Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[N+](C1C=CC(C(O)C(N(C)C)CO)=CC=1)([O-])=O.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1>CCOCC>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Agent: CN(C)C(CO)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 50.05 h

Procedure:
1 part of 2-(4-difluoromethoxyphenyl)-3-methylbutyric acid is dissolved in 1-5 parts (by weight) of solvent comprising an organic solvent such as an aliphatic alcohol, an aromatic hydrocarbon, a keton, a halogenated hydrocarbon, an ether, an ester, or an aliphatic hydrocarbon, etc. After the dissolution is completed, 1-3 moles of resolving agent, an optically active organic base such as 1-(4-nitrophenyl)-2-dimethylamino-1,3-propanediol, quinine, substituted α-aminoethylbenzene and the like, is added. The mixture thus obtained is stirred at -50° C. to 200° C., preferably at 0° C. to reflux temperature of the solvent, for 0.1-100 hours, preferably for 1-10 hours. After the reaction is completed, the reaction mixture is allowed to cool, the solids are then collected by filtration and the filtrate discarded. The solids were added to an aqueous solution of 0.1%-36%, preferably 5%-20%, hydrochloric acid, and heated with stirring at 0° C.-100° C., preferably at 20° C.-50° C., for 0.2-1 hour. Thereafter, the reaction mixture was allowed to cool to room temperature, extracted with organic solvents such as aromatic hydrocarbons, halogenated hydrocarbons, aliphatic hydrocarbons, ethers, ketones, esters and the like, and then remove the solvent in the extract by distillation to give (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid.
Reaction SMILES: Cl[CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@H:4]([OH:6])[CH3:5].C[O-].[Na+].O>CO>[O:7]1[C@@:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([C@H:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of 0.12 g (0.45 mmol) of (2S,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol in 3 mL of methanol was cooled in ice, and 0.12 g (0.6 mmol) of a 28% solution of NaOMe in methanol was added. Reaction was performed for 2 hours, and 10 mL of water was added to stop the reaction. Extraction was performed with ethylacetate (10 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting crude product was purified by column on silica gel to obtain 0.09 g of the title compound (yield: 96%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCl>[CH3:28][S:29]([O:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](O)CC[C@H]2CN1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](OS(C)(=O)=O)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To an ice-cooled solution of ethyl (3S, 4aR, 6R, 8aR) 6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (760 mg, 2.66 mmol) in dry dichloromethane (10 mL) under nitrogen, triethylamine (0.60 mL, 4.3 mmol) and methanesulfonyl chloride (0.33 mL, 4.3 mmol) were added. The resulting mixture was stirred overnight at room temperature and a saturated solution of ammonium chloride was added (10 mL). The layers were separated and the aqueous layer extracted with dichloromethane (10 mL×2). The combined organic phases were washed with 1 N hydrochloric acid (10 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as an oil (0.965 g, 100%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCN3CCOCC3)cc12
Yield: 15 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.359 g, 0.760 mmol) and morpholine (1.0 mL, 11 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol in chloroform. After drying in vacuo at 57° C. for 20 minutes, 3-benzenesulfonyl-5-(2-morpholin-4-yl-ethoxy)-1H-indazole as an off-white foam (0.0443 g, 15.1%) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a light orange foam (0.0411 g). Mass Spectrum (+EI, [M+H]+) m/z 388. 1HNMR (300 MHz, DMSO-d6): δ14.31 (s, 1H), 10.82-88 (br, 1H), 8.03-8.07 (m, 2H), 7.62-7.76 (m, 4H), 7.49 (d, 1H, J=2.10 Hz), 7.26 (dd, 1H, J=9.14 Hz and 2.28 Hz), 4.54 (s, 2H), 4.02 (d, 2H, J=11.71 Hz), 3.80-3.87 (m, 2H), 3.51-3.73 (m, 4H), 3.19-3.31 ppm (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:20][CH:21]=1
Reactant: ClCc1ccncc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ccncc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=333.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:11]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[NH:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=2)=[O:23])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:11]([C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[NH:21][C:22]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=2)=[O:23])[CH2:34][C:35]([OH:37])=[O:36])(=[O:10])[CH3:9]
Reactant: CC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
TFA (5 mL) was added to a solution of 1,1-dimethylethyl [acetyl((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 9, 138 mg, 0.3 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (100 mg, 83%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([SH:13])[CH2:11][SH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:14]([O:16][CH:17](OCC)OCC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][S:12][CH:17]([O:16][CH2:14][CH3:15])[S:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(S)CS
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1-t-butyldimethylsilyloxy-2,3-dimercaptopropane (example 47) (32.00 g, 134 mmol) in toluene (400 mL) were added triethylorthoformate (29.0 mL, 174 mmol, 1.3 eq) and pyridinium p-toluenesulfonate (200 mg). The solution was strirred at 120°-130° C. for 6 hr then was quenched at room temperature with a solution of saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the organic layer was dried with magnesium sulfate and evaporated under reduced pressure. The crude product was obtained in 94% yield (37.17 g) as a 1:1 mixture and was used without further purification. 1H NMR (300 MHz, CDCl3) δ: 0.06 and 0.07 (2s, 6H, CH3), 0.89 (s, 9H, t-butyl), 1.22 and 1.23 (2t, 3H, J=7.0 Hz, CH3), 3.28-3.70 (m, 5H, H-5, CH2O, H-4), 3.75-4.00 (m, 2H, CH2O), 6.19 and 6.20 (2s, 1H, H-2).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([S:20][CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([S:20][CH2:21][CH2:22][C:23]2[O:24][C:1](=[S:2])[NH:26][N:25]=2)[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]=1[OH:15])([CH3:5])[CH3:7]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SCCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Thiophosgene (0.34 mL, 4.40 mmol) is added dropwise to a -78° C. solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (1.5 g, 4.40 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane to afford 1.0 g (59%) of 5-[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 123.5°-124.5° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+:36]>C(O)C>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([NH2:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: [NH4+]
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reaction time: 4 h

