Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH3:25][O:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:3][CH:4]=3)[C:17]=2[CH:18]=1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Reactant: CCCCC(=O)Cl
Solvent: CC#N
Product: CCCCC(=O)Nc1ccc(C2=N[C@H]3CCN(C)C[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
3 g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine and 6,2 g of valeric acid chloride are heated to the boil under reflux in 70 ml of acetonitrile for 7 hours. The reaction mixture is evaporated to dryness in a vacuum, water is added to the residue, the reaction mixture is made alkaline with potassium carbonate and extracted with methylene chloride. The solution is concentrated by evaporation, the crude product is dissolved in ethanol and a slight excess of hydrochloric acid in ethanol is added, whereby the title compound crystallizes in dihydrochloride form (melting point: 230°-235°).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])(=O)=O)=CC=1.[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:31][C:21]([F:20])([F:30])[CH2:22][CH2:23][S:24]([CH:27]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11])[C:28]#[N:29])(=[O:25])=[O:26]
Reactant: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 1.0 g of 7-octynyl p-toluenesulfonate and 0.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature. The reaction mixture was stirred at room temperature for 2 hours, at 60° C. for 2 hours, and then at 90° C. for 6 hours. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.28 g of 2-(3,3,3-trifluoropropylsulfonyl)-9-decynenitrile (hereinafter referred to as the present compound (25)).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24]Br)=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC.O1CCCC1>[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24][CH2:7][C:6]#[N:8])=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(CBr)c(Br)cc1OCc1ccccc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(CCC#N)c(Br)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of n-butyllithium (1.8 mL of a 2.5 M solution in hexane, 4.5 mmol) in 5 mL of tetrahydrofuran is added a solution of acetonitrile (1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 15 min. A solution of 5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene (0.7 g, 1.8 mmol) in 3mL of tetrahydrofuran is added and stirring is continued for 1 hour at −78° C. The reaction is quenched by the addition of 15 mL of water and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate and the organic layers combined, then dried with sodium sulfate. After reducing in vacuo, the crude product is purified by flash chromatography using a gradient of 95:5 to 4:1 hexanes/ethyl acetate as an eluent. The clean fractions are combined, reduced in vacuo and dried to yield 0.343 g of 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white solid, mp 52-53° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:7]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:35](=[O:37])[CH3:36])[CH:7]=1
Reactant: COc1ccc(OCCOC2CCCCO2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(OCCOC2CCCCO2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 84 %

Procedure:
To a solution of 5.0 g (10.7 mmol) crude 1c in 50 ml ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 1d was obtained in 84% yield (4.5 g, 8.9 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C@@H:7]([NH:12][CH3:13])[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[C@@H:7]([N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=1)[CH3:13])[CH2:8][CH:9]([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CN[C@@H](CC(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Yield: 50 %

