Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc2sc(S(N)(=O)=O)nc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole) and 4-dimethylaminopyridine (100 mg.) in pyridine (15 ml.) is added octanoyl chloride (1.7 ml.) over a period of 5 minutes. The reaction mixture is stirred 11/2 hours, poured into ice water and dilute hydrochloric acid, extracted into ethylacetate, washed with water, dried over magnesium sulfate and chromatographed on 35 g of silica gel (ethyl acetate - hexane 1:1) to give 2-sulfamoyl-5-benzothiazolyl octanoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[F-].[Cs+].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 17.5 h
Yield: 87 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.82 g), acetonitrile (50 ml), cesium fluoride (455.7 mg) and t-butyl acrylate (5.7 ml) were mixed at room temperature, and the mixture was stirred at 80° C. for 17.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the obtained residue were added water and ethyl ether, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether, and the organic layers were combined. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/6) to give the title compound (8.38 g, 87%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.Cl.[NH2:17]N>C(O)C>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:5]2[NH:17][N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NN
Reactant: CSc1nccc(C(=O)/C=C/N(C)C)n1
Agent: Cl
Solvent: CCO
Product: CSc1nccc(-c2ccn[nH]2)n1

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]prop-2-en-1-one (1-4, 1.0 g, 4.48 mmol, 1 equiv) and hydrazine hydrochloride (0.62 g, 8.96 mmol, 2 equiv) in ethanol(20 mL) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate(2×50 mL) and sat. sodium bicarbonate solution. The combined organic extracts were dried over magnesium sulfate and concentrated to a solid which was triturated with ether to provide 2-(methylthio)-4-(1H-pyrazol-5-yl)pyrimidine (4-1) as a tan solid. 1H NMR (500 MHz, CDCl3) δ 10.8 (br s, 1H), 8.55 (d, 1H, J=5 Hz), 7.68 (d, 1H, J=5 Hz), 7.40 (br s, 1H), 6.96 (br s, 1H), 2.63 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as yellow solid, MS (ESI+): m/z=394.0797 ([M+H]+, 1Br).
Reaction SMILES: BrCCC=C.C(Br)C=C.[CH2:10]([C:14]1[C:15](=[O:31])[N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH:12]=C>>[OH:24][C:23]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15](=[O:31])[C:14]=1[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: C=CCCBr
Solvent: C=CCBr
Product: C=CCc1c(O)c2cccnc2n(-c2ccccc2)c1=O

Procedure:
In a similar manner, substitute 4-bromo-1-butene for allyl bromide in part B(1) of Preparation 1 to prepare 3-(3-butenyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=NNS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(Cc2ccc3c(c2)OCO3)=NNS(=O)(=O)c2ccc(C)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/c2ccc3c(c2)OCO3)cc(OC)c1
Temperature: 80 °C
Yield: 116.4 %

Procedure:
39.4 g of N-[1-(3,5-dimethoxyphenyl)-2-(3,4-methylenedioxyphenyl)ethylidene]-N′-tosylhydrazine (0.084 mol) prepared as in Example 30, 19.9 g of potassium ter-butoxide (0.177 mol) and 3.9 g of Triton X100® are introduced into a three-necked round-bottomed flask comprising 190 ml of toluene. The mixture is brought to reflux for 4 h, cooled to approximately 80° C. and 130 ml of water are introduced. Separation by settling is carried out and the aqueous phase is re-extracted with 90 ml of toluene. The toluene phases are washed with 50 ml of water and concentrated to result in 27.8 g of a brown solid, which is taken up in 30 ml of methanol and maintained for 1 h under agitation. The precipitate is filtered off, washed on the filter with methanol and dried. 16.6 g of (E)-3,5-dimethoxy-3′,4′-methylenedioxy-stilbene is recovered in the form of a brown solid, which exhibits a melting point of 96° C., i.e. a yield of 69% with respect to the starting hydrazone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Br)cc1

