Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([CH:27]([CH3:28])[C:26]([F:25])([F:36])[F:37])[CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(c1cccc(O)c1)C(F)(F)F
Product: CC(NC(=O)c1coc(Oc2cccc(C(C)C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 86.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (30 mg, 0.08 mmol) was reacted with 3-(1-trifluoromethylethyl)phenol (20 mg, 0.11 mmol) to give the title compound (37 mg, 88%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([N+:29]([O-])=O)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.C(O)C.[In]>O>[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[S:24][C:20]([C:3]3[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]4[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]4=[O:19])[N:4]=3)=[CH:21][C:22]=2[CH:28]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Agent: [In]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(N)ccc3s2)n1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A mixture of 1-(2-(5-bromo-4-(5-nitrobenzo[b]thiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (996 mg, 1.97 mmol), ethanol (100 mL) and indium powder, 100 mesh (1.13 g, 9.85 mmol) was heated to reflux with stirring. After 1.5 h the reaction mixture was cooled to r.t., diluted with water (40 mL) and filtered through a pad of celite. The yellow precipitate (collected on the celite) was purified by reverse phase chromatography (0.1% TFA in AcCN:H2O/10:90 to 95:5). The product fractions were combined, then passed through a 1 g SCX cartridge. The fully loaded cartridge was then washed with MeOH (4 mL) and 2 M ammonia in MeOH (8 mL). Elution of the desired compound was brought about by washing the cartridge finally with DMSO (4 mL). The solvent was removed in vacuo, employing a Genevac, to yield the title compound (142 mg, 15%) as a yellow amorphous solid. 1H NMR: δ (d6-DMSO, 400 MHz) 1.29 (s, 6 H), 3.39-3.54 (m, 4 H), 5.20 (s, 2 H), 6.83 (d, J=8.61 Hz, 1 H), 7.02 (s, 1 H), 7.62 (d, J=8.61 Hz, 1 H), 7.68 (s, 1 H), 8.38 (s, 1 H), 8.48 (s, 1 H), 10.82 (s, 1 H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1.[CH2:12]([OH:15])[CH2:13][CH3:14]>>[Br:2][C:3]1[CH:8]=[C:7]([O:15][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1
Reactant: CCCO
Reactant: O=[N+]([O-])c1ccnc(Br)c1
Agent: [Na]
Product: CCCOc1ccnc(Br)c1
Temperature: 95 °C
Yield: 58 %

Procedure:
To a solution of sodium (480 mg, 21 mmol) dissolved in 1-propanol (45 mL), was added 2-bromo-4-nitropyridine [(3.2 g, 19.2 mmol), J. Med. Chem. 46(7), 1273-1276; 2003] and the mixture was heated at 95° C. for 2 hours. The solvent was then evaporated under reduced pressure and the residue was suspended in chloroform and filtered. The filtrate was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue. The residue was distilled and title product was obtained during a temperature range of 145-150° C., as a solid in 58% yield, 2.67 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:11][S:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:10][CH:11]=1)=[O:6]
Reactant: COCNC(=O)C1CSC(c2ccccc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COCNC(=O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stiffing continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1-h. Yield: 27.3%. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([OH:13])[C:9]=1[CH:14]([CH3:16])[CH3:15].[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:13][C:10]1[C:9]([CH:14]([CH3:16])[CH3:15])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:12][N:11]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1c(O)noc1-c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1Cl
Yield: 72 %

