Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(N(CC)CC)C.S(F)(O[C:13]([F:20])([F:19])[C:14]([F:18])=[C:15]([F:17])[F:16])(=O)=O>COCCOCCOC>[F:19][C:13]([Cl:1])([F:20])[C:14]([F:18])=[C:15]([F:17])[F:16]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: FC(F)=C(F)C(F)(F)Cl
Temperature: 0 °C
Yield: 93 %

Procedure:
A 300-mL four-neck flask provided with a Dimroth condenser, a dropping funnel, and a thermometer was charged with triethylamine hydrochloride (97 g, 703 mmol) and 50 mL of diglyme, and the mixture was stirred by a magnetic stirrer. The Dimroth condenser was cooled using a −20° C. refrigerant, and the reaction flask was cooled to 0° C. in an ice bath. With the dropping funnel, perfluoroallyl fluorosulfate (135 g, 586 mmol) was dropped over about one hour in such a manner that the temperature in the flask was maintained at 10° C. or lower. After the dropping, the mixture was stirred for one hour. The Dimroth condenser was replaced by a Liebig distillation apparatus. The flask was allowed to reach room temperature (25° C.), and the resulting product (having a boiling point of 12° C.) was distilled. An amount of 100 mL of water was added to the flask to terminate the reaction. As a result, 90.7 g of the target perfluoroallyl chloride (purity: 99 GC %) was obtained as a distilled component (yield: 93%). The distillation residue was determined by NMR analysis to include carboxylic acids and ammonium fluorosulfate which were probably generated from hydrolysis of unreacted perfluoroallyl fluorosulfate in terminating the reaction, and an excess amount of triethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: Nc1ccc(C(=O)O)cn1
Product: CN1CCN(C(=O)c2ccc(N)nc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 6-amino-nicotinic acid and 1-methylpiperazine. The reaction mixture was stirred overnight at 0° C. DCM was used for dilution and extraction instead of EtOAc. The dried organic phase was concentrated to afford an impure sample of the title compound which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH:16]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[C:17]([O-:19])=[O:18].[NH4+]>>[C:1]([O:18][C:17](=[O:19])[CH:16]([NH2:15])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[NH:25])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N=C(N)NCCCC(N)C(=O)[O-]
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [NH4+]
Product: CCCCCCCCCCCC(=O)OC(=O)C(N)CCCNC(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31 g (70 mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 16.06 g (84 mmol) of ammonium 2-amino-5-guanidinopentanoate. The round bottomed flask is placed in an ice bath and the dodecanoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-5-guanidinopentanoic dodecanoic anhydride.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([OH:36])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH3:37])[CH2:11][C@H:12]([NH:26][C:27]([C:29]1[O:30][CH:31]=[C:32]([O:36][CH3:39])[C:33](=[O:35])[CH:34]=1)=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(=O)c(O)co1)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1coc(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C[C@@H](C)C(=O)OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester (54 mg, 0.106 mmol) in DMF (1 mL) is added K2CO3 (29.2 mg, 0.211 mmol) and MeI (16.5 mg, 0.116 mmol), and the resulting mixture is stirred at room temperature overnight. Then ice/water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to give (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester which is used without further purification. HPLC Retention time 1.55 minutes (condition C): MS 526.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)COCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with benzyloxy acetyl chloride.
Reaction SMILES: [CH:1]1([C:6]#[C:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC#CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)=C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 73.1 %

Procedure:
To a suspension of 3-cyclopentylprop-2-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was added 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This mixture was stirred at room temperature for 50 minutes. The reaction mixture was partitioned between ethyl acetate and dilute HCl. The aqueous portion was separated and extracted with ethyl acetate. The combined organic extracts were washed with dilute HCl and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl acetate/hexanes) to yield the desired product (540 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[CH:15]=[CH:16]3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 6).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH3:33][CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=O.O>C1COCC1>[CH3:35][CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:33]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC(C)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A suspension of benzyltriphenylphosphonium bromide (3.20 g, 7.38 mmol, 1.0 equiv.) in THF (14 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 4.6 mL, 7.38 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (2.04 g, 11.1 mmol, 1.5 equiv.) in THF (5 mL) was added, and the mixture was stirred at 65° C. for 18 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane) to yield 1.45 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([C:9]#[C:10]C(O)C)(C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O1CCOC[CH2:17]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:9]#[CH:10])[CH:5]=[C:4]([CH3:17])[N:3]=1
Reactant: CC(O)C#CC1(C)C=CN=C(N)N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cc(C)nc(N)n1