Procedure:
A 3.5 g. portion of ethyl 1-(4-bromophenyl)-5-cyano-4-pyrazolecarboxylate was reacted with 2.15 g. of potassium hydroxide in 50 ml. of ethanol underreflux for 2 hours to obtain 2.45 g. of the desired product, m.p. 251°-252.5°. The elemental analysis was as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:16][CH2:17][CH2:18][CH3:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH2:13][CH2:14][CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCC1(CCCC)CCSc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 1.68 g (5.38 mmol) of 6-bromo-4,4-dibutylthiochroman (Compound 33), 0.28 g (1.5 mmol) of copper (I) iodide and 2.5 g (25 mmol) of triethylamine was degassed with argon for 15 minutes at -78° C. To the suspension was added 1.18 g (71 mmol) of (trimethylsilyl)acetylene and 0.24 g (0.35 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture was heated to 55° C. for 22 hours.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C:11]([CH3:28])([OH:27])[CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>CN(C=O)C.[NH4+].[Cl-]>[Br:26][C:23]1[CH:22]=[N:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:11]3([CH3:28])[O:27][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:14][CH2:15]2)=[N:25][CH:24]=1
Reactant: CC(O)(CN1CCCN(c2ncc(Br)cn2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(CN2CCCN(c3ncc(Br)cn3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C

Procedure:
The 1-(2-Bromo-4-nitro-imidazol-1-yl)-3-[4-(5-bromo-pyrimidin-2-yl)-[1,4]diazepan-1-yl]-2-methyl-propan-2-ol (600 mg, 1.15 mmol) in DMF (4 ml) was treated with NaH (33 mg, 1.4 mmol) at 0° C. and heated to 60° C. for 2 h. The reaction mixture is cooled, diluted with saturated NH4Cl (aq) and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to titled compound (384 mg, 75%). ESI MS m/z 439 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 2H), 7.4 (s, 1H) 4.15 (d, J=23 Hz, 1H), 3.81 (m, 5H), 3.06 (d, J=38 Hz, 1H), 2.95 (m, 2H), 2.85 (m, 1H), 2.75 (m, 1H), 2.62 (d, J=29 Hz, 1H), 1.63 (m, 2H), 1.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: Oc1ccccc1F
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Fc1ccccc1OCCCBr
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a solution of 2-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed by Cs2CO3 (0.232 g, 0.713 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0274 g, 26.2%). EI-MS Rt (2.24 min).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.[CH:21]([Mg]Br)=[CH2:22]>O1CCCC1>[NH:1]1[C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:13]=2[CH:22]=[CH:21]1
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of 4-tert-butyl 1-methyl 2-nitroterephthalate (prepared according to Gao, Y. et. al WO2001070737) (2.15 g, 7.64 mmol) in tetrahydrofuran (30 mL) was added a 1M solution of vinylmagnesium bromide in tetrahydrofuran (23.0 mL) at −40° C., followed by stirring at room temperature for 18 hours. The reaction mixture was quenched by the addition of a solution of 1 M aqueous ammonium chloride, and the organic portion of the solvent was evaporated. The resulting material was partitioned with ethyl acetate (300 mL), and the organic layer was separated then washed with 10% aqueous citric acid (100 mL) and brine, dried over sodium sulfate, filtered and the solvent was concentrated. The resulting crude material was purified by column chromatography (hexane:ethyl acetate 9:1 to 7:3 eluent) to give 4-tert-butyl 7-methyl 1H-indole-4,7-dicarboxylate (0.58 g, 27%). 1H NMR (400 MHz, CDCl3): 10.00 (bs, 1H), 7.88 (dd, 2H), 7.43 (m, 1H), 7.19 (m, 1H), 4.00 (s, 3H), 1.66 (s, 9H). MS (EI) for C15H17NO4: 274 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[CH:33][CH:32]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][NH:37]4)=[CH:33][CH:32]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 97.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 6-aminoindole (0.054 g, 0.72 mmol), the title compound (0.179 g, 98%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13]C([C@@H]3CCCN3C(=O)[C@H](NC(=O)C)CC3C=CC(C4C=CC=CC=4)=CC=3)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:41]([NH:43][C:44](=[O:66])[NH:45][C@H:46]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)[C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54](O)=[O:55])=[O:48])[CH3:42]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:54]([C@@H:50]3[CH2:51][CH2:52][CH2:53][N:49]3[C:47](=[O:48])[C@H:46]([NH:45][C:44]([NH:43][CH2:41][CH3:42])=[O:66])[CH2:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)=[O:55])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Product: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 69 %

