Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH3:34].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][CH2:33][CH3:34])(=[O:44])[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:42]
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), adipic acid monoethyl ester (0.25 g, 1.44 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified by chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.275 g), melting point: 88° C.
Reaction SMILES: ONC(=N)C1C2C(C=CC=1)=NN(CCCC(OCC)=O)C=2.[OH:22][NH:23][C:24](=[NH:42])[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[N:28][N:29]2[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][C:52]=1[O:53][CH:54]([CH3:56])[CH3:55])[C:47](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:43][C:44]1[CH:45]=[C:46]([C:47]2[O:22][N:23]=[C:24]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[N:28][N:29]4[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:42]=2)[CH:50]=[CH:51][C:52]=1[O:53][CH:54]([CH3:55])[CH3:56]
Reactant: CCOC(=O)CCCn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCOC(=O)CCCn1cc2c(C(=N)NO)cccc2n1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.2 %

Procedure:
A solution of a mixture of ethyl 4-{4-[(hydroxyamino)(imino)methyl]-2H-indazol-2-yl}butanoate & ethyl 4-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}butanoat (D56) (4 g, 13.78 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (2.96 g, 13.78 mmol), EDC (2.91 g, 15.16 mmol) and HOBT (2.321 g, 15.16 mmol) in DMF (40 ml) was stirred at RT for 3 hrs to form intermediate then heated at 120° C. for 2 hrs to cyclise. The solution was cooled, diluted with EtOAc, washed with water 3× dried (magnesium sulphate) and evaporated. Purified by flash chromatography eluting with EtOAc/iso-hexane 1:3. The combined fractions were evaporated to give the title compound (1.5 g) as a white solid. MS (ES): C24H2535ClN4O4 requires 468; found (MH+) 469. δH (CDCl3, 400 MHz): 1.24 (3H, t), 1.46 (6H, d), 2.31 (4H, m), 4.12 (2H, q), 4.55 (2H, t), 4.73 (1H, m), 7.08 (1H, d), 7.52 (1H, dd), 7.62 (1H, d), 8.06 (1H, dd), 8.10 (1H, dd), 8.29 (1H, d), 8.70 (1H, d).
Reaction SMILES: [OH:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1c2nnc(=O)n-2c2ccc(Cl)cc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 4-hydroxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml of methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][C:5]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]([Br:32])=[CH:19][C:18]=2I)=[C:4](I)[CH:3]=1.CCCCCC.[Br-].[Mg+2].[Br-].[CH:44]([C:47]1[CH:52]=[C:51]([CH:53]([CH3:55])[CH3:54])[CH:50]=[C:49]([CH:56]([CH3:58])[CH3:57])[C:48]=1[B:59](OC)OC)([CH3:46])[CH3:45]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][C:5]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]([Br:32])=[CH:19][C:18]=3[B:59]([C:48]3[C:49]([CH:56]([CH3:57])[CH3:58])=[CH:50][C:51]([CH:53]([CH3:55])[CH3:54])=[CH:52][C:47]=3[CH:44]([CH3:46])[CH3:45])[C:4]=2[CH:3]=1
Reactant: COB(OC)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: CCCCCCCCOc1cc(-c2cc(OCCCCCCCC)c(Br)cc2I)c(I)cc1Br
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1cc2c(cc1Br)B(c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1cc(Br)c(OCCCCCCCC)cc1-2
Temperature: 25 °C

