Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1.Cl>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: OC[C@@H]1CCCCN1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2CO)c(C)c1
Reaction time: 1.5 h
Yield: 20 %

Procedure:
(S)-Piperidin-2-ylmethanol (1.1 eq.) was dissolved in dichloromethane (4 ml/mmol) and cooled, and triethylamine (2.5 eq.) was added. A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (1 eq.) in dichloromethane (2 ml/mmol) was added dropwise at 0° C., and then stirring was carried out for 90 min at room temperature. Hydrogen chloride solution (eq., 0.5 mol/l, 2 ml/mmol) was added, stirring was carried out for 15 min, and the phases were separated. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 20%
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[O-]CC.[Na+]>C(O)C>[CH:13]1([C:11](=[O:12])[CH:10]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (9.30 g, 75.00 mmol, Aldrich) and cyclopropyl methyl ketone (6.30 g, 75.00 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.79 ml, 7.50 mmol). After stirring for 2 hours at room temperature, additional 4-fluorobenzaldehyde was added (1.86 g, 15.00 mmol). The reaction mixture was stirred for 2 hours, concentrated to 1/3 volume and partitioned between 50% saturated NH4Cl/EtOAc (100 ml/250 ml). The layers were separated and the aqueous portion was extracted with EtOAc (twice) and the combined organics were washed with H2O (twice) and brine, dried (Na2SO4) and concentrated. The yellow oily residue was distilled (Vigroux column, bp 115°-120° C., 0.6 mm Hg) to afford the title compound as a colorless oil (12.8 g, 89.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7](C)[C:4]=1[CH:5]=O.[C:18](O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH3:16][O:15][C:8]1([CH:7]=[C:4]([CH3:5])[C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]1[O:13][CH3:14])[CH:18]=[CH:19][C:20]([OH:22])=[O:21]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC1=C(OC)C(OC)C(C=CC(=O)O)(OC)C=C1C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
2,3,4,5-Tetramethoxy-6-methylbenzaldehyde (17.3 g, 72.1 mmol), malonic acid (22.5 g, 216 mmol) and piperidine (1.7 ml) were dissolved in pyridine (50 ml). The reaction was conducted for 5 hours, while the temperature was gradually raised from 50° C. to 100° C. The solvent was removed under reduced pressure. The residue was acidified with 2N hydrochloric acid, extracted and concentrated. Recrystallization of the product from ethyl acetateisopropyl ether gave 1,2,3,4-tetramethoxy-5-methylcinnamic acid (Compound 20, 14.3 g, 70%). m.p. 117°-118° C. δ 2.31 (3H), 3.78 (3H), 3.83 (3H), 3.90 (3H), 3.96 (3H), 6.59 (1H), 7.94 (1H), 11.2 (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl.CO>[CH:30]1([O:24][C:23]([C:18]2([C:20]([O:22][CH:30]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OC1CCCCCCC1)(C(=O)OC1CCCCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 84 %

Procedure:
The title compound was prepared as a white gum from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclooctanol according to the procedure of Example 1; yield 84%; Rf =0.30 (10/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.30-1.39 (brd, 3H), 1.40-1.92 (m, 28H), 2.72-2.87 (m, 1H), 3.06-3.30 (m, 2H), 3.39-3.52 (m, 2H), 3.80-3.91 (m, 1H), 5.02-5.13 (m, 1H), 5.40-5.80 (m, 1H), 6.71-6.89 (m, 4H), 7.21-7.37 (m, 2H), 7.44 (s, 1H), 8.73 (brs, 1H), 10.11 (brs, 1H); MS (ES) m/z (relative intensity): 679 (M+, 100).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:34]([F:33])([F:43])[F:44])=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1

Procedure:
A solution of trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid as TFA salt (18.4 mg, 0.04 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (10.5 mg, 0.06 mmol, 1.5 equivalents) and DMAP (1.3 mg, 0.26 equivalents) in dichloromethane (1 ml) was cooled with stirring in an ice bath. EDCl (12.7 mg, 0.066 mmol, 1.65 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed to give the crude product, which was further purified by RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 5-40% CH3CN/H2O, 0.1% TFA, 25 min) to give the final product (5.33 mg, 21.5%). MS (ES+): m/e 507.21 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[C:23]([C:25]#[N:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]#[N:26])=[CH:22][N:21]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white foam. MS (ISP): m/z=406.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1.[I-].[K+]>CN(C)C=O.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: C1CNCCNC1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(C(CCCN2CCCNCC2)c2ccc(F)cc2)cc1

