Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH:18](Br)[C:17]=1O)=[O:15])[CH3:12]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:13][C:14]([CH:16]1[C:17]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:3][CH2:2][F:1])[C:18]=2[CH2:19][CH2:20][CH2:21]1)=[O:15])[CH3:12]
Reactant: FCCNc1ccccc1
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of (2-fluoro-ethyl)-phenyl-amine (24; prepared according to Example 4(a)) (560 mg, 4.0 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (29) (500 mg, 2.0 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (4 mL) and dry zinc chloride (820 mg, 6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The product was dissolved in ethyl acetate/ether (30 mL/150 mL) and washed with 2 N HCl (40 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated to afford 447 mg (91%) of 9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (30) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.3, 20.4, 21.7, 26.4, 38.5, 43.1 (d, JCF=15 Hz), 60.6, 76.6, 77.0, 77.4, 82.1 (d, JCF=173 Hz), 106.9, 108.5, 118.9, 119.4, 121.1, 127.1, 136.2, 136.7, 174.9.
Reaction SMILES: [Cl-].[NH+]1C=CC=CC=1.C[O:9][C:10]1[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][CH:13]=[CH:14][CH:15]=1>Cl>[C:17]1([NH:16][C:11]2[C:10]([OH:9])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccnc1Nc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: Oc1cccnc1Nc1ccccc1
Temperature: 200 °C