Procedure:
5-(2-Chlorophenyl)-3-hydroxy-4-isopropylisoxazole (0.13 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.15 g, 72%) as a colorless powder.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:31]1[S:35][C:34]([CH:36]=[O:37])=[N:33][CH:32]=1)[C:27]([OH:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:34]3[S:35][C:31]([CH:26]([OH:25])[C:27]([OH:30])([CH3:28])[CH3:29])=[CH:32][N:33]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)C(O)c1cnc(C=O)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)C(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 94.2 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.35 g), 5-(1,2-dihydroxy-2-methylpropyl)-1,3-thiazole-2-carbaldehyde (0.21 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (27 mg), triethylamine (0.06 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.52 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 550 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7]C[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:23])[CH:21]=[CH2:22].[C:24](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>>[Br-:7].[C:20]([O:19][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])[CH2:1][N+:2]1[CH:6]=[CH:5][N:4]([CH3:24])[CH:3]=1)(=[O:23])[CH:21]=[CH2:22]
Reactant: Cn1ccnc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCCCCCCCCCCBr
Product: C=CC(=O)OC(CCCCCCCCC)C[n+]1ccn(C)c1
Product: [Br-]

Procedure:
This intermediate is then quaternarized with 3-methylimidazole. Under N2 atmosphere, a mixture of 11-bromoundecylacrylate (6.08 g, 20 mmol) and 1-methylimidazole (1.64 g, 20 mmol) and a small amount of 2,6-di-tert-butyl-4-methylphenol (inhibitor) was stirred at 40° C. for 48 h, and yielded a viscous liquid. The viscous liquid was purified by the precipitation method with diethyl ether to obtain yellow viscous liquid 1-(2-acryloyloxyundecyl)-3-methylimidazolium bromide. The viscous liquid was dried under vacuum at room temperature as the white waxy solid (5.73 g, 74%). 1H NMR (400 MHz, CDCl3): 10.66 (1H, m, N—CH—N), 7.34-7.25 (2H, s, N—CH═CH—N), 6.36-6.35 (1H, m, CH2═CH), 6.14-6.11 (1H, m, CH2═CH), 5.81-5.79 (1H, m, CH2═CH), 4.30-4.29 (2H, t, N—CH2(CH2)10O—), 4.11 (3H, s, N—CH3), 1.90-1.82 (2H, t, N—CH2(CH2)10O—), 1.66-1.62 (2H, m, —OCOCH2CH2), 1.30-1.24 (14H, m, —CH2CH2(CH2)7CH2CH2—). Elemental analysis: Calculated: C18H32BrN2O2, C, 55.67%; H, 8.31%; N, 7.21%. Found: C, 55.22%, H, 7.79%, N, 7.35%. mp: 37.2° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(Cl)(Cl)=S.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[CH2:27][C:28]#[N:29].[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH2:36][C:37]([NH2:39])=[O:38]>>[C:1]1([NH:7][C:8](=[S:9])[C:27](=[C:22]2[N:21]=[CH:26][CH:25]=[CH:24][NH:23]2)[C:28]#[N:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([NH:7][C:8](=[S:9])[CH:36]([C:31]2[N:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[C:37]([NH2:39])=[O:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC(=O)Cc1ncccn1
Reactant: N#CCc1ncccn1
Agent: S=C(Cl)Cl
Solvent: Nc1ccccc1
Product: N#CC(C(=S)Nc1ccccc1)=C1N=CC=CN1
Product: NC(=O)C(C(=S)Nc1ccccc1)c1ncccn1

Procedure:
In the first step of the synthesis, the phenyl isothiocyanate 14 (which may be readily prepared by reaction of an aniline with thiophosgene) is coupled with a 2-(pyrimidin-2-yl)acetonitrile 11 or 2-(pyrimidin-2-yl)acetamide 12 in the presence of a base to give a 3-(phenylamino)-2-(pyrimidin-2(1H)-ylidene)-3-thioxo-propionitrile 15 or 3-(phenylamino)-2-(pyrimidin-2-yl)-3-thioxopropanamide 16. In the second step, ring closure of the compound of formula 15 or 16 is achieved by reaction with an agent such as bromine/acetic acid or potassium ferricyanide, to give a 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetonitrile 6 or 2-[benzothiazol-2(3H)-ylidene]-2-(pyrimidin-2-yl)acetamide 8. If the compound of formula 6 has been prepared, it is then hydrolyzed to a compound of formula 8, as in Reaction Scheme 1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:11].[S:12]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)[S:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][Cl:19]>C(#N)C>[Cl-:19].[S:12]([CH2:21][CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:2]([CH3:1])=[C:3]1[CH3:11])[S:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N+:2]([CH3:1])=[C:3]1[CH3:11].[Cl-:19]
Reactant: Cc1nc2ccccc2n1C
Reactant: O=C(CCl)NCCSSCCNC(=O)CCl
Solvent: CC#N
Product: Cc1n(CC(=O)NCCSSCCNC(=O)Cn2c(C)[n+](C)c3ccccc32)c2ccccc2[n+]1C
Product: [Cl-]
Yield: 129.8 %

