Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([O:48][CH2:49][CH2:50][O:51][CH3:52])[CH:46]=[CH:47][C:39]=3[O:38][CH3:37])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COCCOc1ccc(OC)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OCCOC)ccc4OC)C3)CC2)nc2ccccc21
Yield: 79.6 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.32 g, 0.6 mmol, Preparation 12.1), 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (0.16 g, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.72 mmol), 1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol), diisopropyoethylamine (0.2 mL, 1.2 mmol) and dichloromethane (20 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 5% methanol in dichloromethane and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.32 g of the title compound, Rf=0.46 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[C:6]([Cl:26])[CH:5]=1.[NH:27]1[CH2:31][CH2:30][N:29]=[C:28]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][C:28]2[NH:29][CH2:30][CH2:31][N:27]=2)[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9]
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1Cl

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 72 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 100 μL of DIPEA in 500 μL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 440 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][C:39]([OH:43])([CH:41]=[CH2:42])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:42][CH2:41][C:39]([OH:43])([CH3:40])[CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: C=CC(C)(C)O
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Product: CC(C)(O)CCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.2 g, 0.352 mmol) and 2-Methyl-3-buten-2-ol (0.110 ml, 1.056 mmol), the title compound was obtained as a solid (83 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.76 (s, 1H), 8.28 (d, J=5.49 Hz, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.35 (d, J=6.04 Hz, 1H), 7.29 (t, J=7.69 Hz, 1H), 6.31 (d, J=5.49 Hz, 1H), 4.28 (s, 1H), 3.71 (m, 4H), 3.50 (m, 4H), 2.81 (m, 2H), 1.77 (m, 2H), 1.12 (s, 6H); MS (ESI): 620 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:20]([C:21]#[C:22][Si](C)(C)C)=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:27])[CH:3]=1.[F-].[Cs+]>CO>[NH2:1][C:2]1[C:20]([C:21]#[CH:22])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:27])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1Oc1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: C#Cc1cc(Oc2cc(F)ccc2C(=O)OCC)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 242C (2.69 g) in methanol (20 mL) was added CsF(5 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH2:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1.C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH:24][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2ccccc2OC)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-amino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (240 mg, 0.703 mmol) in pyridine/DCM (1 ml/1 ml) was added succinic anhydride (84 mg, 0.843 mmol) and stirred at room temperature for 1 hour. Then, the mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC to give (S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. HPLC Retention time 1.29 minutes (condition A): MS 442.4 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([N:18]([CH2:27][CH2:28][CH2:29][CH3:30])[C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1)CCC>N1CCCCC1>[CH2:4]([NH:1][C:19]1([NH:18][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=[CH:21][C:22]([CH:11]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:25][CH2:26]1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Product: CCCCNC1(NCCCC)C=CC(C=Cc2ccc([N+](=O)[O-])cc2)=CC1
Yield: 43.6 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (9.92 g, 0.055 mol) and 4-dibutylamino-benzaldehyde (14.32 g, 0.055 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a red solid, 4.12 g (0.012 mol, 16%) of the desired product.
Reaction SMILES: CI.[F:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[C:8]([F:10])[CH:9]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC#N>[F:3][C:4]1[CH:5]=[C:6]([S:11][CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(F)cc(S)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSc1cc(F)cc(F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methyl iodide (2.91 g, 20.5 mmol) was added dropwise to a stirred mixture of 3,5-difluorobenzenethiol (2.00 g, 13.7 mmol) and potassium carbonate (5.67 g, 41.0 mmol) in dry MeCN (24 mL) at room temperature. The reaction mixture was stirred at 80° C. for 2 h. After cooling, the mixture was filtered under vacuum, washed with MeCN and concentrated under reduced pressure to give the sub-title compound, which was used directly in the next step without further purification (1.74 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:21])([C:22]2[CH:27]=[CH:26][C:25]([C:42]3[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=3)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCC(O)(c1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 54.9 %

