Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[CH:34]=O.C(O)(=O)C>CO.ClCCl>[CH3:40][O:39][C:37]1[CH:36]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[CH:38]=1)[CH2:34][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:9]2=[O:21])[CH2:16][CH2:17]1
Reactant: O=C1N(CCN2CCNCC2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN2CCN(CCN3CCC(c4ccc(F)cc4)(c4ccc(F)cc4)C3=O)CC2)cc(OC)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of the product from Example 63C (1.85 g, 4.80 mmol) in methanol/dichloromethane (50 mL) was added 3,5-dimethoxybenzaldehyde (0.80 g, 4.80 mmol), macroporous-cyanoborohydride resin (8.09 g, 4.80 mmol, 2.24 mol/g) and acetic acid (1.6 mL, 4.80 mmol). The reaction was stirred at 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. The title compound was dissolved in methanol (10 mL) and treated with HCl (1.25 M in methanol, 5.1 mL), concentrated and dried under vacuum to give the title compound as the corresponding hydrochloride salt. MS (DCI) m/z 536.3 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[C:4]([F:11])[N:3]=1.[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:8][C:7]1[C:2]([O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]#[N:13])=[N:3][C:4]([F:11])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C#N)c2)c1F
Temperature: 45 °C

Procedure:
To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol) dissolved in acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2 mmol) and cesium carbonate (1.44 g, 4.4 mmol). The reaction was heated in an oil bath at 45° C. for 16 hours and partitioned with ether and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent removed in vacuo. Chromatography on silica gel with methylene chloride/hexane (7/3) gave 3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)-oxy]benzonitrile; NMR (CDCl3) 7.55 (m,2), 7.45 (m,2), 2.24 (s,3) ppm.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:12][NH:13][C:4]2=[CH:3][CH:2]=1)=[C:8]([N:10]=[O:11])[NH2:9].[H-].[Na+].[C:16]([CH:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1)([O:18]C)=[O:17].[CH3:28][OH:29]>O1CCCC1>[C:16]([OH:18])(=[O:17])[C:28]([OH:11])=[O:29].[NH:13]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]([C:8]2[N:9]=[C:16]([CH:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)[O:11][N:10]=2)=[N:12]1
Reactant: NC(N=O)=C1NNc2ccccc21
Reactant: COC(=O)C1CN2CCC1CC2
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(=O)O
Product: c1ccc2c(-c3noc(C4CN5CCC4CC5)n3)n[nH]c2c1
Temperature: 25 °C

Procedure:
[1H-Indazol-3-yl]amide oxime (190 mg) was dissolved in anhydrous tetrahydrofuran (50 ml) to which was added 4A molecular sieves. After stirring for 15 minutes sodium hydride (100 mg of 55% dispersion in oil) was added and the mixture stirred for a further 15 minutes before the addition of 3-carbomethoxy-1-azabicyclo[2.2.2]octane (400 mg). The resulting mixture was then heated at reflux for six hours, then cooled to room temperature. Methanol (10 ml) was added, the solution filtered and the solvent evaporated. The residue was purified by chromatography on silica using CH2Cl2 /CH3OH/NH4OH 90/10/1 as eluant to afford a colourless oil (300 mg). This was further purified by treatment with a solution of oxalic acid in acetone to afford the title compound, m.p. 215° C. (dec). Found: C, 58.22; H, 5.44; N, 19.41. C18H17N5O6 requires C, 57.92; H, 5.13; N, 19.30%; δH (360 MHz, D2O) 1.98 (2H, m, CH2CH2 --N), 2.26 (2H, m, CH2CH2 --N), 2.75 (1H, m, CH--CH2CH2 --N), 3.51 (3H, m, CH2CH2N), 3.97 (3H, m, CH2CH2N), 7.35 (1H, t, J=4 Hz, H-6), 7.54 (1H, t, J=4.9 Hz, H-5), 7.68 (1H, d, J=4 Hz, H-7), 8.03 (1H, d, J=4 Hz, H-4); m/z (M+, free base 95%) 295 (95), 238 (15), 212 (100), 159 (40), 143 (35), 96 (70), 83 (60).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31].C(#N)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:28]([NH:32][C:33]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: CCCCN=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and butylisocyanate (0.094 g, 0.84 mmol) in 3 ml of tetrahydrofuran is stirred for a day at ambient temperature. Aminomethylpolystyrene resin EHL (Novabiochem, 200-400 mesh, 2% DVB) (200 mg, approximately 1 mmol) is added and stirring is maintained for three hours. After filtration on frit then concentration of the filtrate in a rotavapor, the residue obtained is passed through an RP18 silica column (eluent: acetonitrile-trifluoroacetic acid 0.1N: 5-5); a beige-coloured powder is obtained with a yield of 43%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and insoluble substances were removed off by filtration. The filtrate was condensed and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1.5/1) to give 3.1 g (43%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(OCC)C>C(Cl)Cl>[C:13]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[OH:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2ccccc2c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Oc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To solution of 2-methoxy-1-phenylnaphthalene (13.0 g, 55.5 mmol) in methylene chloride (300 mL), added dropwise was solution of boron tribromide (670 mL) (1M in methylene chloride) at −78° C., and the mixture reacted for three hours while slowly raising the temperature to ambient temperature. Then, mixture of ice (150 g) and diethyl ether (250 mL) was added thereto. The organic layer was isolated, and the aqueous layer was extracted with diethyl ether. The combined organic layer was dried over magnesium sulfate and evaporated to remove the volatile substances. Purification via silica gel column chromatography (eluent: mixture of hexane and methylene chloride) gave 1-phenylnaphthalen-2-ol (10.0 g, yield: 81.8%) as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCOCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 88.9 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (160 mg, 0.441 mmol), morpholine (0.077 mL, 0.883 mmol) and ethanol (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-morpholinopyrimidin-4-amine (162 mg, 0.392 mmol, 89% yield). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=1.90 Hz, 1H); 8.20 (s, 1H); 7.72 (dd, J=8.77, 2.34 Hz, 1H); 6.75 (d, J=8.92 Hz, 1H); 6.67 (s, 1H); 3.95 (s, 3H); 3.68 (d, J=5.26 Hz, 8H). m/z (ESI, +ve ion) 414.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[Na+].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:17]=1)=[N:13][C:14](=[S:16])[N:15]=2)([O-:7])=[O:6].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])=[O:26]>CN(C)C=O.O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[NH:27][C:25](=[O:26])[N:24]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:16][C:14]1[NH:13][C:12]2[CH:17]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][C:11]=2[N:15]=1
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc2c(c1)=NC(=S)N=2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCCCCSc1nc2ccc([N+](=O)[O-])cc2[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 337 %

