Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:22]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[O:23])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])[CH3:4].[F:30][C:31]1[CH:38]=[CH:37][C:34]([NH:35][CH3:36])=[CH:33][CH:32]=1>CN1C(=O)CCC1>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][NH:24][C:22]([C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([CH:3]([N:35]([C:34]3[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=3)[CH3:36])[CH3:4])[CH:6]=1)[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])=[O:23]
Reactant: CC(Br)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccc(F)cc1
Agent: Br
Solvent: CN1CCCC1=O
Product: CC(c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A solution of 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (85 mg, 0.16 mmol) and 4-fluoro-N-methylaniline (0.077 mL, 0.64 mmol) in NMP (1 mL) was stirred at room temperature for 4 h then at 45° C. for 1 h. The reaction mixture was allowed to cool to room temperature and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to afford N-(2-(dimethylamino)ethyl)-8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (42.0 mg, 53.1%) as a white solid. Mass Spectrum: M+H+ 497. NMR Spectrum: (CDCl3) 1.66 (d, 3H), 2.33 (s, 6H), 2.33 (bs, 2H), 2.60 (bs, 2H), 2.61 (s, 3H), 3.09-3.24 (m, 4H), 3.44-3.57 (m, 4H), 3.57-3.66 (m, 2H), 5.36 (q, 1H), 5.48 (s, 1H), 6.75 (dd, 2H), 6.77 (dd, 2H), 7.14 (bs, 1H), 8.33 (s, 1H), 8.44 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1Cl
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of 5.734 g (13.1 mmol) 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol, and 14.83 g (65.6 mmol) tin chloride dihydrate was heated to reflux under N2. Removed heat at 2½ hours and added a large volume of ice water. Made basic with sodium bicarbonate and stirred for 2 hours. With mixture still basic, extracted with chloroform, stirred organic layer with Darco, dried with sodium sulfate and filtered. Stripped solvent and dried in vacuo, giving 2.86 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=407.3, 409.3.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
4.8 mL of trifluoroacetic acid solution containing 0.48 g of tert-butyl 2-(benzamido)-4-(3-phenylpropyl)benzoate was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=1:1] to obtain 0.20 g of 2-(benzamido)-4-(3-phenylpropyl)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C:13](=[O:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([OH:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: -40 °C

Procedure:
A mixture of (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (1.462 g, 6.79 mmol) from Step A in methanol (20 mL) was cooled in an dry ice/acetone bath to −40° C. Sodium borohydride (0.514 g, 13.58 mmol) was added in portions over 5 minutes. The reaction allowed to warm to room temperature overnight, then it was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with 3×150 mL of ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ol: 1H NMR (300 MHz, CDCl3) δ ppm 7.38-7.16 (m, 5H), 4.21-4.04 (m, 1H), 3.66 (d, J=12.8, 1H), 3.51 (d, J=12.8, 1H), 3.07 (d, J=9.3, 1H), 2.65-2.53 (m, J=11.8, 2H), 2.52-2.43 (m, 1H), 2.18-2.07 (m, J=7.5, 16.3, 2H), 2.05-1.94 (m, J=8.7, 12.6, 1H), 1.84-1.74 (m, J=6.2, 1H), 1.49-1.34 (m, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([O:13]CC)=[O:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.O1CCOCC1.[OH-].[Li+].Cl>O>[C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([OH:13])=[O:12])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C)n(C(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)nn1C(C)(C)C
Temperature: 40 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylate (0.60 g, 2.85 mmol) in a mix of ethanol:water:dioxane (1:1:1, 9 mL) was added lithium hydroxide (0.48 mg, 11.4 mmol). The mixture was stirred at 40° C. for 5 hours. The solution was checked by LC-MS and diluted with water (10 mL) and the pH adjusted to 2 with 1N HCl. The solution was extracted with EtOAc (2×10 mL) and the combined organic phases washed with brine (20 mL), dried (NaSO4), and concentrated in vacuo to obtain 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylic acid (0.50 g, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.4 (s, 1H), 5.47 (s, 1H), 2.42 (s, 3H), 1.56 (s, 9H); MS (ESI) m/z: 183.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH2:10][CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=32)[C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1(O)[CH:25]=CC=[CH:22][CH:21]=1>>[C:18]1([O:17][C:15]([C:3]2[C:4]3=[N:5][C:6]4[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=4[N:8]3[CH2:9][CH2:10][C:2]=2[OH:1])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:25][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Product: O=C(Oc1ccccc1)C1=C(O)CCn2c1nc1ccccc12
Reaction time: 16 h

