Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]>ClCCl>[CH2:9]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH3:10]
Reactant: COC(=O)CC(=O)Cl
Reactant: CCNc1ccccc1
Solvent: ClCCl
Product: CCN(C(=O)CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Dichloromethane was added to a dry round bottom flask at 20-25° C. under nitrogen atmosphere. Methyl 3-chloro-3-oxo-propanoate (2.59 ml, 24.15 mmol) was added, followed by N-ethylaniline (2.97 ml 24.13 mmol), and the solution was stirred at r.t. for 14 h, then the solvent was removed under reduced pressure to obtain a yellowish oil. Yield: 100%. Te purity of the isolated product: 98% (HPLC, area %).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=3)[N:20]=1)[CH:12]2[OH:30].N1C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=3)[N:20]=1)[CH:12]2[O:30][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: CCCCN=C=O
Reactant: O=C1c2ccc(Cl)cc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2cc(Cl)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.67 h

Procedure:
n-Butyl isocyanate (11.2 cc.) is added over the course of 15 minutes to a suspension of 5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.5 g.) in acetonitrile (350 cc.) and triethylamine (0.2 cc.) heated at the reflux temperature. Pyridine (10 cc.) and triethylamine (5 cc.) are added and refluxing is continued for a further 40 minutes. After filtering hot and then cooling, the precipitate formed is filtered off and recrystallised from acetonitrile (250 cc.) to give 5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-n-butylaminocarbonyloxy-isoindolin-1-one (3.3 g.) melting at 228°-230° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:23]I>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:23])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: CI
Reactant: O=S(=O)(NCCCCCO)c1ccc(-c2ccccc2)cc1
Product: CN(CCCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(5-hydroxypentyl)-amide and methyl iodide, the title compound was obtained. δC (CDCl3, 62.9 MHz): 22.7, 27.4, 32.2, 34.7, 50.0, 62.7, 127.4, 127.9, 128.5, 129.1, 136.0, 139.3 and 145.4.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C.[I-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: C#Cc1ccc(N)c(C#N)c1C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Yield: 72.7 %

Procedure:
A solution of 3.5 grams (0.022 mole) of 2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(l) iodide in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture was filtered to remove a solid. The aqueous layer and the organic layer were separated, and the aqueous layer was washed with ethyl acetate. The ethyl acetate wash was combined with the organic layer, and the combination was washed with an aqueous solution of 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with methylene chloride and filtered. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile, mp 136°-138° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14].[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:15])[CH2:13][CH3:14])(=[O:18])[CH3:17]
Reactant: CCC(=O)c1[nH]c2cc(Cl)ccc2c1N
Reactant: CC(=O)Cl
Product: CCC(=O)c1[nH]c2cc(Cl)ccc2c1NC(C)=O

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-propionylindole (Example 87) and acetyl chloride. m.p.: >270° C. 1H-NMR (DMSO-d6) δ: 11.72 (1H, br s), 9.93 (1H, br s), 7.59 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.07 (1H, d, J=8.4 Hz), 2.94 (2H, q, J=7.0 Hz), 2.15 (3H, s), 1.09 (3H, t, J=7.0 Hz)
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:24]([NH:26][C:27](=[O:45])[NH:28][C:29]1[CH:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32]([C:33]([OH:35])=O)=[CH:31]N=1)[CH3:25].C(NC(=O)NC1C=C(NCC2C=NC=CC=2)C(C(O)=O)=CN=1)C.[Cl:69][C:70]1[CH:71]=[C:72]([CH:74]=[CH:75][CH:76]=1)[NH2:73]>CN(C=O)C>[Cl:69][C:70]1[CH:71]=[C:72]([NH:73][C:33](=[O:35])[C:32]2[CH:31]=[CH:2][C:29]([NH:28][C:27]([NH:26][CH2:24][CH3:25])=[O:45])=[CH:37][C:36]=2[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:74]=[CH:75][CH:76]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cccc(Cl)c1
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: CCNC(=O)Nc1cc(NCc2cccnc2)c(C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1ccc(C(=O)Nc2cccc(Cl)c2)c(Nc2ccccc2)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.092 g, 0.480 mmol) and 1-hydroxybenzotriazole monohydrate (0.073 g, 0.480 mmol) were added to a stirred solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid, vi (0.100 g, 0.320 mmol) in DMF (3 mL) at room temperature. After 15 min, 3-chloroaniline (0.061 g, 0.480 mmol) was added and the reaction mixture stirred at 40° C. for 24 h. The mixture was cooled to room temperature, poured onto water and extracted with EtOAc (3×30 mL). The combined organic phase was washed successively with water (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (2×20 mL), dried (MgSO4), and reduced in vacuo to give the crude product. This was triturated with EtOAc to afford Compound 4 (0.021 g, 0.051 mmol, 16%) as a colourless powder. 1H NMR (300 MHz, DMSO-d6): δ 10.44 (1H, s), 9.83 (1H, s), 9.16 (1H, s), 8.58 (1H, s), 7.96-7.90 (2H, m), 7.63 (1H, d, J 8.2), 7.45-7.36 (3H, m), 7.32-7.27 (3H, m), 7.20-7.13 (2H, m), 3.15 (2H, dq, J 7.2 and 6.1), 1.07 (311, t, J 7.2); [M+H]+ m/z=410.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]1[O:34]C(C)(C)[O:32][C:31](=O)[CH:30]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH:21][C:31](=[O:32])[CH2:30][C:29]([C:25]1[S:26][CH:27]=[CH:28][C:24]=1[Cl:23])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Product: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2sccc2Cl)c1