Procedure:
Part E. To a suspension of sodium hydride (0.04 g, 60% mineral oil dispersion, 0.001 mol; washed free of mineral oil with hexane) and sodium iodide (0.15 g; 0.0011 mol) in N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, cooled to 0°, a solution of 6-nitrobenzimidazol-2-thione (0.975 g; 0.005 mol) in N,N-dimethylformamide (5 mL) was added slowly. The reaction mixture was stirred for 30 minutes and then a solution of N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea (0.42 g, 0.001 mol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred for 1 hour and then allowed to warm to ambient temperature and stirred an additional 24 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give a viscous oil. The product was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (75:25::v:v) to give the title compound (1.2 g, 0.00337 mol) as a solid, mp 120°-122°. 1H NMR (DMSO-d6) δ13.25 (bs,1H), 8.27 (bs,1H), 8.05 (d,1H,J=7.6 Hz), 7.91 (s,1H), 7.57 (d,1H,J=7.6 Hz), 7.4-7.3 (m,1H), 7.25-7.12 (m,1H), 7.0-6.8 (m,1H), 3.37-3.16 (m,6H), 1.85-1.72 (m,2H), 1.6-1.35 (m,6H), 1.27-1.1 (m,8H), 0.83 (t,3H,J=6.8 Hz).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[O:13])[CH3:12].[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:14][CH2:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)=[O:13]
Reactant: [Br-]
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
25 g (143 mmol) of 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone are dissolved in 750 ml of THF, 64.7 g (172 mmol) of phenyltrimethylammonium tribromide are added, and the mixture is stirred at room temperature for 15 h.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)=[C:4]([Cl:17])[C:3]=1[N+:18]([O-])=O>CC(O)=O.C1COCC1.O.[Zn]>[NH2:18][C:3]1[C:4]([Cl:17])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2Cl)cc1F
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(-c2ccc(N)c(N)c2Cl)cc1F
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To a cooled solution (0° C.) of zinc dust (9.34 g, 143 mmol) in AcOH (33 mL), THF (33 mL) and water (9.5 mL) was added 4′-amino-2′-chloro-3-fluoro-3′-nitrobiphenyl-4-carbonitrile (Preparation 93, 2.6 g, 8.93 mmol) and the reaction was allowed to warm to room temperature for 1 hour before filtering through arbocel. The filtrate was diluted with water (200 mL) and EtOAc (200 mL) and the organic layer was collected, dried over MgSO4 and concentrated in vacuo to afford the title compound (2.41 g, quant).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[CH2:3]1.[C:21](=O)([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[O:22]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C@@H:33]([O:32][C:21](=[O:22])[NH:1][C@@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]2[N:9]=[C:10]([CH3:20])[CH:11]=[C:12]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:13]=2)[CH2:3]1)[CH3:38]
Reactant: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@H](N)C2)n1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2C[C@@H](C)[C@@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 60 °C

