Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>C(O)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[N:17][NH:16][C:14]([C:13]1[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:15]
Reactant: NNC(=O)c1cccnc1Oc1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Oc1ccccc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 2-phenoxypyridine-3-carboxylic acid hydrazide (913 mg, 4 mmol), 3-trifluoromethylbenzaldehyde (696 mg, 4 mmol) in ethanol (40 mL) was refluxed for 13 h. It was cooled to room temperature and some precipitate was observed. The mixture was diluted by water (40 mL) and the solid was collected by filtration and washed with ethanol/water (1:1), dried to give 1.41 g (92%) of the title compound. 1H NMR (CDCl3): 10.84 (s, 1H), 8.63 (m, 1H), 8.23 (s, 1H), 8.16 (m, 1H), 7.91 (bs, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.40 (m, 3H), 7.24 (t, J=7.2 Hz, 1H), 7.18–7.08 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9]O)=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1>Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:24]2[CH:23]=[C:22]([CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:20][C:19]=2[O:18][CH3:17])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CO
Reactant: COc1ccc(CC(=O)O)cc1
Agent: Cl
Product: CCCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC

Procedure:
To the product from step (iii) (0.8 g) in 1M aq HCl (20 ml), 4-methoxyphenylacetic acid (1.8 g) was added and heated under reflux for 48 h. The solvent was evaporated and the residue purified by SCX then by RPHPLC to give the subtitle compound, 164 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 100.8 %

Procedure:
(1-(4-Fluorophenyl)-1H-indazol-5-yl)methanol (2.46 g, 10.2 mmol) was dissolved in 80 mL DCM and treated with commercially available Dess-Martin periodinane (4.3 g, 10.2 mmol). The reaction was complete in 2 h and was filtered through a plug of SiO2 using DCM/hexane (3:1) and concentrated to give 2.47 g (100%) of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde. MS found: (M+H)+=241.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=O)[CH:11]=O.[BH4-].[Na+]>C(O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]1[CH2:11][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: NCCN
Reactant: O=CC(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1csc(C2CNCCN2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 8.2 g of ethylenediamine in 250 ml of ethanol was added to a solution of 17.64 g of the above aldehyde in 250 ml of ethanol at 0° C. This mixture was stirred at room temperature for 1.5 hours, recooled to 0° C. and 9.6 g of sodium borohydride was added. This mixture was stirred overnight, quenched with water and the ethanol removed. The residue was extracted with dichloromethane, washed with water, dried and evaporated. The residue was crystallized with ether-hexane, giving 12 g of 2-(2-thienyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:12]C(=O)C)=[C:4]([O:16][CH3:17])[CH:3]=1.[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[C:7]([C:8]2([CH3:11])[CH2:9][CH2:10]2)=[CH:6][C:5]([NH2:12])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Cl)c(C2(C)CC2)cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)c(C2(C)CC2)cc1N
Yield: 67.3 %

Procedure:
A mixture of N-(4-chloro-2-methoxy-5-(1-methylcyclopropyl)phenyl)acetamide (820 mg, 3.23 mmol), KOH (1.8 g, 32.3 mmol), ethanol (40 mL) and water (20 mL) was stirred at reflux for 12 h. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=20:1) to afford the desired product (460 mg, 67% yield). ESI-MS m/z: 212.4[M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]1[CH:41]=[CH:40][C:34]([C:35](N(C)C)=[O:36])=[CH:33][CH:32]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)C>[CH2:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]1[CH:41]=[CH:40][C:34]([C:35]([OH:1])=[O:36])=[CH:33][CH:32]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)N(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)O)cc1

Procedure:
Aqueous 2N-sodium hydroxide solution (10 ml.) was added to a solution of p-[(1RS, 2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide (Example 7; 0.24 g.) in ethanol (10 ml.) and the mixture was heated under reflux for 16 hours. The ethanol was removed by evaporation and the residue was acidified to pH 1 with aqueous 2N-hydrochloric acid and extracted three times with ethyl acetate (15 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil p-[(1RS, 2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]benzoic acid, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>C1S(=O)(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([Br:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(Br)cc1
Solvent: O=S1(=O)CCCC1
Product: Clc1cc(Nc2ccc(Br)cc2)ncn1
Yield: 11.1 %