Procedure:
Prepared from (3-amino-2′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G23) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) according to the general procedure K. Obtained as a viscous brown oil (154 mg).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31](ON1C(=O)CCC1=O)([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32]>CN(C=O)C>[C:31]([C:2]([NH2:1])([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COc1ccc(C(N)c2cc(C(C)C(=O)O)ccc2OC)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(N)(C(=O)OCC2c3ccccc3-c3ccccc32)c2cc(C(C)C(=O)O)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 3-(α-amino-4-methoxybenzyl)-4-methoxyphenylpropionic acid (1.0 g, 3.17 mmol) prepared in Example 4 was dissolved in 5 ml of DMF containing triethylamine (0.88 ml). To the solution, 1.28 g of Fmoc-OSu was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and 5% citric acid and ether were added to the residue. The resulting power was recrystallized from methanol and ether.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12](/[C:15]2[CH:19]=[C:18]([Cl:20])[S:17][CH:16]=2)\[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:28][NH2:29]>CO>[Cl:20][C:18]1[S:17][CH:16]=[C:15](/[C:12](/[CH2:13][CH3:14])=[C:11](\[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:29][CH3:28])=[CH:6][CH:7]=2)[CH:19]=1
Reactant: CN
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1csc(Cl)c1
Solvent: CO
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1csc(Cl)c1
Yield: 35 %