Procedure:
2,2,2-Trichloro-1-[10-cyclohexyl-benzoyl)-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (0.60 g) was added to a pressure flask containing concentrated ammonium hydroxide (25 mL) and absolute ethanol (25 mL). The mixture was heated in an oil bath held at 110° C. for four hours. On cooling the title compound crystallized out and was filtered off to provide colorless crystals (0.66 g), m.p. 122–123° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][CH2:34][S:35]([NH2:38])(=[O:37])=[O:36])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C@@H:24]1([NH:23][C:22]2[C:17]3[CH:16]=[CH:15][N:14]([C@@H:12]4[CH2:11][C@@H:10]([CH2:33][CH2:34][S:35]([NH2:38])(=[O:37])=[O:36])[C@@H:9]([OH:8])[CH2:13]4)[C:18]=3[N:19]=[CH:20][N:21]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CCS(N)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NS(=O)(=O)CC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethanesulfonamide (32 mg, 0.000057 mol) was dissolved in tetrahydrofuran (1.0 mL, 0.012 mol) and a 1.00 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.100 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with a little water and then concentrated. Purification of the residue by silica gel chromatography, eluting with 0 to 100% of (9:1 EtOAc:EtOH) in DCM, afforded the desired product, (9 mg, 40%). 1H-NMR (400 MHz, MeOD, δ): 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H), 5.85 (t, J=7.7 Hz, 1H), 5.43 (dddd, J=4.2 Hz, 8.4 Hz, 8.4 Hz, 8.4 Hz, 1H), 4.35 (t, J=3.7 Hz, 1H), 3.13 (m, 3H), 2.91 (m, 1H), 2.63 (m, 1H), 2.49 (m, 1H), 2.35 (ddd, J=1.2 Hz, 8.1 Hz, 13.8 Hz, 1H), 2.05 (m, 6H). LC/MS: Rt=1.07 min, ES+ 442 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC(O)=O.O>>[NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1nc(C2CCC(=O)CC2)ccc1N
Temperature: 75 °C

Procedure:
A mixture of 3-Amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)-N-methylpyridine-2-carboxamide (Compound 232C, 0.160 g, 0.549 mmol) in AcOH (1.0 mL, 18 mmol) and H2O (0.2 mL, 10 mmol) was warmed to 75° C. for 2.5 hours, after which, the reaction was cooled and concentrated in vacuo. The residue was taken up in water and basified with a saturated aqueous solution of K2CO3. This mixture was extracted three times with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated to a brown tar. This was taken up in DCM, treated with silica and concentrated and loaded into a sample cartridge. The product was isolated after purification on an ISCO Combiflash unit (eluting with 0-4% MeOH/DCM) as 53 mg of a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ1.97-2.13 (m, 4H), 2.26 (dt, J=14.40, 2.02 Hz, 2H), 2.52-2.59 (m, 2H), 2.77 (d, J=5.05 Hz, 3H), 3.05 (tdd, J=11.43, 3.79, 3.66 Hz, 1H), 6.65 (s, 2H), 7.09 (d, J=8.30 Hz, 1H), 7.20 (d, J=8.30 Hz, 1H), 8.42 (d, J=4.80 Hz, 1H). MS (ES+): m/z=247.87 (90) [M+1]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH:48]1[CH:55]2[CH2:56][C:51]3([OH:58])[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([N:47]([CH:48]1[CH:55]2[CH2:54][CH:53]3[CH2:52][C:51]([OH:58])([CH2:50][CH:49]1[CH2:57]3)[CH2:56]2)[CH3:46])=[O:10]
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)CSCOc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CSCOc1ccc(Cl)cc1Cl)C1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2,4-dichloro-phenoxymethylsulfanyl)-acetic acid (125 mg, 0.47 mmol) in dry THF (20 mL) was added HOBt (76 mg, 0.56 mmol) and EDAC (108 mg, 0.56 mmol). After stirring for 1 hr at room temperature, DIPEA (180 μL) and 4-methylaminoadamantan-1-ol (93 mg, 0.52 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and the residue was purified using prep. HPLC/MS affording crude 2-(2,4-dichloro-phenoxymethylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-acetamide which was used without further purification in the next step.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15](OCC)[C:14]2=[O:26])=[CH:9][CH:8]=1>O>[NH2:5][C:15]1[C:14](=[O:26])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:22]2[C:17]([N:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: [NH4+]
Reactant: CCOc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Agent: CC(=O)[O-]
Solvent: O
Product: Nc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Yield: 70.4 %

