Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20]C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>C(O)(=O)C>[ClH:28].[CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1

Procedure:
Using N-benzyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (820 mg, 2.2 mmol), 4N hydrochloric acid-dioxane (10 ml) and acetic acid (30 ml), a similar procedure to Production Example 213 was carried out to obtain N-benzyl-2-amino-5-indan carboxamide hydrochloride (660 mg, 2.2 mmol) having the following physical properties:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:15](=[O:17])[CH3:16])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)ccn1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (87 mmol) and pyridine (130 mol) in 200 mL dichloromethane was added dropwise acetyl chloride (117 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was washed with hexane to afford 13.5 g of N-(4-bromopyridin-2-yl)acetamide (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22].Cl[C:33]1C=C(S(Cl)(=O)=O)C=C[C:38]=1Cl>>[CH2:33]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:38]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=499.0 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36]C)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12.B(Br)(Br)Br>C(Cl)Cl.CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cncn4C)sc23)c(F)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4O)cc3F)c2s1
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a solution of compound 28c (example 10, scheme 8) (115 mg, 0.21 mmol) in DCM (10 mL) at −40° C. was added BBr3 (1.0M, 0.86 mL, 0.86 mmol). The reaction mixture was allowed to stir for 1 hr then diluted with MeOH (2 mL) and water (1 mL) and concentrated. The residue was purified by preparative HPLC (Thermo C-18 column, gradient MeOH/water from 95:5 to 60:40) to afford title compound 115 (30 mg, 27% yield) as a white solid. 1H NMR (DMSO-d6). δ (ppm): 10.57 (s, 1H), 9.88 (s, 1H), 9.59 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.92 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 7.86 (dd, J=12.7 Hz, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.42 (dd, J=9.0 Hz, J=1.7 Hz, 1H), 7.40 (s, 1H), 6.93-6.84 (m, 2H), 6.75 (t, J=8.0 Hz, 1H), 6.63 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.61 (s, 2H). MS (m/z): 518.1 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>CN1C(=O)CCC1.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 ml) was added dropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) in NMP (50 ml). After the addition was complete, the mixture was stirred at ambient temperature for 1 h. After this time, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (150 ml), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[CH2:9][OH:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:21][O:22][CH2:23][O:10][CH2:9][C:6]1[CH:7]2[CH2:8][CH:3]([CH2:4][CH:5]=1)[C:2]2([CH3:11])[CH3:1]
Reactant: COCCl
Reactant: CC1(C)C2CC=C(CO)C1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCC1=CCC2CC1C2(C)C
Yield: 100 %

Procedure:
rac-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol (10.0 g, 65.7 mmol), diisopropylethylamine (17.0 mL, 97.6 mmol) and chloromethyl methyl ether (6.5 mL, 85.6 mmol) were stirred in dichloromethane (100 mL) at room temperature for 1 day. After completion of the reaction, the reaction solution was mixed with saturated sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=10/1) to give the desired product (100% yield).
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH2:4][CH3:5].I[CH3:22].O>CN(C)C=O>[CH3:22][N:7]([C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)CC)cc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of sodium hydride (60% active, 31 mg) in dimethylformamide (1 ml) was added a solution of ethyl 4-propionamidocinnamate (160 mg) in dimethylformamide (2 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred for 1 hour at same temperature, and a solution of iodomethane (111 mg) in dimethylformamide (2 ml) was added thereto. The reaction mixture was stirred at same temperature for 2 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacua to give ethyl 4-(N-methylpropionamido)cinnamate (168 mg) as an oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][C:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])([CH3:62])[CH3:61])/[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38]I)[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH:71][C:72]1[CH:73]=[C:74]2[C:79](=[CH:80][C:81]=1[OH:82])[CH:78]=[N:77][N:76]=[CH:75]2.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][C:60]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])([CH3:62])[CH3:61])/[C:27]([NH:29][CH:30]2[C:56](=[O:57])[N:32]3[C:33]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:34]([CH2:38][N:76]4[N:77]=[CH:78][C:79]5[C:74]([CH:73]=[C:72]([OH:71])[C:81](=[O:82])[CH:80]=5)=[CH:75]4)[CH2:35][S:36](=[O:37])[C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc2cnncc2cc1O
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cn3cc4cc(O)c(=O)cc-4cn3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-iodomethyl-3-cephem-4-carboxylate 1-oxide (IIa, 538 mg, 0.5 mmol), 6,7-dihydroxyphthalazine hydrobromide (158 mg, 0.65 mmol) and triethylamine (0.1 ml, 0.7 mmol) in DMF (1.5 ml) was stirred at room temperature for 3 hr. The reaction mixture was diluted with EtOAc (100 ml), washed with aqueous sodium thiosulfate, water, and aqueous sodium chloride, dried over magnesium sulfate and concentrated to yield 547 mg of a crude product, which was chromatographed on a silica gel column (7 g, 5% methanol in chloroform). The desired fractions were combined and concentrated to yield 532 mg (Yield 97%) of the title compound.
Reaction SMILES: CCOC(C)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:11]([NH2:13])=O.CCN(CC)CC>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:11]#[N:13]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N)c(F)c1
Reaction time: 2 h
Yield: 114.1 %