Procedure:
To a mixture of 2-[(3S,4R)-3-amino-4-methylpyrrolidin-1-yl]-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (20 mg) in CHCl3 (10 ml) was added 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (41 mg) prepared in Step 1 of Example 1 and DIEA (19 mg) at room temperature. After 4-hour stirring at 60° C., the resulting mixture was cooled to room temperature and concentrated. The residue was diluted with MeOH (5 mL). To the resulting mixture was added potassium carbonate (100 mg) at 0° C. and stirred at 0° C. for 30 min. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜80/20) to give (2S)-1,1,1-trifluoropropan-2-yl{(3R,4R)-4-methyl-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow foam.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1NC(C2C3C(=CC=CC=3)C([Br:31])=CC=2)=CN=1)=O)C(C)C.C(N(C(C)C)CC)(C)C.COC(=O)NC(C(N1CC(C#N)CC1C1NC(C2C=CC3C(=CC=C([C:74]4[CH:79]=[CH:78][C:77]([C:80]5[NH:81][C:82]([CH:85]6[CH2:91][C:88]7([CH2:90][CH2:89]7)[CH2:87][N:86]6[C:92](=[O:105])[CH:93]([NH:100][C:101]([O:103][CH3:104])=[O:102])[CH2:94][CH2:95][S:96]([CH3:99])(=[O:98])=[O:97])=[N:83][CH:84]=5)=[CH:76][CH:75]=4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:104][O:103][C:101](=[O:102])[NH:100][CH:93]([C:92]([N:86]1[CH:85]([C:82]2[NH:81][C:80]([C:77]3[CH:76]=[CH:75][C:74]([Br:31])=[CH:79][CH:78]=3)=[CH:84][N:83]=2)[CH2:91][C:88]2([CH2:90][CH2:89]2)[CH2:87]1)=[O:105])[CH2:94][CH2:95][S:96]([CH3:99])(=[O:98])=[O:97]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Reactant: COC(=O)NC(CCS(C)(=O)=O)C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(CCS(C)(=O)=O)C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(4-Bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester in Example CK, substituting N-methylmorpholine with five equivalents of diisopropylethylamine.(99%) Example FA: [1-(4-Cyano-2-{5-(6-(4-{2-[5-(4-methanesulfonyl-2-methoxycarbonylamino-butyryl)-5-aza-spiro[2,4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([O:14]CC)=[O:13])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[C:20]2[CH2:23][CH2:24][CH2:25][CH2:26][C:19]=2[C:18]1=[O:27].CS(O)(=O)=O.C(O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[C:20]2[CH2:23][CH2:24][CH2:25][CH2:26][C:19]=2[C:18]1=[O:27]
Reactant: CCOC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Agent: CS(=O)(=O)O
Solvent: O
Solvent: O=CO
Product: CC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 14.4 g. of N-[2,4-dichloro-5-(1-ethoxycarbonylethyloxy)phenyl]-3,4,5,6-tetrahydrophthalimide, 3.40 g. of methanesulfonic acid and 35 ml. of 86% formic acid was refluxed with stirring for 15 hours and the reaction mixture was cooled to room temperature and water was added and the product was extracted with ethyl acetate. The extract was concentrated under a reduced pressure and the oily product was admixed with n-hexane and was triturated to obtain the crystals. The product was recrystallized from benzene-cyclohexane to obtain 8.7 g. of Compound No. 11 shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[NH:58][CH2:57][C@H:56]([OH:59])[CH2:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@H:54]2[CH2:55][C@@H:56]([OH:59])[CH2:57][N:58]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][C:16]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc3ccc(Cl)cc3s2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(Cl)cc3s2)CC1
Product: Clc1ccc2nc(C3CCNCC3)sc2c1
Yield: 81.1 %

Procedure:
A mixture of 0.939 gm (2.7 mMol) 1-tert-butoxycarbonyl-4-(6-chlorobenzothiazol-2-yl)-1,2,3,6-tetrahydropyridine and a catalytic amount of platinum oxide in 20 mL methanol was stirred at room temperature under about 1 atmosphere of hydrogen for about 3 hours. The reaction mixture was concentrated under reduced pressure, the residue dissolved in a minimal volume of ethyl acetate, and the mixture filtered through a bed of flash silica gel, eluting with 1:1 hexane:ethyl acetate. The filtrate was concentrated under reduced pressure to provide 0.663 gm (70%) of the desired compound as a light tan oil.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])([CH3:9])[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=2)=[O:14])([CH3:9])[CH3:8])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.25 g, 0.60 mmol), 4-chlorobenzenesulfonyl chloride (0.125 g, 0.59 mmol) and N-methylmorpholine (0.3 mL, 2.73 mmol) in DMF (5 mL) is shaken at RT for 16 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography (basic alumina, 0-15% methanol in DCM) to obtain the title compound. M+ 504.
Reaction SMILES: C[O-].[Na+].[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:12]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H]1CCCC[C@H]1N
Yield: 67.2 %

Procedure:
Sodium methoxide (0.60 g) was added to a solution of 1.14 g of trans-1,2-diaminocyclohexane and 2.96 g of methyl oleate in 15 ml of benzene, and the mixture was heated under reflux for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate-water. The organic layer was washed with saturated saline, and dried over anhydrous sodium sulfate. After drying it over anhydrous sodium sulfate, the residue obtained was purified by silica gel column chromatography to obtain 2.54 g of the objective compound (yield: 68%).