Procedure:
4,6-Dichloropyrimidine (3.0 g, 20 mmol) was mixed with 4-bromoaniline (3.3 g, 19 mmol) and heated to 125° C. for two hours in tetramethylene sulphone. After cooling the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The organic portion was washed, dried over sodium sulphate, filtered and evaporated. The residue was purified by column chromatography (EtOAc (20%): isohexane) to yield a solid (0.6 g, 11%). M/z 284 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([Cl:17])=[CH:10][C:9]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]>C(O)(=O)C.[Fe]>[CH3:22][O:21][C:19]([C:4]1[C:3]([Cl:23])=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[C:11]([Cl:17])=[CH:10][C:9]=2[F:18])[N:5]=1)=[O:20]
Reactant: COC(=O)c1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)cc(N)c1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2cc(N)c(Cl)cc2F)cc(N)c1Cl
Temperature: 85 °C
Yield: 95.7 %

Procedure:
Iron powder (0.78 g, 13.9 mmol) was added to a slurry of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)pyridine-2-carboxylate (0.5 g, 1.39 mmol) in acetic acid (20 mL) in a 100 mL round bottomed flask. The mixture was heated to 85° C. for 15 minutes. then cooled to room temperature and filtered through celite with ethanol and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3, the layers separated, the aqueous phase extracted with ethyl acetate and the combined organics dried (Na2SO4). Filtration and concentration gave 4-amino-3-chloro-6-(5-amino-4-chloro-2-fluorophenyl)pyridine-2-carboxylic acid methyl ester (0.44 g, 1.33 mmol) as a light brown solid: mp 99-101° C.
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].[NH4+].N1C=CC=CC=1.C(=S)=[S:32]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:32])[N:13]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 98 %

Procedure:
In the same manner as described in Example 11, 9.6 g of adenosine 1-oxide monohydrate was treated with a 5N sodium hydroxide aqueous solution and Diaion SK-1B (ammonium-type) to obtain a residue. 200 ml of pyridine and then 60 ml of carbon disulfide were added to the above residue, and the resulting mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was worked up in the same manner as described in Example 11 to obtain 9.35 g of 2-thioadenosine as crystals having a melting point of 197° C (with decomposition) in a 98% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 1.05 g. of N-benzyloxycarbonylglycine, 0.54 g. of benzylalcohol and 50 ml. of methylene chloride is added dropwise a solution of 1.31 g. of triphenyl phosphine and 1.10 g. of 2,2'-dipyridyl disulfide in 20 ml. of methylene chloride while stirring at room temperature. After completion of the addition, the mixture is stirred at room temperature for an additional 6 hours. The reaction mixture is treated with the same procedure as described above to give 1.36 g. of the desired product melting at 71° - 72°C.
Reaction SMILES: [NH2:1][OH:2].[N:3]1([C:9]#[N:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO.CCOCC>[OH:2][NH:1][C:9]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[NH:10]
Reactant: NO
Reactant: N#CN1CCOCC1
Solvent: CCOCC
Solvent: CO
Product: N=C(NO)N1CCOCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 139.3 %

Procedure:
A mixture of hydroxylamine (4.0 mL, 65 mmol) and morpholine-4-carbonitrile (5.00 g, 44.6 mmol) was heated at 80° C. for 24 h. After cooling to room temperature, the reaction mixture was diluted with MeOH and Et2O, then allowed to stand at room temperature for 2 days. The resultant precipitate was collected by filtration to give 9.02 g of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[O:17]1[CH2:22][CH2:21][NH:20][C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: c1ccc2c(c1)CC[C@H]1NCCO[C@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H]3c4ccccc4CC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 17 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.25 g, 1.12 mmol), (4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine hydrochloride (0.3 g, 1.33 mmol) and triethylamine (0.4 g, 3.95 mmol) in tetrahydrofuran (15 ml) was stirred for 48 hours at 100° C. The mixture was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to give 2-((4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (72 mg, 0.19 mmol, 16%) as pale white crystals.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19](O)=[O:20].C1CCN2C(=NCCC2)CC1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([O:23][C:17]([C:18]1[C:19](=[O:20])[O:1][C:2]([CH3:16])([CH3:15])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl) phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02 g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) was dissolved in 100 mL of CH2Cl2. The mixture was stirred for 14 h at room temperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, then partitioned-between CH2Cl2 and 1M HCl. The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (90% ether/Hex) provided 2.50 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[S:26][C:27]([N:30]=[C:31]=[O:32])=[CH:28][CH:29]=1.C(Cl)Cl.CO>C(Cl)Cl>[Cl:24][C:25]1[S:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:32])=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccc(Cl)s1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (98 mg, 0.307 mmol) was dissolved in 10 ml DCM. TEA (46 mg, 0.45 mmol) was added and the reaction mixture was flushed with Ar. 2-chloro-5-thienylisocyanate (58.8 mg, 0.368 mmol) was added on ice bath, and the resulting mixture was agitated at room temperature overnight. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, low boiling point solvent was evaporated under reduced pressure. Column chromatography (DCM/MeOH=100/1) afforded 87 mg white solid, yield: 59.2%.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCC(OO)=[O:19].C(OO)(=O)C>CC(C)=O>[C:1]([C:9]1[CH:14]=[C:13]([OH:19])[C:12](=[CH:11][CH:10]=1)[OH:15])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: CCC(=O)OO
Agent: CC(=O)OO
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 61 %