Procedure:
2.0 g of 4,4′-dibromo-2,2′-diiodo-5,5′-dioctyloxy-1,1′-biphenyl synthesized as above was put in a 100 ml flask in an atmosphere of nitrogen and 20 ml of tetrahydrofuran was added to dissolve the same. Then, the tetrahydrofuran solution was cooled to −90° C. and 3.4 ml of 1.6M hexane solution was added dropwise. After 1-hour stirring, a solution of 1.5 g of magnesium bromide in 20 ml of tetrahydrofuran was added, warmed to room temperature, and stirred for 1 hour. The mixture was cooled again to −90° C., and 1.01 g of (2,4,6-triisopropylphenyl)dimethoxyborane was added. After warming, the mixture was allowed to react under reflux for 12 hours.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1
Reactant: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A suspended mixture of methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (0.88 g, 2.1 mmol) and sodium hydroxide (4.00 g, 10.0 mmol) in water (50 mL) and methanol (50 mL) was stirred at 60° C. for 2 h. The reaction mixture was concentrated in vacuo to remove most of methanol and acidified with concentrated hydrochloric acid to pH 1-2. The solid residue was filtered off, washed with water (50 mL) and dried in vacuo to afford 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.64 g, 75%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.29-6.95 (m, 4H), 6.55 (s, 1H), 6.37 (s, 1H), 5.08 (ABq, 2H), 4.74 (ABq, 2H), 4.44 (t, J=8.7 Hz, 2H), 3.01-2.80 (m, 2H); MS (ES−) m/z 403.4 (M−1).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([NH:10][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:7][CH:8]=[CH:9][C:2]=12.[ClH:45].[ClH:45].[N:1]1[S:5][N:4]=[C:3]2[C:6]([NH:10][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: Nc1cccc2nsnc12
Reactant: ClCCCl
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2cccc3nsnc23)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
302 mg Benzo[1,2,5]thiadiazol-4-ylamine and 435 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmol) and 600 mg sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 40 mg of the polar diastereomer of N′-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a red solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.15 ml) in 2-butanone (2 ml) (35 mg; m.p. 122-125° C.).
Reaction SMILES: Cl.Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.Cl[C:31]1[N:36]=[C:35]([C:37]2[S:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:45]([OH:46])[C:39]=3[CH:38]=2)[C:34]([CH3:47])=[CH:33][N:32]=1.NCCCN1CCN(C)CC1>>[CH3:47][C:34]1[C:35]([C:37]2[S:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:45]([OH:46])[C:39]=3[CH:38]=2)=[N:36][C:31]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:32][CH:33]=1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(O)cccc2s1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2c(O)cccc2s1

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2-(2-chloro-5-methylpyrimidin-4-yl)benzo[b]thiophen-4-ol and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 398 [M+H].
Reaction SMILES: CO[C:3](=[O:24])[C@H:4]([CH2:22][OH:23])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.Cl.COC(=O)[C@H](CO)[NH2:30].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]3[O:24][CH:3]=[C:4]([C:22]([NH2:30])=[O:23])[N:5]=3)=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: NC(=O)c1coc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C

Procedure:
N-[4-(4-Fluorophenoxy)benzoyl]-L-serine methyl ester. To an ice cold solution of 4-(4-fluorophenoy)benzoic acid (0.79 g, 3.4 mmol), L-serine methyl ester hydrochloride (0.59 g, 3.7 mmol), and a 1-hydroxybenzotriazole hydrate (0.57 g, 3.7 mmol) in DMF (20 mL) was added N-methylmorpholine (82 mL, 7.4 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.72 g, 3.7 mmol). The resulting solution was allowed to warm to room temperature overnight and was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined ethyl acetate layers were washed with water (3×), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the desired product as an oil. 1H NMR (DMSO-d6): 8.51 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.28 (t, J=8.4 Hz, 2H), 7.18-7.13 (m, 2H), 7.04 (d, J=9.0 Hz, 2H), 5.06 (t, J=6.3 Hz, 1H), 4.53 (q, J=7.8 Hz, 1H), 3.79 (t, J=5.4 Hz, 2H), 3.71 (s, 3H).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[N:7][C:8]=1[F:9].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:50][NH2:51])[CH:47]=[CH:48][CH:49]=1>>[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:10]([C:5]3[CH:6]=[N:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:51]2)[CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cnc(F)c(Cl)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
240 mg (0.86 mmol) of the compound of Example 15A is reacted analogously to the synthesis of the compound of Example 20A with 230 mg (1.29 mmol) of 3-chlorophenylhydrazine hydrochloride. After hydrolysis, 21 mg (7% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([O:14][CH3:15])=[CH:7][CH:6]=1)[OH:4].[CH2:16]([CH2:23][C:24](=O)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H][H]>C(O)C.[Pt]>[OH:4][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([O:14][CH3:15])=[CH:7][CH:6]=1)[CH2:2][NH:1][CH:24]([CH3:25])[CH2:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(C(O)CN)cc1C(N)=O
Reactant: [H][H]
Reactant: CC(=O)CCc1ccccc1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(C(O)CNC(C)CCc2ccccc2)cc1C(N)=O