Procedure:
A mixture of the pyridobenzimidazo derivative VII prepared as in Example 1 (3.5 g, 13.6 mM) and phenol (7.0 g, 74.5 mM) in xylenes (350 mL) was heated to reflux under argon for 6 h and left at room temperature for 16 h. The resulting solid precipitate was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC, using methylene chloride and THF as eluents followed by recrystallization of the desired fractions from methylene chloride and acetone to give the title compound as a solid: mp 176°-178° C.; MS: 307 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH3:20])[CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[N:4]=[C:5]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:6]2[S:11][C:10]([CH2:12][N:13]([CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[S:35]([CH3:34])(=[O:37])=[O:36])[CH3:20])=[CH:9][C:7]=2[N:8]=1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyrrolidin-2-ylmethyl-amine hydrochloride salt (380 mg) in dichloromethane (10 mL) was added triethylamine (0.30 mL) and methane sulfonyl chloride (71 μL). The mixture was stirred at room temperature for 2 h and then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organics were washed with brine (20 mL), dried, reduced in vacuo and purified by column chromatography to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methanesulfonyl-pyrrolidin-2-ylmethyl)-methyl-amine as an off-white solid (124 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:17][N+:14]([O-:16])=[O:15])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@H](C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.2 %

Procedure:
The unsaturated ester (2) (2.95 g, 16.2 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 70° C. with nitromethane (1.9 mL, 35.2 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 22 mL, 22.0 mmol). After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with 2N HCl (30 mL) followed by brine (50 mL). The organic phase was collected, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 1:9) to give 1.152 g (29%) of a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cn1ccc(-c2ccc(C=O)cc2)n1
Product: Cn1ccc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>Cl.O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:2][CH2:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)=[O:30])[CH:24]=1
Reactant: NCCC1CCN(S(N)(=O)=O)CC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a mixture of 1.95 g. (0.008 mole) of 4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (~40° C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting crystalline precipitate was then recovered by means of suction filtration and thereafter recrystallized twice from acetonitrile to afford 0.997 g. of pure product. In this way, there was ultimately obtained a 36% of 4-[2-(4-chloropicolinamido)ethyl]-1-piperidinesulfonamide, m.p. 186°-187° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:55]([N:49]1[CH2:50][CH2:51][CH2:52][C@@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 61 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and benzoyl chloride as the starting materials in 61% yield. LCMS for C31H31ClN7O2 (M+H)+: m/z=568.0.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30])=[CH2:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[OH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:22]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1O
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (3.46 g) and 2-vinylphenol (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (5.55 g) and N-chlorosuccinimide (1.78 g), and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.70 g).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
0.71 ml (0.71 mmol, 2.98 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 122.8 mg (0.238 mmol) 3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (55) in 5 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 90 min at 0° C. and then for 5 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 119.3 mg (0.24 mmol, 99.91%) 3-(3′-Benzyl-4″-hydroxy-2,3″-disobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (56) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.86 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.87 (m, 1H, CH), 2.43 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.09 Hz, CH2), 2.61 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.93 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.95 (s, 2H, CH2Ph), 5.51 (s, 1H, OH), 6.88 (d, 1H, J=2.05 Hz), 6.95 (m, 2H), 6.97-7.26 (m, 11H). MS (EI): m/z=502 (40), 501 (100), 458 (4), 367 (10), 327 (7), 307 (8), 263 (8), 91 (43). HR-MS (EI): Calcd. for C36H39NO: 501.303164. Found: 501.303902.
Reaction SMILES: C1(C[O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc(O)nc1
Reaction time: 4.5 h
Yield: 99.7 %

Procedure:
To a solution of N-{6-[(phenylmethyl)oxy]-3-pyridinyl}acetamide (0.210 g, 0.87 mmol) in EtOH (10 mL) at rt was added Pd—C (0.046 g of 10 wt % on activated carbon (dry basis), ca. 50 wt % H2O; ca. 0.022 mmol Pd). The mixture was placed under an atmosphere of H2 and stirred for 4.5 h. The mixture was filtered through Celite (EtOAc wash) and concentrated in vacuo, affording 0.132 g of the title compound as a colorless solid: MS (ESI) m/z 152 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:20]1[CH:25]=CC=C[CH:21]=1>>[CH:20]([O:14][C:13]([CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12]1)=[O:15])([CH3:25])[CH3:21]
Reactant: O=C(O)C1CC(c2ccc(Cl)cc2)=NO1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C1CC(c2ccc(Cl)cc2)=NO1
Yield: 75 %

