Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl>[CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:3]#[C:4][Si:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C#C[Si](C)(C)C)c1ccccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C#C[Si](C)(C)C)c1ccccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
A solution of 20.9 grams (95.7 mmol, 1.0 eq) of phenol 6 in 92.0 mL of CH2Cl2 was stirred in a 250 mL round bottom flask under argon at room temperature. To this colorless solution was then added 580 mg (4.8 mmol, 0.05 eq) of N,N-dimethylaminopyridine followed by 46.0 mL (574 mmol, 6.0 eq) of pyridine. This solution was then cooled to 0° C. in an ice water bath. Once cooled, 19.3 mL (114.8 mmol, 1.2 eq) of Tf2O was carefully added to the cold solution. Once the addition of Tf2O was complete, the ice water bath was removed and the black solution was stirred at room temperature until complete by TLC (7:1 hexane:EtOAc, KMnO4 stain). Upon completion (˜30 minutes), the solution was diluted with Et2O and washed with 1.0 M HCl twice, followed by washings with water and brine. The organic fraction was then dried over MgSO4, concentrated and purified via vacuum distillation yielding 24.88 grams (74% for two steps) of a colorless oil, Rf 0.69 (7:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.76 (dd, J=7.8 Hz, 1.7 Hz, 1H), 7.41 (dt, J=1.2 Hz, 7.6 Hz, 1H), 7.34 (dt, J=1.7 Hz, 7.8 Hz, 1H), 7.29 (dd, J=1.5 Hz, 8.5 Hz, 1H), 4.14 (q, J=7.1 Hz, 1H), 1.52 (d, J=7.1 Hz, 3H), 0.21 (s, 9H). 13C-NMR (500 MHz, CDCl3): 146.66, 135.94, 129.88, 128.92, 128.82, 121.33, 118.73 (q, J=320 Hz), 107.57, 87.12, 27.40, 23.56, 0.21. 19F-NMR (500 MHz, CDCl3): −74.37. IR (cm−1): 2960 (w), 2169 (w), 1757 (w), 1422 (s), 1214 (s), 1142 (s), 886 (s), 844 (s), 761 (m). HRMS (EI) calcd. for C14H17F3O3SSi: 350.0620. found: 350.0619.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1>N1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ncc([N+](=O)[O-])s1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ncc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of o-toluoyl chloride (17 g) in a few milliliters of pyridine was added dropwise to a suspension of 2-amino-5-nitrothiazole (16 g) in pyridine (100 ml), initially at room temperature, then at 0°. After the addition was complete, the reaction mixture was stirred for 2 hr at room temperature, and was then quenched in ice-water. Recrystallisation of the precipitated amide from 2-methoxyethanol afforded 2-methyl-N-(5-nitro-2-thiazolyl)benzamide, m.pt. 228°-230°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:15](=[O:24])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Cc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
m-Toluidine (5 g, 46.64 mmol) and pyridine (3.77 mL, 46.64 mmol) were dissolved in dry dichloromethane (25 mL). To the reaction mixture, cinnamoyl chloride (7.72 g, 46.64 mmol) was added and stirred for 3 h at 0° C. The reaction mixture was extracted with dichloromethane washing with water and 2N HCl. The solvent was removed and the crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (47 grams) in N,N-dimethylformamide (886 mL) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6:1 hexane/methylene chloride to afford 32 grams of the title compound. 1H NMR δ 7.02 (s, 2), 3.71 (br s, 2), 2.91 (qq, 2, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:16])[CH2:4][C:5](=O)[CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[K+].O.NN>C(O)COCCO>[CH3:16][C@H:3]([CH2:4][CH2:5][CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][OH:1]
Reactant: CC(C)CCC[C@@H](C)CC(=O)C[C@@H](C)CO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CO

