Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:20]([O-:22])=[O:21])=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 49.6 g of N-(4-chloro-2-fluorophenyl)phthalimide and 180 ml of concentrated sulfuric acid was cooled in an ice bath, and a mixed acid consisting of 22.7 g of 60% nitric acid and 18 ml of concentrated sulfuric acid was slowly added dropwise under stirring (reaction temperature<10° C.). After the dropwise addition, the stirring was continued under cooling in an ice bath for 1 hour and then at room temperature for 1 hour. The reaction mixture was poured into ice-water, and the precipitated solid was collected by filtration. The resulting solid was washed successively with water and methanol and dried under reduced pressure to give 57.2 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][CH:15]([C:16]#[N:17])[CH2:4][C:3]=2[CH:6]=1
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)OC(C#N)C2
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
2-Hydroxy-4,5-dimethoxybenzaldehyde (25.5 g, 0.14 mol), chloroacetonitrile (12.4 g, 0.168 mol) and potassium carbonate (116 g, 0.84 mol) was dissolved in DMF (150 ml). The mixture was stirred for 10 minutes at 165° C. The solvent was concentrated under reduced pressure. The residue was separated in two parts, water was added and the first part was extracted with diethyl ether and the second part extracted with DCM. The second part was evaporated under reduced pressure and dissolved in ether and washed once with water. The organic layers was combined and evaporated under reduced pressure. The crystalline residue was washed with warm methanol (700 ml) and filtered. The residue was dissolved in 225 ml DCM and diethyl ether (450 ml) was added. The crystals formed was collected giving 14.6 g (51% yield) of product. Mp. 162° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=1[OH:31])=[O:27])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C@@H:6]1([O:24][C:25]2[C:26]([O:28][C@H:29]([C@H:32]([CH2:34][OH:35])[OH:33])[C:30]=2[OH:31])=[O:27])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC2=C(O)[C@@H]([C@@H](O)CO)OC2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
After dissolving 2-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)ascorbic acid (300 mg, 0.6 mmol) in methanol (10 ml), a solution of potassium carbonate (600 mg) in water (9 ml) was added and the mixture was stirred for 30 minutes. The reaction solution was neutralized with IR-120(H+), the resin was filtered off, and washing was performed with methanol and a 50% methanol aqueous solution. The filtrate and washing solution were combined and concentrated, and then water was added and the mixture was lyophilized to obtain 2-O-(β-D-glucopyranosyl)ascorbic acid as amorphous crystals (190 mg, 100% yield). 1H-NMR (δppm, D2O); 3.1-3.3 (4H, m), 3.4-3.5 (3H, m), 3.58 (1H, d), 3.80 (1H, t), 4.61 (1H, d), 4.66 (1H, d). FABMS (−) m/z: 337.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[OH:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(NCCO)nc3c(Sc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenylthiopyrimido[5,4-d]pyrimidine (melting point: 253°-255° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5])[CH3:2].[I:17]I.[OH-].[K+].S([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:15][CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]ncc2c1OC
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]nc(I)c2c1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.4 %

Procedure:
To 15 mL of a solution of 1.33 g of 4-methoxy-1H-indazole-5-carboxylic acid ethyl ester in N,N-dimethylformamide were added 1.95 g of iodine and 0.85 g of potassium hydroxide, stirred at room temperature for 1 hour and 40 minutes, added with another 0.8 g of iodine, and stirred for 3 hours and 20 minutes. Thereafter, 10% sodium hydrogen sulfite aqueous solution was added, extracted twice with ethyl acetate, and the organic layer was washed once with saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to afford 1.68 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6]>CO>[OH:6][CH:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(=O)c2ccncc2)c1OC
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC
Reaction time: 22 h
Yield: 92.5 %

Procedure:
A solution of 4-(2,3-dimethoxybenzoyl)pyridine (12) (2.10 g, 8.6 mmol) in MeOH (10 mL) is treated with 5% Rh/alumina (0.72 g). The mixture is hydrogenated in a Parr shaker at 55 psig for 22 hours. After filtration through Celite7 filter aid, the filtrate is concentrated at reduced pressure to give the title compound (11) as a solid (2.0 g, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.CCOC(C)=O>N1C=CC=CC=1>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]4[CH:8]=3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(-c2cn3cc(F)ccc3n2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3cn4cc(F)ccc4n3)cc2)cc1
Yield: 35.8 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-fluoroimidazo[1,2-a]pyridin-2-yl)aniline (100 mg, 0.44 mmol) and 4-dimethylaminobenzoyl chloride (81 mg, 0.44 mmol) in dry pyridine (5 ml) to give the title compound (59 mg, 36%) as a pale yellow solid after work-up and flash chromatography (1:1 DCM/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH2:30]([SH:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1[S:32][CH2:30][CH3:31]
Reactant: CCS
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSc1cnn(-c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)c(=O)c1Cl
Yield: 46 %

