Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: Cc1cccc(-c2ccc(Cl)nc2)n1
Product: CCN1CCN(c2ccc(-c3cccc(C)n3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethyl-piperazine and 6′-chloro-6-methyl-[2,3]bipyridinyl.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[ClH:20].[N:23]1([CH2:22][CH2:21][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1OCCN1CCOCC1

Procedure:
B-16a is prepared analogously to B-15a starting from N-hydroxyphthalimide (5.0 g, 30.7 mmol), potassium carbonate (4.24 g, 30.7 mmol) and N-(2-chloroethyl)morpholine hydrochloride (6.27 g, 33.7 mmol). The product is isolated as the hydrochloride. Yield: 4.22 g.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].[OH-].[Na+]>>[C:1]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[F:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccccc1F
Reaction time: 0.5 h
Yield: 103 %

Procedure:
Acetic anhydride (81 cm3, 856 mmol) was added dropwise to a stirred mixture of 2-fluorophenol (60.0 g, 535 mmol) and aqueous sodium hydroxide (4 N, 214 cm3, 856 mmol) at 0° C. After the reaction had been stirred for 30 min the aqueous layer was separated from the organic portion and washed with dichloromethane (150 cm3). The combined organic extracts were washed with aqueous sodium hydroxide solution (4 N, 150 cm3) and then brine (100 cm3). The organic phase was dried (Na2SO4) and the solvent was evaporated in vacuo to afford the title compound (84.9 g, >100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([OH:16])=O)=[O:10])=[CH:4][CH:3]=1.C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH:38]1[CH2:40][CH2:39]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([NH:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)Nc1ccc(N)nc1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC2CC2)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round-bottomed flask was charged 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoic acid (70 mg, 0.26 mmol), DCM (1 ml), and DMF (1 ml). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74 mg, 0.39 mmol) was then added. The reaction mixture was stirred for 10 min before (aminomethyl)cyclopropane (27 μl, 0.31 mmol) was introduced. The reaction mixture was stirred at RT under N2 for 16 h. The reaction was partitioned between DCM (15 ml) and brine (10 mL). The aqueous layer was back exacted with DCM (3×10 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide N3-(6-aminopyridin-3-yl)-N1-(cyclopropylmethyl)-4-methylisophthalamide as an off-white solid. m/z: 325.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=O.Cl[CH:21]([C:27]([O-:29])=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>CN(C)C1C=CN=CC=1.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[N:14]([CH2:15][CH3:16])[C:27](=[O:29])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=1
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2ccc(C)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50 ml dichloroethane solution containing 7.5 g of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine were added 5 ml of monoethyl chloromalonate and 6.5 g of 4-dimethylaminopyridine. The whole was stirred at room temperature for 30 minutes, and then further under heating at an oil bath temperature of 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and, after adding 1M hydrochloric acid, extracted with chloroform. The organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate to chloroform-ethyl acetate) to obtain 7.10 g of ethyl 4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylate as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](OC=C)(=[O:24])[CH3:23]>COC(C)(C)C>[C:22]([O:14][C@@H:11]1[CH2:12][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)(=[O:24])[CH3:23]
Reactant: C=COC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)O[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 49 %

Procedure:
Combine (+/-)-cis-3-tert-butyldimethylsilyloxycyclopentanol (2.119 g, 9.8 mmol, prepared in example 29), pancreatin (6.2 g, 3 weight equivalents), triethylamine (0.9 mL, 6.5 mmol) and vinyl acetate (4.3 mL) in tert-butyl methyl ether (12 mL) and stir for 27 hours at room temperature. Then filter the reaction through diatomaceous earth and concentrate the filtrate under vacuum (room temperature/15 mmHg). Purify the residue by column chromatography [silica gel, 55 g, hexane (300 mL) followed by 5% ethyl acetate/hexane (500 mL)] to provide the (1R,3S)-(+)-3-tert-butyldimethylsilyloxycyclopentanyl acetate (1.23 g, 49% yield, 98% ee as determined from gas chromatography with a chiral column) and (1S,3R)-(-)-3-tert-butyldimethylsilyloxycyclopentanol (771 mg, 37% yield, 92% ee as determined from its acetate derivative followed by GC chiral column analysis, see example 30a).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20]2)(=[O:13])=[O:12])(=[O:4])=[O:3].[OH-].[Na+].O1CCCC1>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20]2)(=[O:12])=[O:13])(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of ethyl 7-{[2-(methylsulfonyl)phenylsulfonyl]amino}-1H-indole-2-carboxylate (1.84 g), 8N aqueous sodium hydroxide solution (2.50 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (1.67 g, yield 97%) as yellow crystals. melting point>304° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (2.0 g, 6.46 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.12 g, 7.12 mmol) according to the general procedure IIb. Obtained as an off-white solid (0.6 g, 24%). MS (ISP) 387.1 [(M+H)+]; mp 185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH2:33][CH:34]=[O:35])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C@:29]([CH2:33][CH2:34][OH:35])([OH:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C