Procedure:
Using the procedure described for example 97f 0.190 g of 1-[2-(R)-(3-ethyl-ureido)-3-(4-methoxyphenyl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid was converted into 0.180 g (69%) of the title compound. (+)-APCI-MS: 519(MH+).
Reaction SMILES: [I-].[N+:2]([C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH3:15])([O-])=O>[Pt]=O.C(O)C>[NH2:2][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH3:15]
Reactant: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: O=[Pt]
Agent: [I-]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1N
Yield: 87 %

Procedure:
A suspension of 2-(o-nitrostyryl)-1-methylpyridinium iodide (40.5 mg., 0.11 mole) prepared according to the method of L. Horwitz, J. Org. Chem., 21, 1039 (1956) in 200 ml. of ethanol is hydrogenated in a Parr hydrogenation apparatus employing 0.3 g. of platinum oxide catalyst while maintaining a reaction temperature of from about 50° to 75° C. When the hydrogen uptake ceases (about 3 hours), the reduction mixture is filtered, the filtrate evaporated and the resulting residue taken up in 500 ml. of water. The aqueous solution is basified with 40% sodium hydroxide and extracted with several 200 ml. portions of ether. Ethereal extracts are combined, washed with water, dried over magnesium sulfate, and the ether evaporated. Distillation of the resiude thus obtained provides 20.8 g. (87% yield) of 2-(o-aminophenethyl)-1-methylpiperidine base having a boiling point of 121°-125° C. at 0.04 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Br:8][C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[NH:9][C:10](=[O:13])[CH2:11][NH:1]2
Reactant: Nc1cc(Br)ccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNc2cc(Br)ccc2N1
Yield: 34.1 %

Procedure:
A mixture of N-(2-amino-4-bromophenyl)-2-chloroacetamide (4.5 g, 17.0 mmol), sodium iodide (101 mg, 2.0 mmol) and sodium carbonate (3.6 g, 33.8 mmol) in 300 ml acetonitrile was refluxed overnight under an atmosphere of nitrogen. Then the acetonitrile was removed under vacuum. The resulting solid was suspended in 150 ml water acidified to pH 5-6 with 1 N HCl. Extraction with ethyl acetate, washing of the combined organic layers with brine, drying over MgSO4, removing the solvent under reduced pressure and purification of the crude product by flash chromatography on silica gel (petroleum ether/ethyl acetate, 1.5/1) yielded 6-bromo-3,4-dihydroquinoxalin-2(1H)-one (1.3 g, 5.8 mmol, 34%) as yellow solid.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=[O:46])[N:7]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:33]=2)[C:8]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH:10]=1)(=O)[NH2:2]>C(Cl)Cl>[C:1]([C:4]1[NH:5][C:6](=[O:46])[N:7]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:33]=2)[C:8]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH:10]=1)#[N:2]
Reactant: CCOC(=O)n1cc(-n2c(-c3cn(CCCN4C(=O)c5ccccc5C4=O)c4ccccc34)c(C(N)=O)[nH]c2=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)n1cc(-n2c(-c3cn(CCCN4C(=O)c5ccccc5C4=O)c4ccccc34)c(C#N)[nH]c2=O)c2ccccc21
Temperature: 50 °C
Yield: 67.9 %