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid tert-butyl ester (6 g, 29.8 mmol) was dissolved in THF (250 mL) and treated with diisopropylethylamine (7.8 mL, 44.7 mmol) and p-t-butyl-benzyl bromide (6.03 mL, 32.8 mL). The reaction was heated to 40° C. overnight, then filtered and concentrated. The residue was chromatographed on silica gel eluting with 5% EtOAc/hexanes to give 5.1 g (50%) of (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([O:36][CH3:37])[N:35]=2)[N:32]=1.[Cl-].[Na+]>CN(C)C=O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([O:36][CH3:37])[N:35]=4)[N:32]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1cn2nc(Cl)ccc2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn2nc(OCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
251 mg of 4-(diphenylmethyl)-1-piperazinepropanol was dissolved in 14 ml of N,N-dimethylformamide; 36 mg of a 60% sodium hydride dispersion in mineral oil was added, followed by stirring at 60° C. for 30 minutes. After cooling, 149 mg of 6-chloro-2-methoxyimidazo[1,2-b]pyridazine was added, followed by stirring at 90° C. for 4.5 hours. After cooling, ice water and sodium chloride were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:2); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected; the crystal precipitated was recrystallized from ethyl acetate to yield 99 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: Nc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 34.3 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 5-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 78 mg of the target compound.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:5][N:6]=1.[N+]([O-])(O)=O.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>P(=O)(O)(O)O.O.Cl>[S:3]1[C:4]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:5][N:6]=[CH:2]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1cnc(N)s1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)CCC(Cc1cncs1)C2
Temperature: -8 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
2.1 g of ethyl 6-(2-amino-5-thiazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was dissolved in 23 ml of phosphoric acid and 12 ml of concentrated nitric acid was added thereto. - A solution of 0.46 g of sodium nitrite in 4 ml of water was added dropwise to the mixture. The resulting mixture was stirred at -8° C. for 20 minutes. The reaction mixture was added to a solution of 5.28 g of cuprous chloride in 7 ml of concentrated hydrochloric acid at -5° C. The resulting mixture was stirred at -8° l to 0° C. for 1.5 hours and 100 ml of an ice-cold water was added thereto. The mixture was neutralized by adding sodium carbonate and the resulting mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo. The residue was dissolved in 15 ml of acetic acid and 14.4 g of zinc powder was added portionwise thereto under heating. The mixture was heated under reflux for 2 hours. After cooling, the insoluble material was removed by filtration. The filtrate was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with water, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of methanol and chloroform (2:98 by volume) for elution to give 1.27 g of ethyl 6-(5-thiazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [C:1]([CH:3]([N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:19]([O:21]CC)=O)[CH3:4])#[N:2].[BH4-].[Na+]>CO.C1COCC1>[CH3:4][CH:3]1[N:5]2[C:9]3[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:13][C:8]=3[CH:7]=[C:6]2[C:19](=[O:21])[NH:2][CH2:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc2cc3n(c2n1)C(C)CNC3=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a solution of diethyl 1-(1-cyanoethyl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (807 mg, 2.56 mmol) in methanol/THF (14 mL, 1:1 v/v) at 0° C. is added sodium borohydride (968 mg, 25.6 mmol). The cold bath is removed and the reaction mixture is stirred for 30 min, at which point the reaction vessel is sealed and warmed to 60° C. After being stirred for 4 h, the mixture is cooled to room temperature and diluted with EtOAc. The organic phase is washed twice with 1Ma aqueous NaHSO4 and once with brine, is dried (Na2SO4), filtered and concentrated to provide the title compound as a light yellow solid (298 mg, 43%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (640 mg, yield: 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: O1C=CC(C2C3C(=NC=C(N)C=3)NC=2)=C1.C([N:35]1[CH:39]=[C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[N:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[NH:35]1[CH:39]=[C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[CH:47]=3)[NH:42][CH:41]=2)[CH:37]=[N:36]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]cc(-c3cnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3)c2c1
Agent: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1cnc2[nH]cc(-c3cn[nH]c3)c2c1
Yield: 14.3 %

Procedure:
Inhibitor 52 was synthesized following the method described for preparation of 48 using 51 (326 mg, 0.60 mmol). The crude reaction mixture was neutralised with saturated aqueous NaHCO3 and extracted with AcOEt. Combined organic extracts were dried (MgSO4), concentrated and purified by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 52 (25.62 mg, 14%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 1.54 (s, 9H), 7.54 (s, 1H), 7.93 (s, 2H) 8.18 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H); MS (ES) m/z 341 (MH++MeCN).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[O:22]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[CH:30]=2)[O:25][CH2:24][CH2:23]1
Reactant: O=Cc1cnc2c(c1)OCCO2
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.9 %

Procedure:
To a solution 211 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one and 120 mg of 2,3-dihydro(1,4)dioxino(2,3-b)pyridine-7-carbaldehyde in 22 mL of chloroform, 88 mg of acetic acid was added, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture, 232 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 2 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=10:1 to obtain 185 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[S:30](N)([NH2:33])(=[O:32])=[O:31]>O1CCOCC1>[NH2:33][S:30]([N:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:3]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: NS(N)(=O)=O
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CN(S(N)(=O)=O)C1