Procedure:
A mixture of 3.98 g. (0.0174 mole) of (2R,6R)-1-hydroxy-2,6,10-trimethylundecan-4-one, 108 ml. of diethylene glycol, 25 g. of KOH and 43.5 ml. of hydrazine hydrate was stirred and heated until distillation began. Distillation was then continued until the internal temperature of the reaction mixture reached 195° C. then the mixture was maintained at reflux for 4 hours. After cooling, the resulting mixture was treated with ice and 3 N aqueous HCl and worked-up by ether extraction in the manner of Example 1 giving 2.9 g. of a pale yellow oil. This material was chromatographed on 180 g. of silica gel. Elution with 4:1 parts by volume hexane-ether yielded (2R,6R)-(+)-2,6,10-trimethylundecan-1-ol which was evaporatively distilled affording 2.22 g. of a colorless oil, b.p. 90°-105° C. (bath temperature) (0.2 mm Hg.); [α]25D+9.44° (c 2.04, hexane).
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH:8]=[CH:7][N:6]=1)#N.[ClH:20].[OH2:21]>CCO>[ClH:20].[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:21])=[O:1])[CH:10]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc(CO)ccn1
Temperature: 25 °C

Procedure:
Solid sodium hydroxide (22.2 g, 0.554 mol) is added to a stirred solution of 2-cyano-4[{(tert-butyldimethylsilyl)oxy}methyl]pyridine in 300 mL EtOH and 50 mL water. The reaction mixture is then heated at reflux for 15 h. After cooling to room temperature, the solution is adjusted to pH 1-2 by addition of 6N HCl, then the mixture is concentrated to dryness in vacuo. The solid residue is washed with ethanol, then dried in vacuo to give crude 4-(hydroxymethyl)pyridine-2-carboxylic acid hydrochloride as a tan solid. The crude salt is disolved in 280 mL DMF, then 18.2 g (0.131 mol) of potassium carbonate is added, followed by 4.8 mL (0.0554 mol) of allyl bromide. The resulting mixture is allowed to stir at room temperature for 48 h, then concentrated under high vacuum. This residue is taken up in ethyl acetate and washed three times with saturated LiCl and finally with brine. The aqueous washings are combined and extracted with CH2Cl2. The combined organic layers are dried over Na2SO4 and concentrated. Silica gel chromatography eluting with 97:3 CH2Cl2-MeOH gives allyl 4-(hydroxymethyl)pyridine-2-carboxylate as a dark oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1nc(Br)cnc1N
Yield: 92.3 %

Procedure:
A mixture of methyl 3-aminopyrazine-2-carboxylate (8.35 g, 54.53 mmol) and N-bromo-succinimide (9.705 g, 54.53 mmol) was stirred in MeCN (100 mL) at room temp overnight. The resultant precipitate was filtered, washed with MeCN and dried to give the desired product as a yellow solid (11.68 g, 92% Yield); 1H NMR (400.0 MHz, DMSO) 3.85 (s, 3H), 7.55 (br s, 2H) and 8.42 (s, 1H) ppm; MS (ES+) 233
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].N(C(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)[C@@H](C(NCC(N)=O)=O)CCC(=O)O.N(C(OCC1C=CC=CC=1)=O)[C@@H](C(NCC(N)=O)=O)CCCCN.N(C(C)=O)[C@@H](C(NCC(N)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH2:3][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Reactant: NC(=O)CNC(=O)[C@@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(N)=O
Agent: NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 66 %

Procedure:
For accurate comparison, the D-isomers Z-D-Phe-OBn, Z-D-Ala-OBn, Z-D-Glu-OMe, Z-D-Lys-OBn, and Ac-D-Phe-OBn (15-19) of the representative L-amino acids Z-L-Phe-OBn, Z-L-Ala-OBn, Z-L-Glu-OMe, and Z-L-Lys-SBn (1-4) examined in the previous ligation examples were used. The stereoselectivity of SBL-WT for L-amino acids was clear (Table 4), because none of the D-amino acid esters evaluated gave dipeptide products with WT as the catalyst. All of the S166C-MEs yielded dipeptide products containing D-amino acids Z-D-Phe-Gly-NH2, Z-D-Ala-Gly-NH2, Z-D-Glu-Gly-NH2, Z-D-Lys-Gly-NH2, and Ac-D-Phe-Gly-NH2 (20-24). While each of these enzymes still showed a preference for L-amino acids, yields of up to 66% of Z-D-Phe-Gly-NH2, using S166C—SCH2C6H5, over 0% for WT, demonstrated a dramatic improvement in SBL's acceptance of D-amino acids.
Reaction SMILES: [C:1]([NH2:7])(=[NH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([CH:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12](OCC)=[O:13])(=O)[CH3:9].[OH-].[K+].O>CO>[CH2:2]([C:1]1[N:7]=[C:12]([OH:13])[C:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH3:9])[N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: CCCCC(=N)N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(C)c(CC(=O)OCC)c(O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.1 %

