Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:28]([NH:30][C@H:31]([C:50](O)=[O:51])[CH2:32][C:33]1[N:37](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:36]=[N:35][CH:34]=1)=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:28]([NH:30][C@@H:31]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[C:50]([NH:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([OH:5])[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:51])=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1

Procedure:
In an analogous manner to that described in Example 13, by reacting (1RS,2R,3S)-3-amino-4-cyclohexyl-1-(2-furyl)-1,2-butanediol with N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there was obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-propionamide (1:1 mixture of epimers) as a pale yellow solid, MS: 657 (M+H)+. The more polar epimer (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-propionamide, MS: 657 (M+H)+, can be separated from the above mixture by chromatography.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[C:9](OC)[CH:8]=1)(=[O:6])=[O:5])(C)C.F[C:37]1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=CC=1C.FC1C=CC(C(N2CCC3(C4C=NN(C)C=4C4C=CC=CC=4O3)CC2)=O)=C(C)C=1>>[CH3:33][N:29]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:18]3([CH2:19][CH2:20][N:15]([C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:1])(=[O:5])=[O:6])=[C:8]([CH3:37])[CH:9]=4)=[O:14])[CH2:16][CH2:17]3)[C:32]=2[CH:31]=[N:30]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1F
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Agent: Cc1cc(F)ccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(C)(=O)=O

Procedure:
A mixture of (2-methoxy-4-(methylthio)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (320 mg, 0.74 mmol) and 30% hydrogen peroxide (250 μL) in acetic acid (3 mL) was heated at 80° C. for 45 min. The mixture was diluted with water and was extracted with ethyl acetate. The organics were washed with sat. aq. NaHCO3 and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography eluting with 70-100% ethyl acetate in hexanes to give (2-methoxy-4-(methylsulfonyl)phenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 467.2. found 468.2 (M+1)+. Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 1H), 7.63-7.41 (m, 4H), 7.28 (t, J=7.7 Hz, 1H), 7.18-7.04 (m, 2H), 4.46-4.35 (m, 1H), 4.14-4.05 (m, 3H), 3.98-3.90 (m, 3H), 3.53-3.36 (m, 1H), 3.28 (s, 3H), 3.30-3.14 (m, 2H), 2.09-1.77 (m, 4H). (4-(Isopropylsulfonyl)-2-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was also synthesized using the procedures described above. (1-Methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)(3-methyl-4-(methylsulfonyl)phenyl)methanone was synthesized from (4-fluoro-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures described above. (4-(Isopropylsulfonyl)-2-methylphenyl)(1-methyl-1′-1-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone was synthesized from (4-fluoro-2-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone using the procedures above.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][NH:28][C:27]1=S>CN(C=O)C.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.[Hg](Cl)Cl>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:27]4[NH:28][CH2:29][CH2:30][N:26]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: S=C1NCCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1NC1=NCCN1
Temperature: 140 °C
Yield: 22 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol 0 and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite™. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].C([N:34]([CH2:37][CH3:38])CC)C.[ClH:39].[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1C(=N)OCC>CN(C)C=O>[ClH:39].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:37](=[NH:34])[CH2:38][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH3:40])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: CCN(CC)CC
Reactant: CCOC(=N)c1ccccc1OC
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1CC(=N)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 100 °C