Procedure:
To a solution of the above 5-(2-amino-1-hydroxyethyl)-o-anisamide in ethanol (70ml) was added benzyl acetone (1.5g), and the mixture was gently refluxed for 1 hour. The cooled solution was then added to a suspension of pre-reduced 5% platinum on charcoal (0.4g) in ethanol (10 ml) and hydrogenated until uptake was complete. Hydrogen uptake was complete within 14 hours. The catalyst and solvent were removed to leave 5-[1-hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]-o-anisamide as an oil (2.36g) which slowly crystallised on rubbing with ether, m.p. 110°-148°.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:12]=[C:13]([N:15]([CH:17]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].CI.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:29][C:27]1[CH:28]=[C:23]([CH:17]([N:15]([CH3:16])[C:13]2[CH:14]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:41])=[O:2])[CH:10]=[C:11]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=3)[CH:12]=2)[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:24]=[C:25]([F:30])[CH:26]=1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(C)C(CCC(C)C)c2cc(F)cc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CC(C)CCC(c1cc(F)cc(F)c1)N(C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 80 °C
Yield: 50 %

Procedure:
A solution of 2-(5-{[1-(3,5-Difluoro-phenyl)-4-methyl-pentyl]-methyl-amino}-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester, compound 29e, (0.25 g, 0.4 mmol), MeI (0.3 ml, 4 mmol), Cs2CO3 (0.72 g) and acetonitrile in a sealed reaction tube was heated to 80° C. overnight. The solvent was removed by vacuum and the crude was purified by preparative TLC to give the title compound (50% yield). Calcd. MW 575.67 Found MH+ 576.3.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4](O)=[CH:3][CH:2]=1.[OH-:14].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>Cl[Cu].[Cu].O>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:14][C:21]1[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=1[CH3:23]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: [OH-]
Reactant: Cc1ccc(Cl)cc1
Agent: Cl[Cu]
Agent: [Cu]
Agent: [K+]
Solvent: O
Product: Cc1ccccc1Oc1ccccc1-c1ccccc1
Reaction time: 15 h
Yield: 83.3 %