Procedure:
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in acetonitrile (10 mL) was added of 0.15 mL of ethylmercaptan and 0.280 mg of potassium carbonate. The mixture was heated to reflux for 2 h. The suspension was filtered and the solid was washed with ethyl acetate to gave the title compound (0.220 g, 46%). Mp 80–100° C., 1H NMR (DMSO-d6) 8.8 (1H, d, 3 Hz), 859 (1H, d, 6 Hz), 8.37 (1H, s, NH), 7.98 (1H, d, 6 Hz, 3 Hz), 7.92 (1H, t, 3 Hz), 7.86 (1H, s), 7.46 (1H, d, 9 Hz, 3 Hz), 7.40 (1H,s), 7.27(2H, m), 7.04(1H, d, 9 Hz), 3.12 (2H, q, 6 Hz), 1.47 (3H, t, 6 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(O)C.O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:10]([CH3:9])[CH2:11][CH2:12][OH:13])[CH:5]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNCCO
Solvent: O
Solvent: CCO
Product: CN(CCO)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g (0.1 mmol) 2,4-dichloropyrimidine in 120 ml ethanol and 20 ml water, cooled to 0° C., 11.3 g (0.15 mol) 2-(N-methylamino)ethanol is added. The resulting mixture is stirred at room temperature for ½ h., then concentrated to dryness and finally partitioned between CH2Cl2 and a NaHCO3 saturated solution.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([OH:9])=[CH:11]1)[CH3:22]
Reactant: CCn1cc(OC(=O)c2ccccc2)c(=O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCn1cc(O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-ethyl-4-oxo-1,4-dihydroquinol-3-yl benzoate (6.29 g), piperidine (2.1ml) and dichloromethane (60 ml) was stirred under nitrogen at ambient temperature for 3 days. Further piperidine (0.5 ml) was added and the mixture stirred for 24 hours. The solvent was removed by distillation and the residual solid triturated with diethyl ether (20 ml) to give the novel compound 1-ethyl-3-hydroxy-4-quinolone, m.p. 180°-182°.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=4[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)=[CH:31][CH:32]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1
Yield: 4.7 %

Procedure:
Methyl 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}phenoxy)methyl]benzoate (0.12 g, 0.28 mmol) was dissolved in a mixture of THF/water (7/1, 5 ml) and LiOH (0.03 g, 1.13 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). Workup by addition of HCl (1 ml, 1M), extract the product by adding two portions of EtOAc (5 ml). The pooled organic phases were dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (starting with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Evaporation gave 6 mg of 2-[(4-{2-[4-(1H-imidazol-1-yl)phenoxy]ethyl}-phenoxymethyl]benzoic acid (yield 4.7%).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl>[C:4]1([CH2:3][CH:2]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]4[CH2:22][CH2:23][C:24]5[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=54)=[CH:18][N:17]=3)=[CH:12][CH:11]=2)[N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC2=CN=C(c3ccc(C(Cl)Cc4ccccc4)cc3)N3CCC(=C23)N1
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Product: O=C1C=CC2=CN=C(c3ccc(C(Cc4ccccc4)N4CCCC4)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 247b and pyrrolidine according to the procedure described in Example 245, with the exception of chloroform as solvent. Received 40 mg (11%).
Reaction SMILES: C(O)(=O)C(O)=[O:3].C(O)(=O)C(O)=O.[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=2)=[N:17][N:16]=[C:15]1[CH2:37][C:38]#[N:39].[OH-].[Na+]>Cl>[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)=[N:17][N:16]=[C:15]1[CH2:37][C:38]([NH2:39])=[O:3]
Reactant: Cn1c(CC#N)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(N)=O)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 28.4 %