Procedure:
To a 0° C. EtOAc (150 mL) solution of 3-fluoro-4-nitrobenzamide (4.85 g, 26.4 mmol) and Et3N (5.34 g, 52.8 mmol) was added dropwise a CH2Cl2 (50 mL) solution of 1,1,1-trichloroacetyl chloride (5.28 g, 29.04 mmol). The reaction was complete in 2 h (TLC, 1:1 hexane:EtOAc), then it was washed with 1N HCl, dried (MgSO4) and evaporated to give 4.1 g of the corresponding nitrile.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[C:30]([Cl:32])[C:29]([Cl:33])=[C:28]([Cl:34])[CH:27]=4)[N:20]=3)=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[Cl:32][C:30]1[CH:31]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]4)=[N:14][CH:15]=3)[CH:24]=[CH:23][N:22]=2)[CH:27]=[C:28]([Cl:34])[C:29]=1[Cl:33]
Reactant: C=CCOC(=O)N1CCN(c2ccc(-c3ccnc(Nc4cc(Cl)c(Cl)c(Cl)c4)n3)cn2)CC1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cc(Nc2nccc(-c3ccc(N4CCNCC4)nc3)n2)cc(Cl)c1Cl
Yield: 41.7 %

Procedure:
A solution of 4-(2-(4-allyloxycarbonylpiperazin-1-yl)pyridin-5-yl)-N-(3,4,5-trichlorophenyl)-2-pyrimidineamine (170 mg,0.33 mmol) in dichloromethane and DMF (3 ml,1:1 mixture) was stirred with acetic acid (1 ml), dichloro-bis(triphenylphosphine)palladium (II) (15 mg) and tri-n-butyltin hydride at room temperature for 5 min. The reaction was added to a saturated aqueous NaHCO3 solution, which was extracted with ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane and then subjected to column chromatography (silica gel with 1% ammonium hydroxide-8% methanol-dichloromethane) to give the title compound (60 mg) as an off-white solid m.p. 208-211°. δH(d6 DMSO) 10.03(1H, s), 8.91 (1H, d, J 2.5 Hz), 8.51 (1H, d, J 5.4 Hz), 8.22 (1H, dd, J 9.1, 2.5 Hz),8.16 (2H, s), 7.43 (1H, d, J 5.4 Hz), 3.56 (4H, m) and 2.78 (4H, m).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=O.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: CCCCN
Solvent: COC(OC)OC
Product: CC(=O)CC(=O)C=Cc1cc(O)ccc1Br
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
Ethyl acetate (3.1 mL), 2,4-pentanedione (4.25 mL, 41.4 mmol) and boron trioxide (2.6 g, 38 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 2-bromo-5-hydroxybenzaldehyde (1.26 g, 6.27 mmol) and trimethyl orthoformate (0.70 mL, 6.4 mmol) in 6 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (3.1 mL, 31 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (15 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) twice followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a yellow crystal (0.12 g, 7%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:38][NH:39][C:40]1=[N:41][C:42](=[O:52])[S:43]/[C:44]/1=[CH:45]\[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:38][NH:39][C:40]1=[N:41][C:42](=[O:52])[S:43]/[C:44]/1=[CH:45]\[CH:46]1[CH2:51][CH2:50][N:49]([C:11]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:13])[CH2:48][CH2:47]1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2oc3ccccc3c2C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
To a solution of 3-methyl-1-benzofuran-2-carboxylic acid (19.4 mg) in N,N-dimethylformamide (1 mL) were added 1-hydroxybenzotriazole (16.2 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23 mg), and the mixture was stirred at 0° C. for 5 min. To the reaction mixture were added triethylamine (0.28 mL) and (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (29.8 mg), and the mixture was further stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (19.3 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccccc1OCc1ccccc1
Yield: 99.7 %

Procedure:
To a stirred solution of 2-benzyloxynitrobenzene (9.92 g, 43.3 mmol) and NiCl2 (20.3 g, 157 mmol) in MeOH (350 mL) was added portionwise NaBH4 (8.09 g, 214 mmol) at 0° C. After disappearing of the starting material (monitored by TLC), the mixture was evaporated off. The black precipitate was dissolved in 1N HCl, then acidic solution was alkalified by the addition of 1N NaOH and extracted with EtOAc. The extracts were washed brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with CHCl3 as eluent gave 2-benzyloxy aniline (8.60 g, 100%) as a reddish oil. 1H-NMR (CDCl3) δ3.71 (broad s, 2H), 5.06 (s, 2H), 6.68-6.86 (m, 4H), 7.32-7.44 (m, 5H); FAB-MS m/z 200 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].O.C(OC(C)C)(C)C>N1C=CC=CC=1>[C:12]([O:11][CH:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)(=[O:14])[CH3:13]
Reactant: OC1CCc2c(Br)cccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(=O)OC1CCc2c(Br)cccc21