Procedure:
3-{4-[1-(4-Bromo-phenyl)-1-hydroxy-heptyl]-benzoylamino}-propionic acid methyl ester (350 mg, 0.74 mmol), potassium carbonate (304 mg, 2.2 mmol), 4-trifluoromethylphenyl boronic acid (279 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 mL/5 mL) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[1-Hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (220 mg) as yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.Br.[C:17](OCC)(=O)C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]([O:15][CH3:17])=[O:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)OCCC2C(=O)O
Agent: Br
Product: COC(=O)C1CCOc2cc(O)ccc21
Temperature: 130 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To 7-methoxy-3,4-dihydro-2H-chromene-4-carboxylic acid (0.71 g, 3.41 mmol) was added HBr (0.276 g, 3.41 mmol) and the reaction was heated at 130° C. for 3 hours. The reaction was cooled and concentrated, and the residue was loaded onto a silica gel samplet. The product was eluted using a gradient of 0.5% MeOH/CH2Cl2 containing 0.5% acetic acid to 10% acetic acid/CH2Cl2 containing 0.5% acetic acid. The isolated product was dissolved in MeOH (5 mL) and concentrated sulfuric acid (1 mL) was added and the reaction heated at 75° C. After 2 hours, reaction was cooled, diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 0.5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2, to provide the title compound (0.312 g, 43.9% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([C@H:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:56][C@@H:54]([C:51]4[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=4)[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc([C@@H](C)N)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)c2ccc(C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-1-(4-methylphenyl)ethylamine (Lancaster) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Yield: 79.5 %

Procedure:
Combine N,N,N′-Trimethyl-N′-(6-nitro-benzothiazol-2-yl)ethane-1,2-diamine (5.79 g, 20.6 mmol) and 5% palladium on carbon (5.02 g) in EtOH (200 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi of hydrogen at room temperature for 18 h. Filter the reaction mixture through filter paper, wash with EtOH (50 mL), and concentrate in vacuo to afford the crude title compound (4.1 g, 80%). The crude product was carried on as is. 1H NMR (400 MHz, DMSO-d6): δ 7.10 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=1.8 Hz), 6.52 (dd, 1H, J=8.4, 2.2 Hz), 4.80 (br s, 2H), 3.51 (t, 2H, J=6.6 Hz), 3.04 (s, 3H), 2.48 (m, 2H), 2.18 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[C:22]3[CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[CH2:26][CH2:27]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)CCCBr
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
9.2 g of sodium carbonate are added to a solution of 10 g of 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)piperidine in 100 cc of chloroform, a solution of 7.2 g of 5-bromo-2-pentanone in 50 cc of chloroform is then added dropwise within 20 minutes, and the mixture is subsequently boiled at reflux for 17 hours. After cooling, the precipitate is filtered off, the filtrate is extracted twice with water, dried over magnesium sulphate and concentrated by evaporation. The residue is filtered over a column of 170 g of silica gel. The fraction eluted with chloroform containing 1% of methanol is dissolved in acetone and acidifed with hydrogen chloride in ether. After the addition of more ether, the hydrochloride of the title compound crystallizes. M.P. 235°-238°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I:22]Cl>CO.ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([I:22])=[C:11]([CH:10]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 1 h
Yield: 71 %

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromethane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dichloromethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na) ; Rf=2.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[CH:22]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=2[OH:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2O)CC1
Temperature: 75 °C

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh3)2Cl2 (600 mg), copper iodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide (30 mL) is heated under an argon atmosphere to 75° C. for 4 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.32 min; Mass spectrum (ESI+): m/z=402, 404 [M+Na]+.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:30]=[CH:29][C:28]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[N:34]=[C:33]([C:49]3[CH:54]=[CH:53][C:52]([C:22]4[CH:23]=[CH:24][C:19]([C:16]5[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=5)=[CH:20][CH:21]=4)=[CH:51][CH:50]=3)[N:32]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccc(-c3ccc(-c4nc(-c5ccc(-c6ccccc6)cc5)nc(-c5ccc(-c6ccccc6)cc5)n4)cc3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 30 ml of tetrahydrofuran cooled to −78° C. in which prepared by dissolving 0.69 g of 4-bromobiphenyl. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2.5 hours. A 1.35 g portion of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine prepared in Reference Example 3 and 0.12 g of tetrakis(triphenylphosphine)palladium(0) were dissolved in 60 ml of tetrahydrofuran and added to this solution, followed by stirring under heating reflux for 2 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained solid was purified by a silica gel column chromatography (developing solvent hexane:chloroform=2:1 to chloroform) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-biphenylyl)-6-[1,1′:4′,1″]terphenyl-4-yl-1,3,5-triazine (1.09 g, yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:40]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.3 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (225.3 mg, 0.50 mmol) was dissolved in methylene chloride (2.0 ml) to which were subsequently added pyridine (0.05 ml, 0.62 mmol) and benzoyl chloride (0.09 ml, 0.77 mmol). After 14 hours of stirring at room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The resulting organic layer was washed with saturated sodium chloride aqueous solution and water in that order, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and recrystallization (ethyl acetate-ether) to obtain 196.3 mg (70.6%) of the title compound in a light brown powder form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[OH:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:8])=[CH:4][C:3]=1[OH:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Cl)c(O)c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 44 %

Procedure:
The title compound is prepared from 4-chloro-3-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 44% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=328 [M+H]+.