Procedure:
24 g (0.24 mol) of 1,4-diazacycloheptane, 7.8 g (0.024 mol) of 4,4-bis(4-fluorophenyl)butyl bromide and 0.14 g of potassium iodide were stirred in 60 ml of dimethylformamide at room temperature for 4 hours. The solvent was stripped off in vacuo, the residue was taken up in methylene chloride, the mixture was extracted by shaking with 2N HCl, the acid phase was brought to pH 11 with concentrated NaOH and extracted with methylene chloride and the extracts were dried and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][CH3:7].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:6]([CH3:7])[C:20](=[O:22])[CH3:21]
Reactant: CNCc1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.1 M) solution of 3-bromo-N-methylbenzylamine (1 eq.), Hunig's base (3 eq) and 4-(dimethylamino)pyridine (5% loading) was added acetyl chloride (1.5 eq). The resulting reaction mixture was stirred at RT for 16 h. After quenching the reaction with sat. aq. NaHCO3, the mixture was extracted with EtOAc. The organic extract was washed with 10% aq. HCl, sat. aq. NaHCO3, and brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[C:14]([O:16]C)=O)=[O:7])([CH3:4])(C)C.[BH4-].[Na+].[C:20](O)(=O)[CH3:21].[BH4-]>O1CCCC1.O>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[CH2:14][OH:16])=[O:7])[CH2:4][CH2:20][CH3:21]
Reactant: CC(=O)O
Reactant: COC(=O)C1NC(=O)C1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A solution of 2.0 g (8.2 mmole) of methyl 3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate in 20 ml of tetrahydrofuran is cooled in ice and a solution of 0.75 g (20 mmole) of sodium borohydride in 10 ml of water is added. The mixture is stirred 20 min at 0° and then 1.5 hr at room temperature. Acetic acid is added dropwise to decompose the excess borohydride and the mixture is concentrated in vacuum. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCO3 ; dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128°-131°.
Reaction SMILES: Br[C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:17][CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:2]2([N:23]3[CH2:24][CH2:25][C:20](=[CH:19][CH2:18][OH:17])[CH2:21][CH2:22]3)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC=C1CCNCC1
Reactant: O=C1NC(=O)C(Br)(c2ccccc2)C(=O)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2ccccc2)(N2CCC(=CCO)CC2)C(=O)N1
Yield: 16.5 %

Procedure:
A mixture of 5-bromo-5-phenylbarbituric acid (2.45 g), 4-(hydroxyethylidene)piperidine (1.053 g) and triethylamine (1.15 ml) in 50 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is purified by silica gel chromatography (40 g; eluent: ethyl acetate/petroleum ether 8:2), to give 450 mg of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (80 mg, 0.23 mmol, Step-1 of Example 353) and sodium hydride (60% in oil, 27 mg, 1.13 mmol) in N,N-dimethylformamide (5 mL) was added tert-butyl (2-bromoethyl)carbamate (76 mg, 0.34 mmol) at room temperature. Then the mixture was stirred at 70° C. for 3 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (30 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (eluting with n-hexane/ethyl acetate=2/1) to give 112 mg (>99% yield) of the title compound as brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][NH:13][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCCO
Product: O=C(NCCO)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and 2-aminoethanol; MS: 205 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:27])[N:13]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:48]1([CH2:54][CH2:55]O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>N(C(OCC)=O)=NC(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH2:55][CH2:54][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:27])[N:13]2[C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OCCN1CCCCC1
Reactant: CC1Cc2c(-c3ccccc3Cl)cc(O)cc2N(c2c(Cl)cccc2Cl)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1Cc2c(-c3ccccc3Cl)cc(OCCN3CCCCC3)cc2N(c2c(Cl)cccc2Cl)C1=O