Procedure:
A mixture of compound 1,2-dimethyl-1H-benzimidazole (2.93 g, 20 mmol) and N,N′-(disulfanediyldiethane-2,1-diyl)bis(2-chloroacetamide) (1.53 g, 5 mmol) in 20 ml of acetonitrile was heated to reflux for 24 h. After cooling, the resulting white solids were collected by filtration and washed with ethyl acetate and dichloromethane to afford 1.94 g of a white powder. Analyses were in accordance with the expected structure.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]([NH:5][C@H:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[N:8]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:7]1=[O:29])=[O:4].C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[S:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:44]1([NH:50][C:51](=[S:52])[NH:1][C@@H:2]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:3]([NH:5][C@H:6]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[N:8]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:7]2=[O:29])=[O:4])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: S=C=Nc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (12 g) and triethylamine (3.83 ml) in tetrahydrofuran (240 ml) was added phenyl isothiocyanate (2.99 ml) at room temperature. After stirring for 4 hours at room temperature, the solvent of the reaction mixture was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S)-3-[[(2S)-2-[N'-(phenyl)thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][C:24]=1[C:39]([F:42])([F:41])[F:40].CCN(C(C)C)C(C)C>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:39]([F:40])([F:41])[F:42]
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Add N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (99 mg, 0.35 mmol), phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (100 mg, 0.35 mmol) and DIEA (135 mg, 1.05 mmol) in THF (4 mL), stir at 80° C. for 2 hrs, Remove the volatiles, suspend the residue in DCM, filter and collect the solid to get the target compound (132 mg, 77%). MS: (M+1): 490.3.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[Li+].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([C:3]1([CH3:15])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of tert-butyl 3-cyanoazetidine-1-carboxylate (0.55 g, 3.04 mmol) in THF (10 ml) was cooled to −78° C. under a nitrogen atmosphere. LHMDS (3.34 ml, 1M THF) was added dropwise and the solution stirred at −78° C. for 1 hr. Methyl iodide was added dropwise and stirring continued for a further 2 h. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel eluting with 20% ethyl acetate/petrol provide the title compound as a pale yellow oil (0.46 g, 77%). 1H NMR (CDCl3) 1.48 (9H, s), 1.71 (3H, s), 3.82 (2H, d), 4.31 (2H, d).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:22]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To the product from step 1 (70 mg, 0.183 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the product as a brown solid, (51 mg, 99%): MS; m/z 282 (M+H): LCMS (UV) 99%: HPLC 98.3%; 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.81 (m, 1H), 1.89-2.00 (m, 2H), 2.02-2.19 (m, 1H), 3.19-3.26 (m, 2H), 3.91-3.98 (m, 1H), 4.25-4.30 (dd, 1H J1=8.4 Hz, J2=10.8 Hz), 4.36-4.40 (dd, 1H J1=3.6 Hz, J2=10.8 Hz), 7.15 (d, 2H, J=9.2 Hz), 7.54-7.59 (m, 2H,), 7.65-7.71 (m, 3H); 7.785 (d, 2H, J=8.8 Hz), 9.4 (s, 2H)
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][C:4]=1[F:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1ccc(Br)c(F)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