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.1 g) and triethylamine (0.125 ml) in dimethylformamide (0.6 ml) was added ethyl 2-methoxybenzenecarboximidate hydrochloride (62 mg) at room temperature. The resulting mixture was heated at 100° C. for 1 hour. The mixture was poured into ice-water, and extracted by ethyl acetate. The extract was purified on a silica gel column (dichloromethane/methanol) and treatment with 4N hydrogen chloride in ethyl acetate solution gave (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[1-imino-2-(2-methoxyphenyl)ethyl]piperazine hydrochloride.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[C:29]([O:30][CH3:31])=[CH:28][C:27]2[C:26]([CH3:33])([CH3:32])[CH2:25][CH2:24][C:23]([CH3:35])([CH3:34])[C:22]=2[CH:21]=1)=O>CS(C)=O>[CH3:31][O:30][C:29]1[C:20]([C:18]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:21][C:22]2[C:23]([CH3:35])([CH3:34])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:33])[C:27]=2[CH:28]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Solvent: CS(C)=O
Product: COc1cc2c(cc1C#Cc1ccc(C)cc1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A solution of 20.2 g (0.18 mole) of potassium tert.-butylate in 45 ml of dimethyl sulfoxide was added dropwise to a solution of 23.2 g (0.09 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate and 22.1 g (0.09 mole) of 2-formyl-5,6,7,8-tetrahydro-3-methoxy-5,5,8,8tetramethylnaphthalene in 270 ml of dry dimethyl sulfoxide at room temperature. The mixture was stirred for 30 minutes, poured onto 1 liter of ice water and extracted three times with ether. The ether phase was washed twice with water, dried over sodium sulfate and evaporated down to give 22.6 g (76%) of a slightly impure product. Recrystallization from methanol gave 15.2 g (51%) of the pure title compound of melting point 127° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]2[CH2:16][O:15][C:14]([CH3:19])([CH3:18])[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>CN(C=O)C>[CH3:18][C:14]1([CH3:19])[O:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][CH2:6][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:17]=2[CH2:16][O:15]1
Reactant: CC1(C)OCc2c(CCOS(C)(=O)=O)cccc2O1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cccc3c2COC(C)(C)O3)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To 2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl methanesulfonate (176 mg, 0.59 mmol, crude above, 1 eq.) in DMF (1.0 mL) was added ethyl piperidine-4-carboxylate (186 mg, 1.18 mmol, 2.0 eq.) at rt. The mixture was stirred at 60° C. for 2 h, cooled to rt, and purified on RP-HPLC (Gemini 21.2 mm×150 mm) using a mixture of CH3CN and water (0.1% HCOOH) as eluent to give ethyl 1-(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl)piperidine-4-carboxylate (100 mg, 49% for two steps). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 2H), 4.86 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.22 (s, 2H), 3.09-2.95 (m, 1H), 2.95-2.79 (m, 4H), 2.76 (s, 1H), 2.66-2.48 (m, 1H), 2.23-1.99 (m, 4H), 1.55 (s, 6H), 1.29 (t, J=7.1 Hz, 3H). LRMS (M+H+) m/z 348.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[CH:35]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(Cc2ccoc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 8.6 mg of (1R)—N-{[1-(3-furylmethyl)-3-phenylpiperidin-4-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].C(N(CC)CC)C.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26].[OH-].[Na+]>ClCCl>[F:10][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:26])=[CH:4][C:3]=1[CH2:2][OH:1]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccc(F)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(CO)c1)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
3-Hydroxymethyl-4-fluoroaniline (34.2 g, 243 mmol) was dissolved in dichloromethane (600 mL) under anhydrous conditions and cooled to 0° C. Triethylamine (120 mL, 0.861 mol) was added, followed by a solution of picolinic acid chloride hydrochloride (86.0 g, 0.483 mol) in methylene chloride (300 mL). The reaction mixture was stirred at 0° C. for 0.5 hours and at room temperature for 1 hour, and poured into ice water (2 L). The resulting mixture was basified with 1N sodium hydroxide solution, extracted with methylene chloride (3×800 mL), washed with brine, and dried over magnesium sulfate to give a brown oil, which was purified by flash chromatography (6 in diameter column, elution with 25% ethyl acetate in petroleum ether) to give the title compound (10.0 g, 18%, mp 99°-122° C.) as the first compound of the column, followed by 2-pyridinecarboxylic acid [[2-fluoro-4-[[(2-pyridinyl)oxomethyl]-amino]phenyl]methyl] ester (46.5 g, 52%, mp 116°-118° C.). Additional title compound can be obtained by treating the ester (25.0 g, 71 mmol) with potassium carbonate (19.8 g, 143 mmol) in water (20 mL), methanol (200 mL), and tetrahydrofuran (200 mL). The mixture was left for 2 days and then concentrated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (500 ml) and the aqueous layer was extracted again with ethyl acetate (2×200 mL). The organic layer was washed with 2.5N sodium hydroxide solution (500 mL) and brine (500 mL), dried, and concentrated to afford more N-(4-fluoro-3-hydroxymethylphenyl)-2-pyridinecarboxamide (15 g, 90%).
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[N:8][N:7]=[N:6]1)#N.[OH-].[Na+].C1COCC1.Cl>O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]2[NH:5][N:6]=[N:7][N:8]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2CCC#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
2-[1-(β-cyanoethyl)-1-H-tetrazol-5-yl]-4'-methylbiphenyl (689mg, 2.34 mmol), 1.0N NaOH (2.62 mL, 2.62 mmol) and THF (15 mL) were mixed and stirred at room temperature. After 15 minutes, water (100 mL) was added and the pH adjusted to 3.0 with conc. HCl. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, dried (MgSO4) and evaporated in vacuo to yield 550 mg of a white powder. M.P.=148.5°-150.0°. The spectral data matched those of a sample prepared via Method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18]O)[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[Br:29]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[Br:29][CH2:18][CH2:17][CH2:16][N:15]1[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=[C:11]1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: BrC(Br)(Br)Br
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCBr)c12
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To a stirred suspension of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (404 mg, 0.961 mmol) and tetrabromomethane (637 mg, 1.92 mmol) in acetonitrile was added triphenylphosphine (504 mg, 1.92 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to afford the desired product as yellow solid (407 mg, 0.842 mmol, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.5 g), 4-methoxyphenyl borate (0.84 g) and potassium carbonate (1.39 g) in toluene/ethanol/water (50/5/5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphine palladium (0.17 g), and the mixture was refluxed for 24 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:15→1:9→1:4→1:2) to give pale yellow crystals of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (1.40 g).
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([C:9]([O-:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O=S(Cl)Cl.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C1C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH3:22])[C:9]([C:3]([CH2:1][CH3:2])([CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])[CH3:19]
Reactant: CCOC(=O)C(CC)(CC)C(=O)[O-]
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(CC)(CC)C(=O)N(CC)CC
Reaction time: 18 h