Procedure:
1 L 3-neck flask is charged with Pyridinium chloride (52.2 g, 452 mmol) and 3-methoxy-N-phenylpyridine-2-amine (9 g, 45.2 mmol). The reaction mixture is heated to 200° C. for 4 h. The reaction mixture is dumped into 5% HCl (200 mL), and extracted with 3×300 mL ETOAC. The organic portion is combined and purified by column chromatography (100% DCM) to yield the desired product.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:17](=[O:19])[CH3:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4]([C:17](=[O:19])[CH3:18])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 1-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Intermediate 3, 10.7 g, 41.2 mmol) in CH2Cl2 (500 mL) at 0° C. was added BBr3 (49.5 mL, 1.0 M in CH2Cl2) via syringe pump over 10 min. The mixture was stirred at 0° C. for 2 h and was quenched with ice-H2O and extracted with Et2O (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (CH2Cl2) to give the title compound as a brown solid (7.6 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.CC1(C)C(C)(C)OB([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[C:28](OC)=[O:29])O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[C:28](=[O:29])[NH:8]2
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C(=O)OC)c1
Reactant: Nc1nccc(Cl)c1I
Product: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Cl)c12
Yield: 48.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (510 mg, 2.0 mmol) and dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalate (705 mg, 2.2 mmol) to provide 266 (280 mg, 48% yield) as a white solid. LC-MS (M+H=289, obsd.=289).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[S:16]([N:19]2[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34]>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[S:16]([N:19]2[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11]([NH:32][C@H:33]([CH3:34])[CH2:35][OH:36])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCC1
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 32 step ii) by reacting the subtitle product of step ii) (12.2 g) with (R)-alaninol (18 ml). Yield: 11.3 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=1[CH2:20][CH:21]([CH3:23])[CH3:22].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2CC(C)C)c1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a stirred solution of T23.5 (0.293 g, 0.9 mmol) in THF (5 mL, 0.9 mmol) at 0° C. was added LAH in THF (2 mL, 2 mmol, 1.0M). The reaction was stirred for one hour and then 1N NaOH(aq) was added to quench the mixture. The reaction was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-20% EtOAc in hexanes) to yield T23.6 as a colorless oil (0.260 g, 97% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1>[I:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: FC(F)(F)c1cc(I)ccc1CBr
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(I)cc2C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28)(0.72 g, 3.38 mmol) in THF (20 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (3.5 ml, 3.50 mmol, Aldrich). The slight suspension was stirred for 30 min. To the yellow solution was added a solution of 1-(bromomethyl)-4-iodo-2-(trifluoromethyl)benzene (for a preparation see within Example 73)(1.24 g, 3.40 mmol) in THF (10 ml). The resulting yellow solution was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo and the residue partitioned between DCM (100 ml) and water (100 ml). To aid the separation, brine (50 ml) and dilute hydrochloric acid (25 ml) were added. The phases were separated and the aqueous phase washed with dichloromethane (50 ml). The organic phases were combined, dried (MgSO4), filtered and the solvent removed in vacuo to leave 2-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione as an orange solid (1.7 g).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)C(F)(F)F)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[NH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Product: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[2-Acetylthiomethyl-5-(trifluoroacetylamino)pentanoyl]-L-proline (1 g.) is dissolved in concentrated ammonia (20 ml.) under a blanket of argon and the solution is kept at room temperature for one hour. The excess ammonia is removed in vacuo and the residue is applied to a column of Dowex 50 in the hydrogen cycle. The column is washed with water and the 1-(5-amino-2-mercaptomethylpentanoyl)-L-proline is eluted with a 2 M buffer of pyridine-acetic acid at pH 6.5. Rf =0.5 [CHCl3, MeOH, 38% AcOH (3:2:1)].
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[F:3][CH:4]([F:7])[CH2:5][O:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC(F)F
Reactant: Brc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under N2, 60% NaH (10.2 g, 254.27 mmol) and 40 mL DMF were added into a 500 mL reaction flask and cooled to 0° C. 2,2-difluoroethanol 12a (23 g, 280.3 mmol) was dissolved in 40 mL DMF and then dropwise added into the mixture within 4 hours at 0° C. The reaction mixture was then warmed to room temperature. After 30 minutes, a solution of bromobenzene (39.92 g, 254.25 mmol) in DMF (40 mL) and CuBr (0.35 g, 2.43 mmol) were added in turn before the reaction mixture was warmed and stirred for 16 hours at 160° C. Thereafter, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with n-hexane. 5% hydrochloric acid (160 mL) was added to the filtrate before the resulting residue was extracted with n-hexane (160 mL×3). The organic extract was washed with saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2,2-difluoroethoxybenzene 12c (32.97 g, yellow liquid), yield: 82.0%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (77 mg, 81%), MS (ISP) m/z=361.4 [(M+H)+], mp 276° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)O.CCOC(C)=O>CCOCC>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(C(O)c2ccccc2Br)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cccc(Cc2ccccc2Br)c1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
LiAlH4 (0.154 g, 4.06 mmol) was suspended in anhydrous Et2O (10 mL) under a N2 atmosphere and cooled (0° C.) with stirring. Anhydrous AlCl3 (1.08 g, 8.14 mmol)was dissolved in ice-cold anhydrous Et2O (20 mL) and added dropwise to the LiAlH4 suspension. After complete addition the suspension was stirred at the same temperature (20 min.). (2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13] (0.68 g, 2.32 mmol) was dissolved in anhydrous Et2O (10 mL) and added dropwise via syringe to the suspension. After complete addition the reaction mixture was heated at reflux (4 h), cooled (0° C.) and EtOAc was added dropwise to destroy the excess of the reagent and the mixture was added to 20% aq. H2SO4 (50 mL). Et2O (50 mL) was added and extracted. The Et2O layer was separated, washed with water, brine, dried (MgSO4) and evaporated to give a reddish yellow oil. The oil was purified by mplc using pet. ether-CH2Cl2 (9:1) as eluent to give 0.485 g (75%) of the pure product as a colorless oil. 1H NMR (CDCl3)d: 3.81 (s, 3H, CH3), 4.14 (s, 2H, CH2), 6.79-7.62 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 42.34, 55.69, 112.07, 122.02, 125.48, 128.07, 128.50, 130.02, 131.66, 133.43.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([CH3:26])[NH:6][C:7](=[O:25])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:24])[C@H:14]([CH3:23])[NH:15]C(OC(C)(C)C)=O)[CH3:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[N:5]([CH3:26])[NH:6][C:7](=[O:25])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:24])[C@H:14]([CH3:23])[NH2:15])[CH3:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the t-butoxycarbonylalanylprolyl-2-azaalanine ethyl ester obtained above is added 15 ml of methylene chloride. The reaction mixture is cooled to 0° and 15 ml of trifluoroacetic acid added. After stirring for 1 hour at 0° and 1 hour at room temperature, the reaction mixture is concentrated in vacuo to yield alanylprolyl-2-azaalanine ethyl ester as its trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:69])/[CH:4]=[CH:5]/[C:6]1[CH:68]=[CH:67][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:66])[C:21]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-])=O)=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][CH:48]=2)[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=2)=[O:23])=[O:11])=[CH:8][CH:7]=1>CN(C)C=O.O.[Zn]>[CH3:1][O:2][C:3](=[O:69])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:66])[C:21]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=2)=[O:23])=[O:11])=[CH:67][CH:68]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)OCCCCCCOC(=O)c2ccc(/C=C/C(=O)OC)cc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc(N)cc2)(Cc2ccc(N)cc2)C(=O)OCCCCCCOC(=O)c2ccc(/C=C/C(=O)OC)cc2)cc1
Yield: 64.4 %