Procedure:
To 0.10 g (0.16 mmol) of the product of step f) was added 10 ml of a solution of TMS-polyphosphate (Yokoyama et al. Synthesis (1982) 591-592) in CH2Cl2. The flask was sealed and heated on an oil bath to 50° C. for 3 hours. The organic phase was diluted to 20 ml with CH2Cl2 and then washed with 10 ml of water, 5 ml of 1M sulfuric acid and finally with 5 ml of brine. The organic phase was evaporated, and the residue was purified by chromatography on silica (CH2Cl2:MeOH 97:3), furnishing 65 mg (67%) of the sub-title product.
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.CC12C(C)(C)[C:28]([C:34]([O:36][CH2:37][C@@H:38]3[C@H:40]([CH2:41][O:42]CC)[C@:39]3([CH3:59])[C:45]3[CH:54]=[CH:53][C:52]4[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=4[CH:46]=3)=O)(CC1)OC2=O>>[CH2:34]([O:36][CH2:37][C@H:38]1[C@@H:40]([CH:41]=[O:42])[C@@:39]1([CH3:59])[C:45]1[CH:54]=[CH:53][C:52]2[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=2[CH:46]=1)[CH3:28]
Reactant: CCOC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 94 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 9b as the starting material afforded the title compound (36 mg, 94% yield) as a colorless oil:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(3-cyanophenyl)amino]-1-piperidinecarboxylate (D5) (750 mg, 2.43 mmol) in DCM (30 ml) was cooled in an ice bath and TFA (6 ml) was added. The reaction mixture was then stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue loaded onto an Isolute SCX cartridge. Elution with MeOH (100 ml) followed by 2M NH3 in MeOH (100 ml) gave the title compound as a white solid (613 mg). δH (CDCl3, 250 MHz) 7.21 (2H, t), 6.93 (1H, m), 6.77 (2H, m), 3.78 (1H, m), 3.35 (1H, m), 3.14 (2H, m), 2.73 (2H, m), 2.06 (2H, m), 1.34 (2H, m). MS (ES): MH+ 202.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCCCCCO)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CCCCCCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
55.6 g (theoretical molar number: 184.1 mmols) of crude N-ethyl-N-(6-hydroxyhexyl)-4-bromoaniline was dissolved in 247 ml of chloroform. Then 24.6ml (1.5 equivalent) of 3,4-dihydro-2H-pyran and 7.0 g (0.2 equivalent) of pyridinium p-toluenesulfonate monohydrate were added. After displacement with argon, a Dimroth condenser and an argon balloon were attached to carry out reflux with heating for 5 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium hydrogencarbonate solution was added thereto to effect neutralization, followed by extracted with chloroform. The organic layer thus formed was dried with anhydrous sodium sulfate and thereafter concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=15/1) to obtain 63.3 g of N-ethyl-N-[6-(tetrahydropyran-2-yl)oxyhexyl]-4-bromoaniline (yield: 90%; a colorless oily liquid). IR Spectrum [ν(cm-1)]: 2924, 1588, 1492, 1348, 1260, 1174, 1116, 1066, 1022, 906, 864, 800; 1H-NMR Spectrum [δ(ppm)]: 1.12(t, 3H, J=7.0 Hz), 1.35-1.95(m, 14H), 3.20(t, 2H, J=7.6 Hz), 3.27-3.51(m, 4H), 3.73(m, 1H), 3.86(m, 1H), 4.57(t, 1H, J=3.6 Hz), 6.50(d, 2H, J=9.1 Hz), 7.24(d, 2H, J=9.1 Hz)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(F)cc3F)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(F)cc3F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.25 g of 4,5-bis(4-methoxyphenyl)-2-(2,4-difluorophenylthio)imidazole in 100 ml of dichloromethane. The mixture is agitated for 3 hours at room temperature, the solution washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to dryness. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.26 g of 4,5-bis(4-methoxyphenyl)-2-(2,4-difluorophenylsulfinyl)imidazole as an amorphous foam.