Procedure:
The title compound was prepared from 7 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-3-methyl-3,4-dihydroquinolin-2(1H)-one, 40 mg of Ph3P, 20 μL of 1-piperidine ethanol, and 20 μL of diethyl azodicarboxylate by a procedure analogous to that described in EXAMPLE 2. Mass spectrum (ESI) 545 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:30])=[C:4]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:3]=1
Reactant: CC1(C)CC(c2cc(Cl)ccn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cc(Cl)cc[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
79 mg of 4-(4-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile were dissolved in 10 ml of dichloromethane and 70 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature for 3 days, then washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 1% (v/v) methanol/ethyl acetate for the elution to give, after trituration with diethyl ether, a solid which was recrystallized from ethyl acetate/petroleum ether. There being obtained 20 mg of 4-chloro-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 173°-174° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7]CCO.[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]S(C)(=O)=O)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:12]
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
NaH (88 mg of a 60% dispersion in oil, 2.2 mmol) was suspended in anhydrous toluene (3 ml) under N2 and chilled to 0° C. Monodispersed diethylene glycol monomethyl ether (0.26 ml, 0.26 g, 2.2 mmol) that had been dried via azeotropic distillation with toluene was added. The reaction mixture was allowed to warm to room temperature and stirred for four hours, during which time the cloudy grey suspension became clear and yellow and then turned brown. Mesylate 5 (0.50 g, 1.0 mmol) in 2.5 ml dry toluene was added. After stirring at room temperature over night, the reaction was quenched by the addition of 2 ml of methanol and the resultant solution was filtered through silica gel. The filtrate was concentrated in vacuo and the FAB MS: m/e 499 (M+H), 521 (M+Na). Additional purification by preparatory chromatography (silica gel, 19/3 chloroform/methanol) provided the monodispersed compound 6 as a clear yellow oil (0.302 g 57%). FAB MS: m/e 527 (M+H), 549 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Reaction time: 0.05 h
Yield: 65.7 %

Procedure:
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (100 mg, 0.30 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (66%) of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.0 (m, 8H), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), and 2.2 (s, 3H). IR (KBr, cm−1) 3367, 3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 1151, 1102, 772, and 714. MS (FD) m/e 402.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>ClC1C=CC=CC=1Cl>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1ccccc1Cl
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1ccccc1Cl
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a mixture of 4-hydroxy-6-methyl-2H-pyran-2-one (10.0 g) and 1,2-dichlorobenzene (9.91 mL) was added 2-chloroaniline (10.1 g) over 10 min at 165° C., and the reaction mixture was stirred at 165° C. for 30 min, and cooled to room temperature. The resulting solid was collected by filtration, and washed with dichloromethane to give the title compound (5.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccccc4s3)cc2)cc1

Procedure:
To 2-(4-aminophenyl)benzothiazole (0.5 g, 2.2 mmol) in pyridine (6 mL) is added para-toluenesulphonyl chloride (0.506 g, 2.7 mmol, 1.5 eq.) in pyridine (4 mL). The reaction mixture is heated at reflux for 10 mins, then cooled and water (10 mL) added. The white precipitate formed is collected on a filter, washed with water, and dried under vacuum to give N-[4-(benzothiazol-2-yl)phenyl]-4-methylbenzenesulfonamide as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[Si](Cl)([C:26]([CH3:29])(C)[CH3:27])(C)C>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])[N:13]([CH2:15][C:17]([O:19][CH2:27][CH:26]=[CH2:29])=[O:18])[C:12]1=[O:20])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 143.4 %

Procedure:
(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-2-azetidinone (6 g) is dissolved in tetrahydrofuran (250 ml), and thereto is added 60% sodium hydride (0.796 g) at 10° C., and the mixture is stirred at 20° C. for 20 minutes. To the mixture is added t-butyldimethylsilyl chloride (3 g) at 10° C., and the mixture is stirred for 10 minutes, and concentrated under reduced pressure to the quarter volume thereof. The concentrated mixture is stirred at 20° C. for 20 minutes, and thereto is added a mixture of bromoacetic acid allyl ester (3.56 g) and tetrahydrofuran (190 ml), and further added thereto dropwise 1M solution (20 ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -50° C. The mixture is warmed to 20° C. over a period of 30 minutes, and concentrated under reduced pressure to a quarter volume thereof. The concentrated mixture is stirred at 20° C. for 2 hours, and thereto is added tetrahydrofuran (190 ml), and further added dropwise a solution of potassium carbonate (2.8 g) in water (40 ml) at 10° C. The mixture is stirred at 20° C. for 15 minutes. To the mixture is added diluted hydrochloric acid [hydrochloric acid (4.2 g) in water (8 ml)] at 10° C., and thereto is added 1N hydrochloric acid (18 ml) under ice-cooling. The mixture is allowed to stand, and the organic layer is collected. The aqueous layer is extracted with chloroform, and the organic layers are combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform→chloroform:methanol=98:2) to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(allyloxycarbonylmethyl)-2-azetidinone (5.7 g) as oil.