Procedure:
A stirred suspension of 2-[(3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-6-hydroxy-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-yl]acetaldehyde (12.9 mg, 0.026 mmol) in methanol (0.5 ml) was cooled to 0° C. in an ice bath. Sodium boro-hydride (3.5 mg, 0.093 mmol) was added to the reaction mixture, resulting in gas evolution. The reaction mixture was allowed to warm to room temperature overnight. The next day, the reaction mixture was directly purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H24ClN3O5 493.14 observed m/e: 494.24 (M+H)+ (Rt 1.17/2 min); 1H NMR δ (ppm) (CD3OD): 7.97 (s, 1H), 7.74-7.77 (m, 4H), 7.71 (d, J=7.7 Hz, 2H), 7.48 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.4 Hz, 1H), 5.58 (qt, J=5.3 Hz, J=10.6 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.29 (d, J=4.9 Hz, 1H), 4.15-4.20 (m, 2H), 3.77-3.84 (m, 2H), 3.71 (abqt, J=8.7 Hz, J=21.2 Hz, 2H), 1.85 (t, J=6.6 Hz, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1>C1COCC1>[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]1[CH:52]1[CH2:53][CH2:54][S:49][CH2:50][CH2:51]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2ccccc21
Reactant: OC1CCSCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (446 mg, 2.56 mmol) was added to a solution of tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (J. Org. Chem., 1995, 60, 1565-1582) (500 mg, 2.13 mmol), triphenylphosphine (672 mg, 2.56 mmol), and tetrahydro-2H-thiopyran-4-ol (Chem. Comm., 2002, 10, 1070-1071) (303 mg, 2.56 mmol) in THF (10 mL). After 20 h, the reaction was concentrated in vacuo and the crude product purified by silica gel column chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 95:5, to give the title compound. MS: m/z=335 (M+1).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(=O)C(O)(C)C)[CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl>O1CCOCC1.O>[NH2:19][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCN1CCC(c2cccc(NC(=O)C(C)(C)O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCN1CCC(c2cccc(N)c2)CC1

Procedure:
A solution of N-hexyl-4-(3-(2-hydroxy-2-methylpropanoylamino)phenyl)piperidine (Example 158) in 1,4-dioxan:5N aqueous hydrochloric acid solution (1:1, 10 ml) was heated under reflux overnight. The reaction mixture was cooled, diluted with water (10 ml) and extracted with diethyl ether (3×10 ml). The pH of the aqueous layer was adjusted to 8-9 using 5N aqueous sodium hydroxide, and extracted with dichloromethane (5×10 ml). The combined extracts were washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as an oil which was not purified further (178 mg, 61% over two steps).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH3:13])[S:9][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=2[N:4]=1.[CH3:20][N:21]1[CH2:26][CH2:25]N[CH2:23][CH2:22]1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:13][C:10]1[S:9][C:8]2[NH:7][C:6]3[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=3[N:4]=[C:3]([N:2]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:12]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N1CCN(C)CC1
Temperature: 130 °C

Procedure:
To a solution of 10-amino-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-7-carbonitrile hydrochloride, prepared as described in the previous step, (0.6 g) in DMSO (6 mL) and toluene (6 mL), was added 1-methylpiperazine (4 mL). The mixture was heated in a 130° C. oil bath for 17 hours. The solution was concentrated, diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL), and then concentrated. The solid was dissolved in dichloromethane (10 mL) and treated with saturated sodium bicarbonate solution. The title compound was collected as a light yellow precipitate, washed with water and dichloromethane, dried, and used in the next step without additional purification. LC-MS: m/z 338 (M+1). 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.19-7.15 (m, 2H), 6.74 (d, 1H), 6.37 (s, 1H), 3.51 (m, 4H), 2.53 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:18][F:19])[CH:8]=C(C#N)[C:6]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:5]=2[O:4]1.[C:20]([OH:23])(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[F:1][CH2:2][C:3]1([CH2:18][F:19])[CH:8]=[C:21]([C:20]([OH:23])=[O:22])[C:14]2[CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:6][C:5]=2[O:4]1
Reactant: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
A mixture of 0.93 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbonitrile, 20 ml of acetic acid, 10 ml of water and 10 ml of sulfuric acid was heated to reflux for 4.5 hours. The reaction mixture was poured Into ice water and the precipitated crystals were filtered off to give 0.83 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid; m.p. 171-172° C.;
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:11][C:10]([CH2:9][CH2:8][O:7][C:6]1[CH:13]=[CH:14][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCOc1ccc(CO)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[4-(hydroxymethyl)phenoxy]propionic acid (0.98 g) and potassium carbonate (0.9 g) in N,N-dimethyl-formamide (5 mL) was added benzyl bromide (0.65 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.1 g).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[O:32])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[O:32])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 2.5 mL, 4.25 mmol) was added at −78° C. to a solution of 4-bromo-1,2-dichlorobenzene (435 mg, 1.93 mmol) in THF (10 mL) under nitrogen atmosphere. The resulting solution was stirred at −78° C. for 15 minutes, and then a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.93 mmol) in THF (2 mL) was slowly added. The reaction mixture was stirred at −78° C. for 20 minutes and then warmed up to room temperature over a period of 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl, then diluted with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give an oil that was purified by flash chromatography (10% to 30% of EtOAc in hexane) to give 143 mg (22% yield) of 3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: C([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[OH-].[Na+].[OH-].[K+]>>[CH2:17]([S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:24])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1SCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1SCc1ccccc1
Reaction time: 8 h