Procedure:
3.0 g of 4-bromo-1-indanol (RS) in 30 ml of pyridine is cooled to 0° C., 2 ml of acetic anhydride is introduced slowly with agitation for 17 hours at ambient temperature. It is then poured into 100 ml of water and 100 ml of isopropyl ether and decanted; the organic phase is washed with water, dried and concentrated to dryness. The residue is taken up in 1,2-dichloro ethane in order to eliminate the pyridine by azeotropy. 3.9 g of expected product is obtained.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:30]=[N:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=3)=[CH:19][CH:18]=2)[CH:6]=[C:5]([CH3:53])[N:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:19][CH:18]=2)[CH:6]=[C:5]([CH3:53])[N:4]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(-c2ccncc2)c(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(-c2ccncc2)c(C)n1
Reaction time: 3 h

Procedure:
6M Hydrochloric acid (1 ml) was added to a solution of 2,6-dimethyl-3-(4-pyridyl)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (A) (800 mg) in dioxan (20 ml) and the mixture was stirred for 3 hours. Volatile material was removed by evaporation and the residue triturated with ether. The ether was separated and the residue was dissolved in methanol. Ether was added to precipitate the product and the solvent was again separated. The residue was then triturated with ether to give 2,6-dimethyl-3-(4-pyridyl)-4-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine dihydochloride (0.51 g), as a solid, m.p. 180° C. (decomposition); NMR (d6 -DMSO, d4 -acetic acid): 2.4(s,3H), 2.75(s,3H), 5.45(s,2H), 7.1(d,2H), 7.25(d,2H), 7.5-7.8 (complex m,5H), 8.0(d,2H), 9.0(d,2H); mass spectrum (positive fast atom bombardment (+ve FAB) DMSO/nitrobenzyl alcohol): 869.4 (2M+H)+ ; microanalysis, found: C,56.7; H,5.3; N,14.9; H2O,8%; C26H22N6O.2HCl.2.5H2O0.2(C2H5)2O requires C,56.7; H,5.5; N,14.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[Cl:17].[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: Cl

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (0.350 mg, 1.12 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine.HCl (385 mg, 1.68 mmol) to afford the desired product (160 mg, 33%) as an off-white solid: ESI MS m/z 432 [C22H30BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(Cl)cc1)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.37 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6 ml) was stirred at room temperature for 2 h. The mixture was filtered and washed with water to give the title compound (89 mg, yield: 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.44 (s, 3H), 4.69 (d, J=10.8 Hz, 1H), 4.96 (d, J=10.8 Hz, 1H), 6.76 (s, 1H), 6.93 (d, 1H), 7.16 (d, J=8 Hz, 1H), 7.33-7.44 (m, 6H), 7.56-7.60 (m, 1H), 12.19 (d, 1H); LC-MS (ESI) m/z: 378 (M+1)+.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.[CH:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][N:3]1[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]1[S:1][CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19](=[O:20])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:40]3[CH2:41][CH2:42][N:37]([C:34]4[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=4)[CH2:38][CH2:39]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(CN4CCN(c5ccccc5)CC4)cc3)cc2)nc2ccsc2c1=O
Yield: 15.9 %

Procedure:
A solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (990 mg), 4,4'-bis (bromomethyl)benzophenone (1.75 g), phenylpiperazine (810 mg) and potassium carbonate (828 mg) in DMF (30 ml) was stirred at 60° C. for 2 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia=250:1:0.1) to provide the title compound as light-yellow syrup (428 mg).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:13].P(Cl)(Cl)Cl.OC[CH:20]1[CH2:29]C[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1(C2CC[N:40](O)[CH2:39][CH2:38]2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[ClH:1].[C:22]1([C:21]2([OH:30])[CH2:20][CH2:29][N:40]([CH2:2][CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:13])[CH2:39][CH2:38]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ON1CCC(c2ccccc2)CC1
Reactant: O=C1c2ccccc2CCC1CCl
Reactant: O=C1c2ccccc2CCC1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClP(Cl)Cl
Solvent: CC(C)O
Product: Cl
Product: O=C1c2ccccc2CCC1CN1CCC(O)(c2ccccc2)CC1

Procedure:
1.95 g. of 2-chloromethyl-1-tetralone, prepared by reaction of phosphorus trichloride and 2-hydroxymethyl-1-tetralone, 3.54 g. of 4-phenylpiperidin-1-ol and 1 g. of potassium carbonate in 20 ml. of isopropanol are heated under reflux for 3 hours. The mixture is evaporated and worked up with water and ether to give 2-(4-phenyl-4-hydroxypiperidinomethyl)-1-tetralone. Hydrochloride, M.P. 164°-167°.