Procedure:
3-(4-chlorophenyl)-2-isoxazoline-5-carboxylic acid (2.2 g) prepared in Synthesis Example 3 was added with 20 ml of benzene and 1.4 g of thionyl chloride. After refluxing for 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 20 ml of toluene and added with 0.7 g of isopropyl alcohol. The mixture was further added with 0.8 g of pyridine at 0 to 10° C. and reacted for an hour at the room temperature. The reaction mixture was washed with a dilute aqueous hydrochloric acid solution and successively with water. The resulting solution was concentrated under reduced pressure and then purified by silica gel column chromatography (eluent; toluene) to give 2.0 g (75% yield) of oily desired product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][CH:34]([CH3:38])[C:35](O)=[O:36].C(N(C(C)C)CC)(C)C.[CH3:48][S:49]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[N:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]3[CH2:71][CH2:70][N:69]([C:72]([NH:74][NH2:75])=[O:73])[CH2:68][CH2:67]3)=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)(=[O:51])=[O:50]>CN(C=O)C.O>[CH3:33][CH:34]([CH3:38])[C:35]([NH:75][NH:74][C:72]([N:69]1[CH2:68][CH2:67][CH:66]([CH2:65][O:64][C:61]2[CH:62]=[N:63][C:58]([C:55]3[CH:56]=[CH:57][C:52]([S:49]([CH3:48])(=[O:50])=[O:51])=[CH:53][CH:54]=3)=[CH:59][CH:60]=2)[CH2:71][CH2:70]1)=[O:73])=[O:36]
Reactant: CC(C)C(=O)O
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)NN)CC3)cn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)NNC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
TBTU (279 mg, 0.87 mmol) and HOBT (24 mg, 0.17 mmol) were added to a mixture of 2-methylpropanoic acid (81 μL, 0.87 mmol), diisopropylethylamine (0.758 mL, 4.35 mmol) in DMF (5 mL) at ambient temperature. The mixture was stirred at ambient temperature for 15 min. The mixture was charged with 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide (352 mg, 0.87 mmol), and was stirred at ambient temperature overnight. The mixture was charged with water and set at ambient temperature overnight. The resulting tan precipitate was filtered, washed with water, and dried in a vacuum oven to give 350 mg (85%) of N′-(2-methylpropanoyl)-4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (d, 1H, J=1.9 Hz), 8.44 (d, 1H, J=2.9 Hz), 8.36 (d, 1H, J=1.9 Hz), 8.29 (d, 2H, J=8.6 Hz), 8.06 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.08-3.96 (m, 4H), 3.25 (s, 3H), 2.80-2.70 (m, 2H), 2.41 (septet, 1H, J=6.8 Hz), 2.08-1.92 (m, 1H), 1.82-1.73 (m, 2H), 1.30-1.10 (m, 2H), 1.02 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:7]=12)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:19]1[C:7]2=[C:6]([CH2:5][CH2:4][NH2:1])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]2[CH2:15][CH2:16][NH:17][CH2:18]1
Reactant: O=[N+]([O-])/C=C/c1c2n(c3ccccc13)CCNCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1c2n(c3ccccc13)CCNCC2
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A solution of 11-[(E)-2-nitroethenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (236 mg, 0.92 mmol) in THF (9 mL) is cooled to 0° C. and treated with lithium aluminum hydride (1M THF, 2.8 mL, 2.8 mmol) with gas evolution. The reaction is heated to reflux for 4 hrs followed by cooling to rt for 16 hrs. At this time, the reaction mixture is quenched by the successive addition of 0.11 mL water, 0.10 mL 5N NaOH, and 0.37 mL water. The resulting thick gelatinous suspension is diluted with dichloromethane (30 mL), filtered through celite, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 20:2.5:77.5 methanol/ammonuim hydroxide/dichloromethane to afford 92 mg of 2-(2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanamine as a yellow syrup. IR (liq.) 3353, 3307, 3087, 3048, 3025, 2935, 2844, 1469, 1426, 1373, 1340, 1324, 1181, 1015, 742 cm−1; MS (FAB) m/z 230 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][C:6]([CH2:27][C:28]([OH:30])=[O:29])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:36]>ClCl>[C:21]1([S:20]([CH2:19][C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:16])[F:17])[CH:13]=[CH:14][C:9]=2[C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:27][C:28]([OH:30])=[O:29])[CH:7]=2)=[O:36])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CS(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (6-methoxy-2′-phenylsulfanylmethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.030 g, 0.07 mmol) in CH2 Cl2 was added 3-chloroperoxybenzoic acid (0.015 g, 0.07 mmol), and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.