Procedure:
To a solution of monoethyl diethylmalonate (28 g. 0.15 mole) in dry benzene (300 ml.) is added SOCl2 (15 ml., 0.21 mole) at 26°-28° C. in 2 min, with mechanical stirring. The reaction solution is gradually heated to 78° over 25 min, then is heated an additional 45 min at 85°-90°. The mixture is concentrated to dryness under reduced pressure, benzene (100 ml.) is added, and the mixture is again concentrated to dryness. The resultant oily residue dissolved in benzene (200 ml.) is treated dropwise with a solution of diethylamine (30 ml., 0.29 mole) in benzene (90 ml.) at 5°-15° over 17 min, and the reaction mixture is refluxed for 7 hours. The mixture is stored for 18 hours at room temperature and is filtered (to remove insoluble salt), is washed with benzene (50 ml.), is dried over MgSO4 and activated charcoal for 15 min, is filtered, and is concentrated to dryness under reduced pressure (bath at 50°-60°). This will yield 29 g. (79%) of ethyl 2-(N,N-diethylcarbamoyl)-2-ethylbutyrate.
Reaction SMILES: [N:1]1([CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C=[CH:4][CH:3]=[CH:2]1.S(Cl)([Cl:16])(=O)=O.Cl[CH2:19][Cl:20]>>[Cl:16][C:2]1[N:1]([CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:19]([Cl:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCCl
Product: CCOC(=O)C(C)n1c(Cl)ccc1Cl

Procedure:
Ethyl 2-(1H-pyrrol-1-yl)propionate (Ger. Offen. No. 2,305,632) in dichloromethane, maintained below 0° C., is treated with two equivalents of sulphuryl chloride to give ethyl 2-(2,5-dichloro-1H-pyrrol-1-yl)propionate. Treatment of this ester with ammonia in the manner of Example 1, gives 2-(2,5-dichloro-1H-pyrrol-1-yl)propionamide.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[C:21]([BH3-])#N.[Na+]>O>[CH3:21][N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCNCc1ccc([N+](=O)[O-])cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CN(CCCCC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85 %

Procedure:
To a solution of 300 mg (1.19 mmol) of N-(p-nitrobenzyl)δ-aminovaleric acid in 6 ml of water were added 450 μl of a 37% aqueous formaldehyde solution (6.1 mmol) and 123 mg of sodium cyanoborohydride (1.96 mmol). This mixture was stirred for 45 min at rt. After quenching with 6 ml of 1 M hydrochloric acid the solution was directly adsorbed on a Dowex 50 (H+ -form) ion exchange column (2×10 cm). The column was subsequently washed with 150 ml water and the product eluted with 0.7 M ammonia. After evaporation, the remaining oil was further purified by silicagel chromatography (1×15 cm, methanol:dichloromethane=1:1). The product containing fractions (Rf =0.22) were collected and the solvent removed in vacuo. 270 mg (85% of product in form of a colorless oil was isolated. Attempts at crystallization failed. 1H-NMR (200 MHz,D2O):8.10 (d,J =8.7/2H), 7.46 (d, J =8.7/2H), 3.83 (s/2H), 2.59 (m(t)/2H), 2.28 (s/3H), 2.03 (m(t)/2H), 1.49-1.39 (m/4H); 13C-NMR (50 MHz, d6 -DMSO): 175.3, 147.8, 146.4, 129.4, 123.3, 60.6, 56.6, 41.8, 34.1, 26.3, 22.5; FAB+-MS:267 (M+1)+. EA (C13H18N2O4. O.H2O) calc. C 55.26 H 7.06 N 9.91, found: C 55.34 H 6.88 N 9.89.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]([CH3:20])([C:18]#[CH:19])[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Cu]I.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>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[C:19]#[C:18][C:13]([CH3:20])([CH3:12])[C:14]([O:16][CH3:17])=[O:15]
Reactant: C#CC(C)(C)C(=O)OC
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)C#Cc1cc([N+](=O)[O-])ccc1N
Temperature: 70 °C
Reaction time: 24 h
Yield: 8.6 %

Procedure:
To a deoxygenated solution of compound 2-bromo-4-nitroaniline (9.43 g, 43.7 mmol), methyl 2,2-dimethylbut-3-ynoate (5.00 g, 39.7 mmol), CuI (754 mg, 3.97 mmol) and triethylamine (8.03 g, 79.4 mmol) in toluene/H2O (100/30 mL) was added Pd(PPh3)4 (6.17 g, 3.97 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. After cooling, the solid was filtered off and washed with EtOAc (50 mL×3). The organic layer was separated and the aqueous phase washed with EtOAc (50 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to obtain methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (900 mg, 9%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=2.8 Hz, 1H), 8.01 (dd, J=2.8, 9.2 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 5.10 (brs, 2H), 3.80 (s, 3H), 1.60 (s, 6H).