Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([CH:31]1[CH2:32][CH2:33][O:28][CH2:29][CH2:30]1)[CH2:7][CH2:6]2
Reactant: O=C1CCOCC1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCN(C1CCOCC1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 77.7 %

Procedure:
The title compound was prepared as described in Example 14.C, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.5 g, 1.39 mmol) and tetrahydro-4H-pyran-4-one (1.084 g, 10.8 mmol) to provide the title compound (0.479 g, 78% yield): ES-MS (m/z) 444 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11ClN4, 296. Found, 295, 297.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:31][CH2:30][N:29]([CH2:28][C@H:24]6[CH2:25][CH2:26][CH2:27][O:23]6)[CH2:34][CH2:33]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1CO[C@H](CN2CCNCC2)C1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(C[C@H]2CCCO2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-1-((tetrahydrofuran-2-yl)methyl)piperazine (1.2 equiv) to give 199 (M+1 466.0)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1C1CCCCC=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:35]1[CH:36]=[CH:37][C:28]([F:27])=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1ccc(F)c2cccnc12
Product: Cc1cc2ccccc2c(-c2ccc(F)c3cccnc23)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-Butoxy-2-(1-(5-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (10) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6 except 5-fluoroquinolin-8-ylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 8.81 (d, J=8.2 Hz, 1H), 8.70 (dd, J=3.3 Hz, J=4.7 Hz,1H), 8.09 (t, J=6.2 Hz, 1H), 7.92 (m, 2H), 7.78 (m, 1H), 7.63 (t, J=9.0 Hz, 1H), 7.42 (t, J=7.0 Hz, 1H), 7.18 (t, J=7.8 Hz,1H), 6.84 (d, J=7.6 Hz, 1H), 5.18 (s, 1H), 2.68 (s, 3H), 0.80 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: −77.9, −123.2. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H25FNO3: 418.47. found: 418.1.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]([C:14]([NH:16][CH:17]([CH3:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)=[O:15])[CH:11]([CH3:13])[CH3:12])=O)(C)(C)C>C(Cl)Cl>[ClH:1].[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[C@H:10]([CH:11]([CH3:12])[CH3:13])[NH2:9])[CH3:28])=[CH:25][CH:24]=1)#[N:27]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Yield: 100 %

Procedure:
Hydrogen chloride gas was introduced into a solution containing 3.7 g of N2-tert-butoxycarbonyl-N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide dissolved in 100 mL of methylene chloride for 1 hour at room temperature. After completion of the reaction, the methylene chloride was removed under reduced pressure, thus obtaining a crude crystal. The crude crystal was washed with acetone to afford 3.1 g of the desired product (yield: 100%). Melting point: 59°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH2:21])[CH3:20])=[CH:7]2.C(O)CCC.Br[C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH:21][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:20])=[CH:7]2
Reactant: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)n1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)n1
Temperature: 110 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(6-methylpyridin-2-yl)quinolin-3-yl)-ethanamine (146 mg, 0.49 mmol) in 1-butanol (5.4 mL, 59 mmol) was added 6-bromopurine (0.107 g, 0.54 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) with heating (110° C.) overnight. solvents were removed and the residue subjected to chromatography, gradient, 89:9:1(DCM:MeOH:NH4OH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][OH:13])=[N:10][CH:11]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:15])=[O:13])=[N:10][CH:11]=1
Reactant: OCc1ccc(OCCCCl)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OCCCCl)cn1

Procedure:
The mixture of 30.0 g of 5-(3-chloropropoxy)-2-pyridine methanol and 1,200 ml of water is stirred vigorously at 5°. To this mixture is added 31.0 g of potassium permanganate in several portions during which time the temperature of the mixture rises to 25° and then the mixture is stirred at 25° for 30 minutes. Then the mixture is filtered, the precipitated manganese dioxide washed with several portions of water, the washing is combined with the filtrate and the resulting aqueous solution is adjusted to pH 5. Then the aqueous solution is evaporated to a small volume and the concentrate is extracted several times with ethyl acetate. After the extracts are combined, the combined ethyl acetate solution is washed and dried. The solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2-pyridinecarboxylic acid melting at 120°-121°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([C:15]([NH2:17])=[O:16])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:21]([S:23]Cl)=[O:22]>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[O:16][C:21](=[O:22])[S:23][N:17]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)SCl
Reactant: CC(C)Oc1ccc(Oc2ncc(C(N)=O)s2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(=O)o3)s2)cc1
Yield: 92.3 %