Procedure:
A mixture of 4.44 g of 4-(2-amino-4-methylpyrimidin-4-yl)-3-butyne-2-ol, 1 g of sodium hydroxide, 5 ml of dioxan and 50 ml of toluene was refluxed for two hours. The toluene layer was decanted from the residue, concentrated under reduced pressure and chromatographed on a silica gel dry column. The product band eluted with (2:3:0.5) ethyl acetate/dichloromethane/THF. Extraction with THF and concentration of the solvent gave 0.75 g of the title compound as a solid, 129°-130° dec.; IR(nujol) 2119 (w, C≡C) cm-1 ; PMR(60 MHz, CDCl3) δ2, 3(s, CH3, 3H), 3.1(s, C≡CH, 1H), 5.3-5.6(bs, NH2, 2H), 6.6(s, Het-H, 1H).
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:7])=[O:5].[ClH:19].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:32][C:31]=3[F:54])=[C:23]2[CH:22]=[CH:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CC(N(C)C)=O>[ClH:19].[ClH:19].[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][C:28]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:2]4[N:18]=[CH:17][CH:16]=[CH:15][C:3]=4[C:4]([N:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[CH3:7])=[O:5])=[CH:32][C:31]=3[F:54])=[C:23]2[CH:22]=[CH:21]1
Reactant: CN(C(=O)c1cccnc1F)c1ccc(F)cc1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)c1ccc(F)cc1
Temperature: 160 °C
Yield: 10.1 %

Procedure:
A mixture of 2-fluoro-N-(4-fluorophenyl)-N-methylnicotinamide (50 mg, 0.2 mmol) and 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoroaniline (122 mg, 0.5 mmol, Compound C of Example 1) in DMA (0.8 mL) was heated in a microwave at 160° C. for 20 min. The product was purified by preparative (RP) HPLC to afford the title compound as a beige solid (11 mg, 11% yield)—dihydrochloride salt. 1H NMR (CD3OD) δ 8.56 (d, 1H, J=3.5 Hz), 8.23 (dd, 1H, J=7.6, 1.0 Hz), 8.19 (d, 1H, J=7.1 Hz), 7.58 (m, 3H), 7.32 (dd, 1H, J=11.2, 2.5 Hz), 7.22 (d, 1H, J=8.6 Hz), 7.04 (d, 1H, J=4.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.47 (m, 4H), 3.27 (s. 3H). MS(ESI+) m/z 472 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][F:10].C([Li])CCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]=[O:20])=[C:3]([CH2:9][F:10])[CH:4]=1
Reactant: FCc1cc(Cl)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(Cl)cc1CF
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 1-bromo-4-chloro-2-(fluoromethyl)benzene (0.5 g, 2.2 mmol) in anhydrous THF (20 mL) was added a solution of n-butyl lithium (1.0 mL, 2.5 M in hexanes, 2.5 mmol) in anhydrous THF (10 mL), at about −75° C. The resulting mixture was stirred for about 30 min at about −75° C. and then DMF (0.34 mL, 4.5 mmol) was added slowly. Over about 1 h the mixture was warmed to about −55° C. and then saturated aqueous ammonium chloride (10 mL) was added followed by diethyl ether (50 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:3) to give 4-chloro-2-(fluoromethyl)benzaldehyde (0.15 g, 0.87 mmol, 39%) as a white solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 5.85 (2 H, d, J=47.8 Hz) 7.52 (1 H, dd, J=8.2, 2.0 Hz) 7.72 (1 H, br s) 7.80 (1 H, dd, J=8.2, 1.4 Hz) 10.04 (1 H, d, J=1.4 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C(C)=CC=CC=1C>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 60, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 85.8%) was a white foam: [α]23589=−21.43° (c=0.35, chloroform); EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307, found 529.0314.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
235 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 74 mg of 2-aminopyrazine, 68 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 95 mg of sodium t-butoxide and 37 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 204 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was dissolved in ethanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as pale yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39]Br)=[CH:34][C:33]=1[O:41][CH3:42])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=4[CH2:10][CH2:9]3)[CH2:2]2)=[CH:34][C:33]=1[O:41][CH3:42])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(CCBr)ccc1OCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(OCc4ccccc4)c(OC)c3)C1)CC2