Procedure:
1.41 kg of valeroamidine and 1.41 kg of diethyl acetylsuccinate were dissolved in 4.5 L of methanol and 1.16 kg of potassium hydroxide was added thereto. The mixture was stirred for 15 hours at room temperature, and then 14 L of water was added while stirring. The obtained solid was filtered, dried, and dissolved in 6 L of ethanol. Then, 840 g of thionyl chloride was added by drop for 2 hours and stirred for 12 hours at 60° C. To this mixture was added a solution of 1.22 kg of sodium bicarbonate in 15 L of water and the produced solid was filtered and dried to obtain 1.35 kg (47.8% yield) of the titled compound.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:7][C@@H:28]2[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH3:5][O:6][N:7]=[C:8]([C:14]([CH2:16]Br)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH3:5][O:6][N:7]=[C:8]([C:14]1[N:4]=[C:1]([CH3:2])[S:3][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Thioacetamide (3.8 g.) was added to a solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (12.6 g.) in ethanol (50 ml.) and the mixture was stirred for 5 hours at 50° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (9.0 g.).
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([SH:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][O:27][C:28](=[O:39])[C:29]([N:32]1[CH2:33][CH2:34][CH:35]([S:38][C:2]2[C:3]([F:25])=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=5)=[CH:10]4)[C:6]=3[CH:24]=2)[CH2:36][CH2:37]1)([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (320 mg, 0.788 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (257 mg, 1.18 mmol), Pd2(dba)3 (36 mg, 0.039 mmol, mol %), XantPhos (46 mg, 0.079 mmol, 10 mol %) and DIPEA (0.55 mL, 3.15 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The crude reaction mixture was diluted with DCM (150 mL) and purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (quantitative yield), impure but taken forward to the next step without further purification. LCMS: RT 2.29 and 2.36 min [M+H]+ 543.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[C:16]=1[C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=[CH:5]2.[Br:28]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:28][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[O:13][C:14]3[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=3[C:16]=1[C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8]2
Reactant: CC(C)(C)CC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)CC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Yield: 44.2 %

Procedure:
Following the procedure described in Step 4 of Example 1, 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-3,3-dimethyl-1-butanone (0.378 g, 1.05 mmol) was brominated using, bromine (0.08 mL, 1.6 mmol), and potassium acetate (1.02 g, 10.4 mmol), in glacial acetic acid (17 mL). Purification by flash chromatography (Biotage apparatus) using 15-20% chloroform in hexane as an eluant furnished the title compound as a dark brown gum (0.203 g). 1HNMR (300 MHz, DMSO-d6): δ10.95 (s, 1H), 8.35 (s, 1H), 8.2 (d, 1H, J=8.3 Hz), 8.0 (d, 1H, J=8.3 Hz), 7.95 (t, 2H, J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.35-7.55 (m, 3H), 2.65 (s, 2H), and 0.85 ppm (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(N3CCNCC3)nc3ccccc23)cc1
Yield: 91.1 %