A biphasic mixture of water (3 mL) and toluene (10 mL) containing (4-bromo-3-fluoro-phenyl)-acetonitrile (457 mg, 2.14 mmol), sodium carbonate (1.00 g, 9.45 mmol), phenyl boronic acid (781 mg, 6.41 mmol) was sparged with nitrogen for 10 min, tetrakis(triphenylphosphine)palladium (250 mg) was added and the mixture heated to reflux for 48 hrs. After cooling, the solution was diluted with EtOAc, washed with water, the organic phase dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (2-fluoro-biphenyl-4-yl)-acetonitrile as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 7.54 (2H, m), 7.46 (3H, m), 7.40 (1H, m), 7.17 (2H, m), 3.79 (3H, s).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:20]=[C:19]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(N(CC)C(C)C)(C)C.[CH:37]1[C:50]2[C:41](=[CH:42][C:43]3[C:48]([C:49]=2C(Cl)=O)=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:39][CH:38]=1.ClCCl.CO>CO.[Pd].ClCCl>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([C:42]3[C:43]4[C:48]([CH:49]=[C:50]5[C:41]=3[CH:40]=[CH:39][CH:38]=[CH:37]5)=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:7])[CH2:13][CH2:12]2)[CH2:20]1)=[O:27])[CH3:24]
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: CCN(CC)C(=O)C1=CN(C2CCN(C(=O)OC(C)(C)C)CC2)CCCC1
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
4-(6-diethylcarbamoyl-2,3,4,5-tetrahydro-azepin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.079 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (10% w/w) (˜30 mg) added. The mixture was shaken under a hydrogen atmosphere (50 psi) for 3 h . The catalyst was removed by filtration through Celite® and the solvent evaporated under vacuum. The residue was dissolved in ethyl acetate (10 mL) under nitrogen, cooled to −78° C. and hydrogen chloride was passed in for a few minutes. The solution was allowed to warmed at room temperature then evaporated to dryness overnight in a stream of dry nitrogen. The residue was dissolved in anhydrous dichloromethane (4 mL), N,N-diisopropylethylamine (5 eq, 70 mL) was added followed by a suspension of anthracene-9-carbonyl chloride (Intermediate 3, 0.088 mmol) in dichloromethane (0.175 mL). The thin layer chromatography (9:1 dichloromethane-methanol) showed a new UV spot at Rf 0.40. After 30 minutes, the solution was washed with a mixed sodium hydrogen carbonate/sodium hydroxide solution, dried over anhydrous sodium sulfate, evaporated and the residue purified by chromatography on silica gel eluting with a 1%-2.5%-5%-10% methanol-dichloromethane gradient to give the title compound (20.4 mg, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH:30][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(NC(=O)N[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 16 h
Yield: 38.3 %

Procedure:
In a dry flask (3R,4S)-3-amino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (77 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2.5 mL) and triethylamine (20 μL, 0.143 mmol) and 3-acetylphenylisocyanate (50 μL, 0.36 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse-phase HPLC (10-90% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (40 mg, 38%). 1H NMR (300 MHz, CDCl3), δ: 7.98 (d, J=8, 1H), 7.83 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 7.56 (m, 1H), 7.46 (m, 1H), 7.01 (m, 2H), 6.87 (m, 1H), 3.09 (m, 1H), 2.51-2.77 (m, 7H), 2.42 (m, 1H), 1.23-1.78 (m, 1H), 1.42 (s, 9H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3142.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20][CH3:21].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([Cl:11])[CH:7]=2)[N:1]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[C:20]=1[CH3:21]
Reactant: CCC(=O)c1ccccc1F
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: Cc1c(-c2ccccc2F)nc2ccc(Cl)cc2c1Cl

Procedure:
Prepared according to Procedure J using 2-amino-5-chlorobenzoic acid (1.5 equiv.) and 1-(2-fluorophenyl)propan-1-one (1 equiv.) in phosphorous oxychloride to afford 4,6-dichloro-2-(2-fluorophenyl)-3-methylquinoline upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=306.0 (M+1).