Procedure:
A solution of 4-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-4H-1,2,4-triazole-3-acetonitrile dioxalate (0.05 g) in 35% hydrochloric acid (1 ml) was heated at 40° C. for 3 h. The mixture was basified with sodium hydroxide and extracted with chloroform. Evaporation of the organic solution gave the title compound (0.01 g) as a white powder.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:8]([C@H:20]([OH:22])[CH3:21])[C:7]1=[O:23].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[OH:22][C@@H:20]([CH:8]1[CH:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[NH:6][C:7]1=[O:23])[CH3:21]
Reactant: COc1ccc(CN2C(=O)C([C@@H](C)O)C2C(=O)OCc2ccccc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H](O)C1C(=O)NC1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(a) 14 g of benzyl 1-(2,4-dimethoxybenzyl)-3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate [which had been synthesized according to a procedure similar to that described in Tetrahedron 46, 1795 (1984)] were dissolved in a mixture of 420 ml of acetonitrile and 420 ml of water. 66.1 g of potassium persulfate and 23.3 g of dibasic potassium phosphate were added to the solution, and the mixture was stirred at 70° C. for 60 minutes. At the end of this time, insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed from the solvent by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel to afford 6.1 g of benzyl 3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(NC(C)C)(C)C.C1C(=O)N([Br:27])C(=O)C1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:27])[C:6]=1[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccc(Br)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl(2-hydroxyphenyl)acetate (14.0 g, 84.3 mmol) in 100 mL of DCM was added diisopropyl-amine (1.70 g, 16.8 mmol) and NBS (15 g, 84.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was poured into 1N HCl, extracted with DCM, and concentrated to give crude methyl(3-bromo-2-hydroxyphenyl)acetate.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[S:15][C:16]([CH:19]3OC(C)(C)C(C)(C)[O:20]3)=[CH:17][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].Cl>CC#N.O.CCOC(C)=O>[OH:1][CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C2OC(C)(C)C(C)(C)O2)s1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
3-(1-hydroxyethyl)-4-(5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)thiophen-2-yl)-1H-isochromen-1-one (Intermediate B29, 940 mg, 2.347 mmol) was dissolved in 20 ml of MeCN and 20 ml of HCl 1M were added. The clear yellow solution was stirred overnight at rt. The mixture was diluted with 50 ml of water and 200 ml of EtOAc were added. then stirred for 20 min. Phases were separated and the organic one was washed again with 100 ml of NaHCO3 sat. sol. Phases were separated again and the organic one was dried over sodium sulfate, filtered and concentrated to dryness to leave 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (700 mg, 2.331 mmol, 99% yield) as a yellow fluffy solid
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(C=NCCCN(C)C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 104 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g), N,N-dimethyltrimethylenediamine (306.6 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 4.5 hours. The resultant solution was washed with water and dried. The solvent was removed from the solution to give brown oil (1.4748 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-[3-(N,N-dimethylamino)propyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[N:5]=[C:4]([C:15]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)O)nc1-c1ccsc1
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)cc(C(=O)NCc2cccnc2)nc1-c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 584.4 %

Procedure:
To a mixture of Example 266A (12 mg, 0.05 mmol), C-pyridin-3-yl-methylamine (6 μL, 0.1 mmol) in N,N-dimethylformamide (400 μL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (17 mg, 0.053 mmol), followed by N,N-diisopropylethylamine (17 μL). The reaction mixture was stirred at ambient temperature for 3 hr. It was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to provide the titled compound as white solid (98 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 9.35 (t, J=6.4 Hz, 1H), 8.56-8.38 (m, 3H), 7.93-7.90 (m, 1H), 7.74-7.66 (m, 2H), 7.40-7.32 (m, 3H), 7.36 (s, 1H), 4.52 (d, J=6.4 Hz, 2H). MS (m/e) 336 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C(C)=CC=CC=1C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20]>>[C:18]([C:19]1[O:3][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:4][N:20]=1)([CH3:22])([CH3:21])[CH3:17]
Reactant: CC(C)(C)C#N
Reactant: CCOC(=O)C(C)=O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1cnc(C(C)(C)C)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of ethyl pyruvate (2.0 g, 17.2 mmol) and HDNIB (9.7 g, 20.7 mmol) in trimethylacetonitrile (15 mL) was heated to reflux for 3 hours. After the reaction mixture was cooled to RT, 2,6-lutidine (0.2 mL, 1.7 mmol) was added. The reaction mixture was refluxed for an additional 8 hours. The reaction was checked by LC-MS and the solvent was removed. The residue was dissolved in CH2Cl2C washed with water and brine, dried (Na2SO4), concentrated in vacuo and purified via silica gel column chromatography (EtOAc/hexane) to obtain ethyl 2-tert-butyloxazole-5-carboxylate (1.0 g, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 4.42 (d, J=7.2 Hz, 2H), 1.49 (s, 9H), 1.43 (d, J=7.2 Hz, 3H); MS (ESI) m/z: 198.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a suspension of L-Pro (247 mg, 2.15 mmol) in pyridine (1 ml) was added acetic anhydride (I ml), and the mixture was stirred at room temperature for 5 min. The solvent was removed in vacuo and the resulting oil was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried over sodium sulfate, and concentrated, and the resulting solid was recrystallized from ethyl acetate to give N-acetyl-L-proline (167 mg, 44%), a white powder: m.p. 108° C. [lit 115° C. (from CHCl3)99 ]; [α]D25 -171° (c, 0.91, CHCl3) [(lit107 -118° (c, 1, H2O)] Anal. Calcd. for C7H11NO3 : C, 53.49; H, 7.05, N, 8.91. Found: C, 53.57; H, 7.09; N, 8.76.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:24])([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:6]([O:8]C)=[O:7]>CO.O.O1CCCC1>[CH3:4][C:5]([CH3:24])([C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
Lithium hydroxide monohydrate (2.13 g, 50.6 mmol) was added to a suspension of methyl α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetate (Description 9, 5.3 g, 16.88 mmol) in methanol (60 mL), water (20 mL) and tetrahydrofuran (20 mL) and the mixture was degassed and stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure and the residue was suspended in hydrochloric acid (1M). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (5.05 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.84 (2H, s), 7.80 (1H, s), and 1.68 (6H, s).