Procedure:
A mixture of Example 100A (1.89 g, 0.0066 mol) and chlorocarbonylsulfenyl chloride (0.64 g, 0.01 mol) in toluene was heated at reflux for 6 hours. The solvent was removed and the residue was purified on silica gel (5˜30% ethyl acetate in hexane) to give 2.05 g of product as an off-white solid (92% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 4.46-4.63 (m, 1H) 6.89-6.98 (m, 2H) 7.14-7.24 (m, 2H) 7.80 (s, 1H). MS (ESI), M/Z: 369.0 (M+32)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncccc2c1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (164 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic: phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (48 mg, 21%), single spot at Rf 0.71 (ethyl acetate). mp 228.0-228.5° C., HPLC purity 99+% (tR 2.43 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 7.98 (3H, m), 7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.7 Hz), 7.39-7.32 (2H, m), 7.20 (1H, t, J=7.9 Hz), 7.05 (1H, s, N—H), 2.75 (3H, s). LCMS: 331.16 (M−). FAB-MS (MH+, C16H13CIN2O2S): calcd 333.0464, found 333.0461.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)(=O)[CH3:12]>CO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH:12]=[CH:11][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: CO
Product: N#Cc1ccc(C=CC(=O)c2ccc(C#N)cc2)cc1

Procedure:
The synthesis employed for the 2,4-substituted dicationic furans 1-6 used 2,4-bis(4-cyanophenyl)furan as the key intermediate and is outlined in scheme 1. This key compound was obtained through a four step approach. A base catalyzed Aldol condensation between 4-cyanobenzaldehyde and 4-acetylbenzonitrile in methanol gave 1,3-bis(4-cyanophenyl)prop-2-en-1-one. Bromination of the double bond of the chalcone (i) in CHCl3 yielded 1,3-bis(4-cyanophenyl)-2,3-dibromopropan-1-one (ii), which was reacted with 2.5 equivalent of MeONa in MeOH to form 1,3-bis(4-cyanophenyl)-3-methoxyprop-2-en-1-one (iii) (Weygand, C.; Bauer, E.; Hennig, H., Ueber Beziehungen zwischen Polymorphismus und Ethylen-Stereomerie. B. 1929, 62, 562-573). The reaction of dimethylsulfonium methylide with the enolether (iii) gave 2,4-disubstituted furan (iv) (Harris, C. M. et al., J. Org. Chem. 1974, 39, 72-77).
Reaction SMILES: [OH2:1].[CH3:2][C:3]1([CH3:12])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:11])=N1.CC(C)=[O:15]>CO>[OH2:15].[CH3:2][C:3]1([CH3:12])[CH2:11][C:5](=[O:1])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: CO
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
A mixture of 250 g of 2,2,4,4,6-pentamethyl-2,3,4,5-tetrahydropyrimidine hydrate, 100 g of acetone and 100 g of methanol is refluxed for 13 hours. The solution is subsequently concentrated in vacuo, and the oil remaining is distilled in vacuo. The yield is 185 g of a slightly yellowish oil, B.P.12 = 80°- 86°C, which, after the addition of about 22 ml of water, solidifies to form crystals of 2,2,6,6-tetramethyl-4-oxopiperidine-hydrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:5]=[CH:4][N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccnc(Cl)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Yield: 91.8 %

Procedure:
2-chloro-4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridine (120 mg, 0.366 mmol) was dissolved in 6 ml tert-butanol. A 50% solution of KOH (2 ml, 26.7 mmol) was added and the mixture was refluxed for 72 h. The reaction mixture was concentrated in vaccuo, the pH was adjusted to 7 by addition of 37% HCl solution, and the aqueous phase was extracted twice with 40 ml of ethyl acetate. The organic phase was washed once with 10 of brine, dried with magnesium sulfate, filtered and evaporated. The title compound (104 mg, 0.336 mmol, 92%) was obtained as a crystalline light yellow solid, MS: m/e=310.1, 312.2 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:5]2[N:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[C:8]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[C:7]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[N:6]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Fc1ccc(COc2nc(N3CCCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 48 mg, 0.085 mmol) was reacted in excess neat piperidine at 80° C. overnight by the general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure, then toluene azeotrope) and flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded the title compound. HPLC Rt=5.36 min. 1H-NMR 500 MHz (CDCl3): δ 1.63 (m, 4H), 1.71 (m, 2H), (bs, 4H), 3.83 (m, 4H), 5.36 (s, 2), 7.02 (d, J=8 Hz, 2H), 7.08-7.20 (m, 7H), 7.31(d, J=1 Hz, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][Cl:1]
Reactant: OCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reaction time: 2 h

Procedure:
Solid N-chlorosuccinimide (0.76 g, 5.72 mmol) was added in portions over 5 minutes to a stirred solution of 3-[2(E)-(quinolin-2-yl)ethenyl]benzyl alcohol (1.14 g, 4.58 mmol) and triphenylphosphine (1.50 g, 5.72 mmol) in dichloromethane (100 ml) at 0°-5° C. The mixture was stirred for a further 2 hours at 0°-5° C. then evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:3).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:10]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18]2[C:13](=[C:14]([O:22]CC3C=CC=CC=3)[CH:15]=[C:16]([CH:20]=O)[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]>>[CH2:8]([C:10]1([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:19][C:18]2[C:13](=[C:14]([OH:22])[CH:15]=[C:16]([CH2:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CCC1(Cc2ccccc2)CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1
Product: CCOC(=O)CCc1cc(O)c2c(c1)CC(CC)(Cc1ccccc1)CC2=O