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(4-benzyloxy-3-methoxy-phenyl)-ethylbromide analogously to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH3:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:17])[CH:13]=[C:14]([NH2:22])[CH3:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc([C@H](C)NC(=O)CC(C)=O)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc([C@H](C)NC(=O)C=C(C)N)cc1
Temperature: 100 °C

Procedure:
To a suspension of (S)—N-[1-(4-methoxy-phenyl)-ethyl]-3-oxo-butyramide (10 g) in toluene (800 ml) was added at 20° C. ammonium acetate (10 g) and the reaction was heated for 20 h at 100° C. in a Dean Stark system. The mixture was concentrated in vacuo and the product obtained was used without further purification in the following reaction step.
Reaction SMILES: Br[CH:2]([CH:18]([CH3:20])[CH3:19])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:27]1([C:33]2[N:34]=[N:35][NH:36][N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH:2]([N:35]3[N:36]=[N:37][C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:34]3)[CH:18]([CH3:20])[CH3:19])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: CC(C)C(Br)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C(C(=O)N1CCC(c2ccc(Cl)cc2)CC1)n1nnc(-c2ccccc2)n1
Temperature: 170 °C
Yield: 21.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one (40 mg, 0.11 mmol), K2CO3 (50 mg, 0.36 mmol) and 5-phenyl-2H-tetrazole (15 mg, 0.1 mmol) in CH3CN (1 mL) was heated at 170° C. for 30 min in a microwave reactor. After this time, the reaction was filtered through a plug of celite, diluted with MeOH and purified directly by preparative HPLC to give 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(5-phenyl-2H-tetrazol-2-yl)butan-1-one (9 mg, 21%) as a solid. MS found: 424 (M+H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:41]>>[OH:41][CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:39][NH:38][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: NCC(O)c1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCC(O)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and (±)-2-amino-1-phenylethanol. Purification was performed using HPLC with a normal phase column. Elution with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) gave the title compound in 77% yield, m.p. 214-215° C. MS [(+)ESI, m/z]: 572 [M+H]+
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21]C(=O)OC(C)(C)C)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[NH2:21][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][N:10]([CH3:20])[C:11](=[O:12])[O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
(S)-tert-butyl 1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (5.78 g, 0.014 mol) was dissolved into a minimal volume of ethyl ether (100 mL) and added to a solution of TsOH (2.92 g, 0.0154 mol) in 20.0 mL of absolute EtOH. This solution was placed on a rotary evaporator and the Et2O was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective de-protection of the BOC group proceeded concurrently with removal of the remainder of the solvent. The reaction was completed by 2 h and gave an off-white solid, which was washed with hexanes:EtOAc (5:1, v/v, 3×10 mL), basified with 1N NaOH (pH>10), and extracted with ethyl ether (3×50 mL). The combined organic extracts were washed with 1N NaOH (3×5 mL) and brine (3×5 mL), dried, decanted and stripped to give the free base of (S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (3.5 g, 80%). 1H NMR (400 MHz, CDCl3): 4.15 (t, J=8.4 Hz, 2H), 3.10 (m, 3H), 2.91 (s, 3H), 1.78-1.56 (m, 5H), 1.50-1.00 (M, 6H), 1.00-0.70 (m, 4H), 0.01 (s, 9H). MS (E/Z): 315 (M+H+).