Procedure:
A solution of 2-chloro-4-phenylquinoline (4.0 g) and anhydrous piperazine (8.0 g) in toluene (4 ml) is heated under reflux for 5 hours. To the reaction mixture is added water and the resulting mixture is extracted with ethyl acetate. The extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (40 g) using chloroform as an eluent. Fractions containing the title compound are pooled and concentrated to give the title compound (4.4 g), m.p. 133°-134° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)[C:2]1=2.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].Cl>C(Cl)Cl.O.CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[O:16])[C:2]1=2
Reactant: O=C(O)COCCc1cccc2ccsc12
Reactant: CCNCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)COCCc1cccc2ccsc12
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
In 10 mL of methylene chloride is dissolved 1.20 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-acetic acid. The solution is cooled to 5° C., 0.49 mL of oxalyl chloride and 0.1 mL of N,N-dimethylformamide are added thereto, and the resulting mixture is stirred at ambient temperature for 1.5 hours. The mixture is then cooled to 5° C., 2.6 mL of diethylamine is added, and the resulting mixture is stirred at ambient temperature for 2 hours. Water is added to the reaction mixture, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.36 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-N,N-diethylacetamide is obtained as an oily product.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26]([OH:27])[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1.[CH2:34]([C:37]#[N:38])[CH2:35]O.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26]([O:27][CH2:35][CH2:34][C:37]#[N:38])[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: N#CCCO
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCOC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
Under ice cooling and stirring, 0.27 ml of thionyl chloride was added 1.5 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 suspended in 30 ml of methylene chloride and the mixture was stirred at the same temperature for 40 minutes. After completion of the reaction, the reaction mixture was condensed under reduced pressure, the residue was dissolved in 12 ml of methylene chloride, 0.81 ml of ethylenecyanhydrin and 0.94 ml of triethylamine were added to the solution under ice cooling and stirring and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. Solid obtained by removing the solvent was washed with a diethyl ether-hexane mixed solution to obtain 1.31 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9]Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: ClCl
Solvent: CC#N
Product: ClCc1ccc(Cl)nc1
Yield: 69 %

Procedure:
1 Mol of 2-chloro-5-methylpyridine and 128 g of acetonitrile are heated to reflux. The mixture is irradiated with UV light and chlorine gas is introduced in a slight excess. The reaction is terminated as soon as 0.37 mol of product has been formed. 0.46 Mol of starting material is simultaneously recovered. Based on the reacted starting material, a yield of 69% results.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][CH2:20]CC(OCC)=O)[CH2:12][C:13]([O:15]CC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:27][CH2:28][CH3:29].[Na+].C([OH:33])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C:13](=[O:15])[CH:19]([C:20]([O:27][CH2:28][CH3:29])=[O:33])[CH2:18]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O-]
Reactant: CCOC(=O)CCCCN(CC(=O)OCC)C(=O)OCc1ccccc1
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Yield: 72 %

Procedure:
To a solution of ethyl 3-[N-benzyloxycarbonyl-N-(ethoxycarbonyl methyl)amino]ethylpropionate (26.8 g, 79.5 mmol) in ethanol (200 mL), sodium ethoxide (20% solution in ethanol, 40.6 mL, 119.3 mmol) was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in water (100 mL). Concentrated hydrochloric acid was added to this solution in an ice bath for acidification, and the solution was extracted with chloroform (100 mL×3). The extract was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 16.7 g (72%) of the title compound as a pale brown oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.C1CCCCC1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])/[C:10](=[CH:22]/[N:23]([CH3:25])[CH3:24])/[CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: O=C1CCCOc2cc(Br)ccc21
Reactant: COC(OC)N(C)C
Solvent: C1CCCCC1
Product: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
8-Bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.0 g, 20.7 mmol) in dimethylformamide dimethylacetal (15 mL) was heated at 110° C. for 18 h. The reaction was allowed to cool to room temperature and cyclohexane (20 mL) was added. The resulting solid precipitate was collected by filtration, washed with cyclohexane and then dried under vacuum at 40° C. to yield 8-Bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one as yellow crystals (5.32 g, 86%). 1H NMR δ (ppm)(CDCl3): 7.73 (1 H, s), 7.61 (1 H, d, J=8.29 Hz), 7.29 (1 H, dd, J=8.29, 1.94 Hz), 7.18 (1 H, d, J=1.91 Hz), 4.28-4.21 (2 H, m), 3.14 (6 H, s), 2.77-2.70 (2 H, m).