Procedure:
A solution of tert-butyl azetidin-3-ylcarbamate hydrochloride (prepared according to J. Antibiot. 1986, 39, 1243-1256, 0.755 g), Proton-Sponge® (0.85 g) and sulfamide (0.42 g) in dioxane (23 ml) was heated at reflux for 48 h. The residue was partitioned between H2O and EtOAc, and the aqueous layer then extracted with further EtOAc (×4). The combined organic extracts were washed quickly with 2M aqueous hydrochloric acid (×3) then with saturated aqueous sodium bicarbonate, H2O and saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to afford the subtitle compound as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:21]([F:24])([F:23])[F:22])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:21]([F:24])([F:23])[F:22])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSc1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
After adding 1.44 g of toluene to 0.48 g (1.17 mmol) of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-(methylthio)phenyl) butan-1-one, 0.28 g (2.34 mmol) of thionyl chloride and 0.19 g (2.34 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction was traced by high-performance liquid chromatography. Since the raw materials did not disappear, 0.14 g (1.17 mmol) of thionyl chloride and 0.09 g (1.17 mmol) of pyridine were added and stirred for 1 hour. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.14 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 0.37 g of 3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-(4-(methylthio)phenyl)-2-buten-1-one (yield 81.8%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8](O)=[O:9])C(=O)C2=CC=CC=C12.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:32]([O:39][NH:40][CH2:41][CH2:42][N:43]1C(=O)C2=CC=CC=C2C1=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][N:40]([CH2:41][CH2:42][NH2:43])[C:8](=[O:9])[CH2:7][CH2:6][NH2:5])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1c2ccccc2C(=O)N1CCNOCc1ccccc1
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NCCC(=O)N(CCN)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
3-Phtalimido-propanoic acid (IV.1) (0.74 g, 3.375 mmol) was dissolved in tetrahydrofuran (15 ml, dried over potassium and distilled) under nitrogen, Triethylamine (0.494 ml, 3.54 mmol, 5% excess) was added to this solution and the mixture was cooled to -15° C. iso-Butyl chloroformate (0.46 ml, 3.54 mmol in 5 ml dry tetrahydrofuran) was added dropwise while maintaining the temperature at -15° C. After 15 minutes, N-benzyloxy-2-phtalimidoethylamine (IV.5) (1 g, 3.375 mmol in 10 ml dry tetrahydrofuran) was added dropwise at -15° C. and under nitrogen. The mixture was stirred during 3 hours at -15° C. and at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate (25 ml). The solution was extracted with water (25 ml), saturated sodium carbonate (25 ml), water (25 ml), 1M hydrochloric acid (25 ml), water (25 ml) and brine (25 ml). The organic solution was dried over magnesium sulfate, filtered and evaporated. The remaining white residue was recrystallized in hexane/ethyl acetate. The title compound was isolated as white crystals that were dried under vacuum. Yield: 53%
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with 2-piperazinone (Alfa) to give the title compound. HR-MS (ES, m/z) calculated for C33H38Cl2N5O3 [(M+H)+] 622.2346, observed 622.2341.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][Cl:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOCC.O>[C:1]([N:8]([CH2:9][CH2:10][CH2:11][Cl:12])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CCCCl)Cc1ccccc1
Reaction time: 0.33 h
Yield: 13.4 %

Procedure:
To a solution of N-Boc-3-chloropropylamine (10.0 g, 51.8 mmol) in THF was added sodium hydride (1.87 g, 78 mmol). After 20 min, benzyl bromide (9.24 mL, 78 mmol) was added and the reaction mixture was heated at reflux for 16 h. After cooling, the reaction mixture was diluted with Et2O (150 mL) and H2O (50 mL), the layers were separated and the aqueous layer was extracted twice with Et2O. The combined organic phases were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The resulting yellow oil was purified by flash chromatography (SiO2, 10% EtOAc-hexane) to give N-Boc-N-benzyl-3-chloropropylamine (1.97 g, 13% yield) as a pale yellow oil.