Procedure:
To a suspension of 2-benzylsulfanyl benzoic acid benzyl ester 2 (113 mg, 0.34 mmol) was added 1.6 mL of 1N NaOH. KOH (1 pellet) was added and the reaction was continued overnight. The acetone was removed and a small amount of water was added. The aqueous solution was washed with CH2Cl2 (3×). The aqueous phase was acidified until pH of 2–3 was reached then extracted with CH2Cl2 (3×), dried with MgSO4 and filtered and concentrated to give a white solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=O)[NH2:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]#[N:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 82.6 %

Procedure:
2.66 g (10 millimole) of N-carbobenzoxy-L-asparagine (Journal of Organic Chemistry, 26, 3356-3360 (1961)) was admixed with 30 ml of dry pyridine and 1.2 ml (12 millimole) of acetic anhydride, and the admixture obtained was stirred at a temperature from 20° to 25° C. for one hour. The reaction solution was then concentrated to a syrup by distilling off pyridine under reduced pressure, and the residue was diluted with 50 ml of 1 N hydrochloric acid. The product deposited as colorless needles was collected by filtration, washed with cold water and dried to afford 2.05 g of N-carbobenzoxy-β-cyano-L-alanine. Yield 83%. This product was found to have the following properties:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][CH2:15][C:16]#[N:17])(=[O:13])=[O:12])([O:3]C)=O.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>ClCCl>[C:16]([C:15]1[N:14]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[S:11](=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]=1[OH:3])#[N:17]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NCC#N
Reactant: COCCOCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCN1C(C#N)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of o-carbomethoxy-N-cyanomethylbenzenesulfonamide (6.25 g) in dichloromethane (50 ml) was added triethylamine (2.5 g) and then beta-methoxyethoxymethyl chloride (3.12 g) at 5°-10° C. After being stirred for 1 hour at room temperature, the mixture was washed with water, dried over sodium sulfate and concentrated. To the resulting oil was added toluene (33 ml) and then 28% sodium methoxide in methanol (4.6 ml) and stirring was continued for an additional 16 hours at room temperature. The mixture was extracted with water (50 ml) and the aqueous layer was acidified to pH 2 with 6N HCl and extracted with dichloromethane. The resulting organic layer was washed with water, dried over sodium sulfate and concentrated to a viscous oil, which was submitted to silica gel column chromatography (SiO2, 100 g) and eluted with a mixed solvent (CH2Cl2 :CH3OH 4:1) to give the title product as a viscous oil.
Reaction SMILES: [C:1]([O-:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[K+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23].[I-].[K+]>CN1CCCC1=O>[C:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(=O)c1ccccc1CBr
Reactant: O=C([O-])/C=C/c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(=O)c1ccccc1CC(=O)C=Cc1ccccc1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
10.4 g (56 millimoles) of potassium transcinnamate and 12.0 g (47 millimoles) of methyl orthobromomethylphenylglyoxalate are dissolved in 250 ml of N-methylpyrrolidone, a pinch of potassium iodide is added and the mixture is stirred for 15 hours at room temperature (23° C.). Thereafter, the mixture is poured onto 500 ml of ice water and extracted with 3×200 ml of methyl tert-butyl ether and the organic phase is washed with water, dried over sodium sulfate and evaporated down in a rotary evaporator. The yield of ketoester is 15.0 g (99%). Thin layer chromatographic analysis shows that it is virtually pure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:24]([C:23]3[C:19]4[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=4[S:21][CH:22]=3)(=[O:25])=[O:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=C1CCCc2c(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)csc21

Procedure:
From 1-(4-fluorophenyl)-piperazine (91 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (120 mg), the title compound (148 mg) was obtained as a colorless solid, in the same way as Preparation Example 41.