Procedure:
A mixture of 1,123 g (6.6 moles) of biphenyl-4-ol. 396 g (6.0 moles) of potassium hydroxide (85%), 1,519 g (12.0 moles) of p-chlorotoluene, and a catalyst mixture consisting of 7.5 g of CuCl, 3.0 g of CuCl2, 3.0 g of CuCO3.Cu(OH)2H2O, 3.0 g of copper powder, and 18 g of activated alumina were heated to reflux with stirring for 15 hr. The reaction was conducted under a nitrogen blanket. Water of reaction was removed by azeotropic distillation, and when the pot temperature had reached 167°, 70 ml of dimethylacetamide, 6.0 g of CuCl, 3.0 g of CuCl2, 3.0 g of CuCO3. Cu(OH)2.H2O, 6.0 g of copper, and 14 g of alumina were added. Refluxing was continued for 4 hr. and approximately 20 ml of p-chlorotoluene was removed by distillation. After an additional 10 hr. of reflux the pot temperature was raised to 230° and 180 ml of p-chlorotoluene was distilled off. The reaction mixture was cooled to about 180° and then poured into ice water with stirring. The resulting precipitate was filtered, washed with water, and recrystallized from ethanol to give 1,303 g (5.0 moles, 76%) of p-biphenylyloxytoluene, mp 97° to 99°. Vacuum distillation followed by recrystallization from ethanol gave colorless platelets of mp 99° to 100°. IR (KBr): 1270 cm-1 (aryl ether). A 988 g (3.8 moles) sample of this compound was dissolved in 7.5 liters of acetic acid, together with 94.5 g (0.38 mole) of cobalt acetate tetrahydrate, and 3.1 g (0.038 mole) of hydrobromic acid. Oxygen was passed through the solution with stirring and heating to 100°. After approximately 3 hours, the reaction was complete. After cooling to room temperature, the resulting crystalline precipitate was filtered and recrystallized from o-dichlorobenzene to give 799 g (2.75 moles, 72%) of colorless crystals, mp 243° to 244°, IR(KBr): 1700 cm-1 (acid carbonyl), 1280 cm-1 (aryl ether). Reaction of 798.0 g (2.75 moles) of acid with 399.0 ml (5.50 moles) SOCl2 in 1500 ml benzene (containing 4 drops pyridine) at 60°-70° followed by vacuum distillation (up to 215° at 0.40 mm Hg) yielded 805.7 g (95.0%) colorless crystals of p-(4-biphenylyloxy)benzoyl chloride of mp 93.5°-94.7° and a light-brown forecut of 20.86 g (2.46%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)=[CH:35][CH:36]=1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2ccc(OC)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-anisaldehyde (16.7 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the isolvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(4-Methoxybenzyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 10 as a colorless oil (18.7 mg, 59%). LRMS 366.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=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.C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)[N:28]=[N:27][N:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Yield: 95.1 %

Procedure:
A mixture of 4-methylphenyl boronic acid (9.7 g; 71 mmol), sodium carbonate (16.7 g; 158 mmol), water (100 ml), methanol (50 ml) and toluene (50 ml) was heated to 60° C. to give a clear solution. Compound C (20.0 g; 55 mmol) was then added, followed by tetrakis(triphenylphosphine)palladium (0.3 g; 0.25 mmol) and the mixture heated at reflux for 3 hours. Toluene (30 ml) was added and the warm mixture was filtered through diatomaceous earth. The organic phase was separated and the aqueous phase extracted with toluene (40 ml). The combined organic phases were evaporated to give a solid which was recrystallised from toluene/petroleum ether (100°-120° C.) (1:1 v/v) to give 5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (D) (18.7 g; 90% yield), m.p. 164°-166° C.; NMR (CDCl3): 2.3(3H, s), 6.45(2H, d), 6.85(4H, m), 7.38(1H, d), 7.65(2H, m), 7.85(1H, d), 8.0(2H, d).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20](=[O:24])[CH2:21][CH2:22]Cl)[CH:14]=3)[S:9][C:8]=2[CH:7]=1)=[O:5].[I-].[K+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[ClH:1].[ClH:1].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20](=[O:24])[CH2:21][CH2:22][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[CH:14]=3)[S:9][C:8]=2[CH:7]=1)=[O:5])[CH3:28]
Reactant: CCNCC
Reactant: O=C(CCCl)c1ccc2c(c1)Oc1ccc(C(=O)CCCl)cc1S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCC(=O)c1ccc2c(c1)Oc1ccc(C(=O)CCN(CC)CC)cc1S2
Product: Cl
Reaction time: 72 h

Procedure:
A mixture of 22.4 g (0.03 mole) 2,7-bis(3-chloropropionyl)phenoxathiin, 1 g of potassium iodide, 75 ml of diethylamine and 75 ml of tetrahydrofuran is allowed to stand for 3 days then filtered and the filtrate evaporated to dryness. The residue is dissolved in ethanol and acidified with etheral HCl to Congo Red. The solution is diluted with ethyl ether and the solid filtered off. The solid is thrice dissolved in methanol, filtered, precipitated with ethyl ether and filtered. The resulting product is dried to give 2,7-bis(3-diethylaminopropionyl)phenoxathiin dihydrochloride. M.P. 189°-190°C.