Procedure:
1.30 g (1.36 mmol) bis[6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)-hexyl]2,2 bis(4-nitrobenzyl)malonate were dissolved in a mixture of 25 ml N,N-dimethylformamide and 2.8 ml water. 2.21 g (8.18 mmol) ferric chloride hexahydrate and 0.716 g (10.95 mmol) Zinc powder were added, the temperature rise to 40° C. The mixture was allowed to react for 1 hours. The black reaction mixture was then partitioned between ethyl acetate and water and filtered. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. A first chromatography on 50 g silica gel using tert-butyl methyl ether as eluant and a second chromatography on 25 g silica gel using toluene: ethyl acetate (9:1) then (4:1) as eluant yielded 0.78 g (64%) of bis[6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl]2,2 bis(4-aminobenzyl)malonate as a yellow powder.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:17])[C:8]([CH:10]1[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:17])[CH3:5]
Reactant: CCOC(=O)C(=O)C1CCC(C)C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCC2C
Yield: 50.3 %

Procedure:
Hydrazine hydrate (0.101 mL, 2.05 mmol) was added to a stirring room temperature solution of 4 (0.4055 g, 2.05 mmol) in EtOH (2.0 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes: 2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.2003 g (50.4%) of 5. 1H (CDCl3, 400 MHz): δ 9.55 (1H, broad s), 4.35 (2H, q, J=7.1 Hz), 3.26-3.16 (1H, m), 2.89-2.63 (3H, m), 2.09-1.98 (1H, m), 1.37 (3H, t, J=7.2 Hz), 1.30 (3H, d, J=6.9 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 128.67, 61.32, 39.73, 32.64, 22.94, 19.62, 14.52 ppm. HPLC: 8.901 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:7][CH:4]1[CH2:5][CH2:6][CH:2]([CH3:1])[N:3]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([OH:26])=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4C(C)CCC4C)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C)N1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of methyl 3-(8-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (150 mg, 0.34 mmol) and NaOH (150 mg, 3.75 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 40° C. Then the mixture was concentrated to 5 mL then adjusted to pH=2 with 2M HCl. The precipitate was filtered and the solid was washed with water (2 mL) and dichloromethane (3 mL) to give 3-(8-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (86 mg, 59%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.79 (s, 1H), 9.13 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.32-8.14 (m, 3H), 7.75 (t, 1H, J=7.8 Hz), 7.54 (t, 1H, J=8.1 Hz), 6.74 (d, 1H, J=7.8 Hz), 6.23 (d, 1H, J=8.7 Hz), 4.12 (s, 2H), 2.13-2.08 (m, 2H), 1.74-1.68 (m, 2H), 1.18 (s, 3H), 1.16 (s, 3H). LC-MS: [M+H]+, 429, tR=1.708 min, HPLC: 97.23% at 214 nm, 95.49% at 254 nm, tR=6.248 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:7]([C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
m-Nitroaniline (10 mmol, 1.4 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 143° C.-145° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)cc1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)cc2)CC1

Procedure:
2-(4-{4-[8-(4-Fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.092 g, 0.240 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.037 mL, 0.360 mmol) in a manner analogous to Example 313 to give product (0.035 g, 31%). MP=209-212° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.79 (d, 1H), 8.22 (m, 2H), 7.82 (d, 1H), 7.60 (d, 2H), 7.35 (m, 2H), 7.12 (m, 3H), 3.13 (s, 2H), 3.05 (s, 3H), 2.92 (m, 2H), 2.82 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.64-1.70 (br m, 4H). MS=473 (MH)+.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10].[Na+].CN(C=O)C>C(Cl)Cl>[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([Cl:3])(=[O:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CN(C)CCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCS(=O)(=O)Cl

Procedure:
Phosgene (12 ml, 1M in toluene) was added to a solution of the subtitle product of step i) in DCM (20 ml) and DMF (2.5 ml) and stirred for 3 h before concentrating in vacuo to afford the subtitle compound as an oil that was used directly in the next step. 1H NMR δ(CD3OD) 3.30 (2H, m), 2.80 (2H, m) and 2.31 (6H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=O)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1ccc2c(c1)CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)CCC(N1CCCC1)=C2
Yield: 100.9 %

Procedure:
To a stirred solution of 6-t-butyl-2-tetralone (5.74 g; 28.37 mmol) in 100 ml of toluene was added 1.5 equiv. of pyrrolidine (3.56 ml; 42.56 mmol). A 100 mg portion of p-toluenesulfonic acid was added and the mixture was refluxed. The water eliminated during the reaction was collected by a Dean Stark trap. After a reflux time of 3.5 hours, concentration of the volatiles under vacuum afforded 7.31 g of the subtitle compound as a purple solid.