Procedure:
To a melt of ammonium acetate (62 g) at 160° C. was added 1-(4-chlorophenyl)-1,2-dihydro-3-ethoxyquinoxalin-2-one (8.8 g) and the temperature was then raised during 5 minutes to 200° C. and maintained at this level for 15 minutes. The melt was cooled, water was added, and the product was filtered off. Crystallisation from ethanol gave the title compound (5.6 g) mp 254°-255° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCc1ccccc1

Procedure:
was prepared from 211d by the same method as compound 212e as colourless crystals (170 mg, 97%): mp 60-100° C.; [α]D22 -103 (c 0.10, MeOH); IR (KBr) 3341, 2947, 1728, 1675, 1531, 1456, 1422, 1339, 1272, 1248, 1221, 1174, 1122, 1056, 982, 699; 1H NMR (CDCl3) δ 7.35 (5H, s), 5.65 (1H, d), 5.48-5.40 (1H, m), 5.10 (2H, s), 4,56-4.57 (2H, m), 3.49-3.30 (2H, m), 2.92-2.59 (2H, m), 2.40-2.27 (2H, m), 1.97-1.67 (4H, m); MS (ES-) 374 (M-1, 100%). Accurate mass calculated for C18H22N3O6 (MH+): 376.1509. Found: 376.1483. Accurate mass calculated for C18H21N3O6Na (MNa+): 398.1328. Found: 398.1315.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=O.P(Br)(Br)[Br:18].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:18][C:7]1[C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(Br)c2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (272 mg, 0.964 mmol) in DMF (5 mL) at room temperature was added slowly phosphorous tribromide (0.1 mL, 1.06 mmol). The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until the pH was greater than 10, and then the reaction mixture was diluted with water and the solid collected by filtration. The product was washed with several portion of water and dried to yield methyl 4,8-dibromoquinoline-6-carboxylate. (M+H)+: 344, 346, 348.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][CH:7]([CH3:9])[CH2:6][CH2:5][O:4]1.[OH-].[Na+].[CH3:12][NH2:13]>>[CH3:9][CH:7]1[CH2:6][CH2:5][O:4][CH:3]([CH2:2][NH:13][CH3:12])[O:8]1
Reactant: CC1CCOC(CBr)O1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNCC1OCCC(C)O1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
2-bromomethyl-4-methyl-1,3-dioxane (160 grams) and 40% aqueous methylamine (150 ml) were charged into a pressure vessel and agitated for a period of about 6 hours at a temperature of about 50° C. under autogeneous pressure. The reaction mixture was cooled to room temperature and sodium hydroxide (40 grams) was added. The reaction mixture was then extracted with methylene chloride. The extract was dried and the methylene chloride stripped off using a rotary evaporator to yield the desired product N-(4-methyl-1,3-dioxan-2-ylmethyl)methylamine.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1>O>[CH3:6][O:7][C:8](=[O:37])[N:9]=[C:10]([S:35][CH3:36])[C:11]([C:25]1[CH:30]=[C:29]([O:31][CH2:45][CH2:46][O:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][O:49]2)[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CCOc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCCOC2CCCCO2)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1 ml of a DMF solution containing 80 mg of {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (78a)), 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give {2-{3-ethoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (76 mg) as a yellow oil.
Reaction SMILES: CN(C)C=O.[Br:6]N1C(=O)CCC1=O.[F:14][C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[NH2:18]>[Cl-].[Na+].O>[Br:6][C:21]1[C:20]([CH3:22])=[CH:19][C:17]([NH2:18])=[C:16]([O:23][CH3:24])[C:15]=1[F:14]
Reactant: COc1c(N)cc(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N)cc(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 81.6 %

Procedure:
With cooling with ice, an N,N-dimethylformamide (10 ml) solution of N-bromosuccinimide (1.84 g, 10.2 mmol) was dropwise added to an N,N-dimethylformamide (20 ml) solution of 3-fluoro-2-methoxy-5-methylaniline (I-26) (1.55 g, 10.0 mmol), taking 25 minutes, followed by stirring for 18 hours with gradually heating up to room temperature. Saturated brine was added to the reaction liquid, followed by extraction twice with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (4:1) was concentrated under reduced pressure to obtain the entitled compound (1.91 g, 81%) as a brown oily substance.