Procedure:
Ethyl bromoacetate is converted to the triphenyl phosphorone, reacted with the product of Example 36 and reduced catalytically to the desired compound using procedures analogous to those described in Example 24.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C@H:8]2[N:10](C(OC(C)(C)C)=O)[C@H:5]([CH2:6][CH2:7]2)[CH2:4]1.Cl>O1CCOCC1>[CH:8]12[NH:10][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([CH2:2][OH:1])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(CO)C2
Agent: Cl
Solvent: C1COCCO1
Product: OCC1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of (1R,5S)-tert-butyl 3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.9 g, 3.7 mmol) and HCl in dioxane (2 N, 5.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to afford the desired product (300 mg crude), which was used in the next step without further purification. LCMS (ESI) m/z: 139.7 [M−H]−.
Reaction SMILES: [OH-].[Li+:2].[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:30][C:31]([O:33]C)=[O:32])=[O:27])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1([C:26]([NH:28][CH:29]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:30][C:31]([O-:33])=[O:32])=[O:27])[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5].[Li+:2]
Reactant: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(=O)[O-])c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Lithium hydroxide (1.436 mL, 2.87 mmol) 2N in water was added to a stirred suspension of methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 35) (400 mg, 0.72 mmol) in THF (40 mL) at room temperature. The resulting suspension quickly went into solution and was then stirred at RT overnight. The following morning a white precipitate had formed. This was filtered and dried in vacuo to give lithium 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (396 mg, 100%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[H-].[Na+].[NH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=1>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([NH:25][C:26]2[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reactant: NC1=CC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reaction time: 21 h

Procedure:
2.41 g of the epoxide of example 1 were solved in 36 ml of dimethylsulfoxide under a protective gas, and 360 mg of sodium hydrid were added. To this stirred suspension was added 1.71 g of 3-amino-cyclopent-2-en-1-one (Chem. Ber. 103, 2403 [1970]) in portions. After 21 hours, the reaction solution was worked up in an aqueous manner and extracted with ethyl acetate. The usual further processing and recrystallisation of the product obtained from ethyl acetate yielded white crystals having a m.p. of 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 34 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone, was converted to the title compound (50 mg, 34%) which was obtained as a white solid. MS: m/e=458.1 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11]Cl)=[N:9][C:5]=2[CH:4]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C(O)C>[Br:2][C:3]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[N:7]([CH:13]([CH3:15])[CH3:14])[C:8]([CH2:10][CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:36])([F:37])[F:22])[CH:25]=4)[CH2:35][CH2:34]3)=[N:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(CCCl)nc2cc(Br)c3ccccc3c21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCO
Product: CC(C)n1c(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)nc2cc(Br)c3ccccc3c21

Procedure:
The compound of the title is prepared by condensing 5-bromo-2-(2-chloroethyl)-1-(1-methylethyl)-1H-naphth[1,2-d]imidazole hydrochloride with 1-(3-trifluoromethylphenyl)piperazine. M.p. 161°-62° C. (from ethanol).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])=[O:17])=[CH:14][N:13]=2)=[C:8]([CH3:25])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])=[O:17])=[CH:14][N:13]=2)=[C:8]([CH3:25])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC(C)CO)cn1
Agent: [Pd]
Solvent: CCO
Product: CCCCc1noc(C)c1CCc1ccc(C(=O)NC(C)CO)cn1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A stirred mixture of 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-N-(2-hydroxy-1-methyl-ethyl)-nicotinamide (example 10, 32 mg, 0.093 mmol) and 10% Palladium on charcoal (5 mg) in ethanol (5 mL) was shaken under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 100:0 to 9:1) afforded the title compound (20 mg, 63%) as a colorless oil. MS: m/e=364.4 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3]C(C)(C)C)=O.[CH2:17]([NH:24][CH2:25]C(OCC)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:17]([N:24]1[CH2:25][C:1](=[O:3])[NH:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:14]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Yield: 102 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step A, except using Boc-L-norleucine (10.5 g, 45.2 mmol), ethyl N-benzylglycinate (8.72 g, 45.2 mmol) and dicyclohexylcarbodiimide (9.33 g, 45.2 mmol). The crude diketopiperazine was triturated with hexane to give the title compound as a white powder (12.0 g). NMR (300 MHz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H, br s), 4.07 (1H, dt, J=3, 6 Hz), 3.87 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).