Procedure:
Following the same procedure as described in example 11, step D, (E)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(5-chlorothiophen-3-yl)but-1-enyl)phenol (0.8 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) at reflux to give 120 mg desired product (35% yield, E). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (bs, 1H), 6.99-7.02 (m, 3H), 6.84-6.89 (m, 2H), 6.62-6.70 (m, 2H), 6.50-6.56 (m, 3H), 3.97 (t, J=5.6 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.26-2.38 (m, 5H), 0.89 (t, J=7.2 Hz, 3H); m/z=414[M+1]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccc(F)cc1Cl
Temperature: 100 °C
Yield: 25 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D57, 60 mg, 0.11 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol), sodium t-Butoxide (13 mg, 00.1375 mmol) were degassed together in toluene (1.2 mL) for 10 minutes before adding bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heating at 100° C. for 30 minutes under microwave conditions. Added more bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heated for a further 30 minutes at 100° C. under microwave conditions. Diluted with EtOAc, washed with sat NaHCO3 solution ×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated under reduced pressure. Residue purified eluting with 0-100% EtOAc/Pent. Solvent evaporated to afford a brown gum of the title compound in 25% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:10]=1[NH:11][CH:12]=[C:13]2[CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:26][N:27]([CH3:41])[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:56]CCCl>C(O)(=O)C>[ClH:56].[ClH:56].[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:10]=1[NH:11][CH:12]=[C:13]2[CH2:14][CH2:15][NH:16][CH:31]1[CH2:30][CH2:29][C:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([N:27]([CH3:41])[CH3:26])[CH2:33][CH2:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2c(OCc3ccccc3)cccc12
Reactant: ClCCCl
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3c(OCc4ccccc4)cccc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Benzyloxytryptamine (200 mg) was dissolved in dry 1,2-dichloroethane (10 ml) and THF (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (180 mg) and glacial acetic acid (43 μl), the mixture was stirred for one hour at RT and then sodium triacetoxyborohydride (248 mg) was added thereto. The reaction mixture was stirred for three days at RT. For working up, the mixture was concentrated, the residue was dissolved in water (15 ml), 2M HCl (2 ml) and diethyl ether (20 ml), the organic phase was separated off, and the aqueous phase was washed with diethyl ether (2×15 ml), brought to pH 11 with 1M NaOH and extracted with ethyl acetate (4×10 ml). The combined ethyl acetate extracts were dried and concentrated, and the residue obtained (351 mg) was purified by flash chromatography (45 g silica gel 60, eluant: MeOH/NEt3 (99:1)). The nonpolar diastereomer (188 mg) was dissolved in 2-butanone/acetone (6 ml/6 ml) while warm and converted with chlorotrimethylsilane (147 μl) into the corresponding dihydrochloride (white solid; 176 mg; m.p. 162-166° C.).
Reaction SMILES: [N:1]1[CH:6]=CC=[CH:3][CH:2]=1.[C:7]([Cl:17])(=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=[O:20])C>CN(C)C1C=CN=CC=1>[ClH:17].[C:7](=[O:16])([O:20][CH2:3][CH2:2][NH:1][CH3:6])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Product: CNCCOC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), and benzyl chlorocarbonate (1.57 mL) was dropwise added. After stirring at room temperature for 2 hrs., pyridine (0.65 mL) and benzyl chlorocarbonate (1.28 mL) were added. After stirring at room temperature for 5 days, pyridine (0.81 mL) was added under ice-cooling and a solution (5 mL) of benzyl chlorocarbonate (1.43 mL) in ethyl acetate was dropwise added slowly. After stirring at room temperature for 2 hrs., ethyl acetate (50 mL) was added to the mixture, washed with water (50 mL), a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hrs., diethyl ether (10 mL) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure to give the title compound (1.99 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>[Pd].C(OCC)(=O)C.CO>[N:18]1([NH:17][C:15]2[CH:14]=[CH:13][C:11]3[NH:12][C:8]([C:5]4[CH:4]=[C:3]([NH2:24])[C:2]([NH2:1])=[CH:7][CH:6]=4)=[N:9][C:10]=3[CH:16]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(-c2nc3cc(NN4CCOCC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2nc3cc(NN4CCOCC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-amine (0.5 g, 1.4 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[5-(morpholin-4-ylamino)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine, as a thick oil that was used in the next step without any purification.
Reaction SMILES: O[CH:2]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1>ClCCl.S(Cl)(Cl)=O>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][C:9]2[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=2)[CH:4]=1
Reactant: CC(C)(C#N)c1cc(C(O)c2cccnc2)cc(C(C)(C)C#N)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(Cc2cccnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 34 (50 mg) in dichloromethane (2 ml) and thionyl chloride (0.1 ml) was heated under reflux for 1 h, then evaporated to dryness under reduced pressure. The residue was dissolved in ethanol, 10% palladium-on-carbon catalyst was added, and the mixture was shaken in an atomosphere of hydrogen at room temperature and atmospheric pressure for 1 h. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(3-pyridylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp 82°-84°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1.C(OCC)C.CCCCC>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:32]=[O:33])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.25 g, Example 1a) in tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of 1.4 M methyllithium in diethyl ether (6.1 ml) was added to this solution over 2 min. The mixture was stirred at −78° C. for 10 min., then a 1.7 M solution of tert-butyllithium in pentane (10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min., then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min., quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitled compound as a solid (2.76 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Cl:12][C:13]([F:21])([F:20])[C:14]([Cl:19])([F:18])[CH2:15][CH2:16]I.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:19][C:14]([F:18])([C:13]([Cl:12])([F:21])[F:20])[CH2:15][CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(Cl)C(F)(Cl)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)CCC(F)(Cl)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.4 %

Procedure:
1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile and 3.1 g of 1,2-dichloro-4-iodo-1,1,2-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 6 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.9 g of 2-(3,4-dichloro-3,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (54)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:17]([C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([C:8]3([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1)#[N:18]
Reactant: CN1OCC(C)(c2cccc(Br)c2)NC1=N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1OCC(C)(c2cccc(-c3cccc(C#N)c3)c2)NC1=N
Yield: 44 %

Procedure:
A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R6=Me, R1=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronic acid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol (1.5 mL), and a 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq) in a microwave vial was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was filtered, concentrated and purified by prep HPLC (B) to give 0.012 g (44%) of 5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8; R6=Me, R1=Me, R21=3-cyanophenyl) as a white solid. 1H NMR (CDCl3) 10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35 (m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.3 (M+H)