant: Nc1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=CNc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 1.3 g (10 mmol) of 2,6-difluoroaniline in 4 ml of pyridine was added 1.94 g (9.2 mmol) of 5-formylamino-3-chlorosulfonyl-1,2,4-triazole over a period of 5 minutes. The mixture was heated with stirring to 70° C. for 4 hours. It was then cooled and dispersed between 25 ml of 1N aqueous sodium hydroxide and 50 ml of chloroform. The aqueous layer was acidified with aqueous hydrochloric acid and filtered. The solids collected were dried to obtain 167 g (60 percent of theory) of the title compound, m.p. 258°-260° C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH:26]=O.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:26][C:25]2[CH:24]=[C:23]([Cl:22])[CH:30]=[C:29]([Cl:31])[CH:28]=2)[N:13]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cc(Cl)cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 3,5-dichloro-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 119 mg of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1([CH3:21])[CH:16]=CC(S(Cl)(=O)=O)=C[CH:12]=1>CC(O)(C)C.N1C=CC=CC=1>[C:11]([O:9][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10])([CH3:21])([CH3:16])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A suspension of 5-bromopyrimidine-2-carboxylic acid (690 mg, 3.40 mmol) in 6.8 mL t-BuOH and 1.9 mL pyridine was stirred at room temperature to 50° C. for 1 hr, and cooled to room temperature. 4-Toluenesulfonyl chloride (1.55 g, 8.12 mmol) was added portion wise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 slowly, extracted with 3×Et2O, dried over Na2SO4, and concentrated. The residue was purified by Biotage column chromatography with 15-25% EtOAc in hexanes to give a yellow solid (497 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 2 H) 1.64 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (0.75 g, 4.6 mmol) in dry DMF (15.5 mL) was added tert-butyl piperazine-1-carboxylate (0.9 g, 4.85 mmol) followed by DIEA (0.91 mL, 5.5 mmol) at 0° C., and the mixture was stirred to room temperature overnight. LCMS showed the reaction was completed. The reaction was diluted with water (120 mL), and the solid was filtered. The residue was washed with water and dried to give the title compound (1.386 g, 96%) as a white solid. MS (ES+) C14H21ClN4O2 requires: 312. found: 313 [M+H]+
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[C:22]1([C:28]#[C:29][C:30]2[O:34][C:33]([C:35](ON3C(=O)CCC3=O)=[O:36])=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:35]([C:33]2[O:34][C:30]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:31][CH:32]=2)=[O:36])[CH2:7][CH2:6]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (53 mg, 0.263 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.11 mL, 0.789 mmol), and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate, prepared as described in Preparation 5 (89 mg, 0.289 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (51 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 7.57-7.53 (m, 2H), 7.44-7.40 (m, 3H), 7.16 (s, 1H), 6.84 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 2.89 (s, 2H), 2.70-2.65 (m, 2H), 2.54-2.47 (m, 2H), 2.39-2.25 (m, 5H), 1.85-1.80 (m, 2H), 1.17 (t, 3H, J=7.2 Hz); MS ESI 395.2 [M+H]+, calcd for [C23H26N2O4+H]+ 395.47.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1CCCCO1
Agent: Cl
Product: O=C(CC1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (17.1 mg, 53.5%), MS (ISP)m/z=457.5[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([OH:23])[CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:23][CH:8]([CH2:9][C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:14])[F:15])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:26])[CH3:25]
Reactant: OC(CN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(CN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 10 h
Yield: 95.1 %

Procedure:
To 36.3 g of 1-morpholino-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol was added 11.2 g of acetic anhydride. The mixture was stirred at 50° C. for 10 hours. This was followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 38.5 g of 1-morpholino-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptyl acetate (yield 95%).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH2:29][OH:30])[CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.[O:31]1CC[CH2:33][CH2:32]1>CNC>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH2:29][OH:30])[CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.[CH3:3][N:4]([CH3:5])[C:32](=[O:31])[CH3:33]
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CO)c1)CC2
Reactant: C1CCOC1
Agent: CNC
Product: CC(=O)N(C)C
Product: O=C([O-])COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CO)c1)CC2

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (2.00 g) was dissolved in a solution of 17.9 g of dimethylamine in 10 ml of tetrahydrofuran, and the solution was sealed in a tube and subjected to 36 hours of reaction at 65° C. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: chloroform/methanol=10/1) to give 1.58 g of amorphous 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate-N,N-dimethylacetamide (Compound 1).