Procedure:
The procedure of Example 8 was followed, except 20 ml of acetone was added as a solvent for para-tert.-octyl phenol and 4.5g (0.05 mol) of perpropionic acid in the form of about 25 weight% acetone solution was added over 20 minutes in place of peracetic acid. Consequently, the conversion of para-tert.-octyl phenol was 6.8%, 4-tert.-octyl pyrocatechol was formed in a yield of 61% based on the converted octyl phenol and the conversion of perpropionic acid was 100%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)Cc3ccc(Cl)cc3)ccc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide 1.15 g., 0.005 mole) triethylamine (0.7 ml, 0.005 mole) and 4-dimethylaminopyridine (5 mg, catalyst) in dimethylformamide (10 ml) is added 2-(4-chlorophenyl)acetyl chloride (0.8 ml). The reaction mixture is stirred for 2 hours, poured into ice water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is distilled at reduced pressure and the residue chromatographed on silica gel as eluant (130 g, 70-230 mesh) using ethylacetatehexane (1:1) to give 2-sulfamoyl-5-benzothiazolyl 2-(4-chlorophenyl)acetate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][O:34]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH:36]4[CH2:35][O:34][C:33](=[O:32])[NH:37]4)=[CH:45][CH:44]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(CC2COC(=O)N2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CC3COC(=O)N3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-[(2-oxo-1,3-oxazolidin-4-yl)methyl]aniline (Specs, 130 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 36.3 %

Procedure:
A microwave tube charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (200 mg; 0.57 mmol), 2-chloro-4-trifluoromethylaniline (0.12 ml; 0.86 mmol), TFA (64 μl; 0.86 mmol) and toluene (1.5 ml) was heated in a microwave at 160° C. for 30 min. The reaction mixture was basified with DIPEA (0.2 ml), volatiles removed in vacuo and the residue purified by prep. LCMS to give 289 as a white solid (109 mg; 36%). δH (400 MHz, CDCl3) 3.13 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.89-6.93 (m, 2H), 7.24-7.28 (m, 1H), 7.62-7.67 (m, 2H), 7.80-7.83 (m, 1H), 7.98 (s, 1H), 8.26 (s, 1H). [M+H]+: 527
Reaction SMILES: C(O[C:4](=[O:23])[C:5]([N:7]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])C1C=CC=CC=1)=[O:6])C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]=[C:15]([CH3:22])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])=[O:23]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C)cc(C)cc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NC(=O)C(=O)Nc2ccccc2O)c(C)c1
Yield: 72.5 %

Procedure:
N-(Mesityl)-oxanilic acid ethyl ester (5.23 g, 24.4 mmol, 1 eq) and 2-aminophenol (2.67 g, 24.4 mmol, 1.0 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (6.8 ml, 50 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (5.26 g, 17.7 mmol, 72.4% yield). 1H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H), 8.84 (s, 1H), 8.11 (s, J=7.7 Hz, 1H), 7.51 (dd, J=8.0, 1.8 Hz, 1H), 7.14 (ddd, J=1.5, 8.1, 7.2 Hz, 1H), 6.92 (m, 3H), 2.30 (s, 3H), 2.22 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.2, 157.9, 148.2, 138.2, 134.9, 129.5, 129.4, 127.7, 124.3, 122.2, 121.1, 118.9, 21.2, 18.6. Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.50; H, 5.96; N, 9.44.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCCC(C=O)CC
Reactant: C=O
Product: CCCCC(C=O)(CC)CO

Procedure:
The same also applies to U.S. Pat. No. 5,235,118, which relates to the reaction of 2-ethylhexanal with formaldehyde to give 2-ethyl-2-(hydroxymethyl)hexanal. Here too, formaldehyde is used in substoichiometric amounts relative to the 2-ethylhexanal, and only a small residue of formaldehyde is present in the product solution. The addition of water with subsequent distillation serves for effective removal of unreacted 2-ethylhexanal.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[O:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]([NH2:36])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:36][CH:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][CH2:27][CH2:28]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CCOc2ccccc21
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCOc4ccccc43)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and chroman-4-amine (Lu, Y. et al. PCT Int. Appl. 2008, WO 2008043019) as a brown solid (37%). MS 478 (MH+).