Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[CH2:17][C:18](OC)=[O:19])[CH2:14]2.O.[OH-].[Na+]>O1CCCC1>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[CH2:17][CH2:18][OH:19])[CH2:14]2
Reactant: COC(=O)CC1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of lithium aluminium hydride (1.58 g, 41.63 mmol) in anhydrous tetrahydrofuran was slowly added a solution of Intermediate 72 (6.2 g, 29.76 mmol) in tetrahydrofuran (55 mL). The reaction mixture was stirred at room temperature overnight. Then water (12 mL), sodium hydroxide 4N (12 mL) and finally water again (36 mL) were added into the solution at 0° C. The mixture was stirred for some minutes and the resulting salts were filtered through a pad of Celite® washing with ethyl acetate (100 mL). The crude was treated with water and methylen chloride and the solvent of the organic layer was removed under reduced pressure to give the title compound as an oil (4.83 g, 90%), which was used in the next step without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-azidobenzoic acid (0.65 g) in acetonitrile-DMF (2:1, 15 ml) were successively added 2,2,2-trifluoroethanamine (0.38 ml), triethylamine (0.67 ml), HOBt (0.79 g) and WSC (0.92 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white powder (0.98 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])#[C:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[CH2:3]([C:2]1[NH:12][C:6]2[C:5]([CH:1]=1)=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=2)[CH3:4]
Reactant: CCC#Cc1ccc(F)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cc2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under an argon atmosphere. 21 g (0.13 mol) 2-but-1-ynyl-5-fluoro-phenylamine were added to 30 g (0.27 mol) potassium tert.butoxide in 120 mL N-methyl-2-pyrrolidinone and the mixture was stirred for 4 h at RT. The reaction mixture was mixed with water and extracted with diethyl ether. The organic phase was dried and evaporated down. The residue was purified on silica gel.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].Cl.[CH2:11]([C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:12].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:11]([C@H:13]1[CH2:18][N:17]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:26]([F:28])([F:29])[F:27])[C:30]([F:31])([F:32])[F:33])=[CH:21][CH:20]=1)[CH3:12]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 19 h
Yield: 17.2 %

Procedure:
2-Thiophenesulfonyl chloride (0.28 g, 1.5 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g, 1.5 mmol), Hünig's base (0.81 mL, 4.6 mmol), and DMF (7.7 mL) at room temperature. After 19 h, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4) and purified via column chromatography (40 g of silica, 20 to 33% EtOAc in hexanes) to give 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.13 g) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=5.1 Hz, 1H), 7.59-7.49 (m, 3H), 7.19-7.13 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 3.77 (d, J=11.0 Hz, 3H), 3.49 (d, J=12.7 Hz, 1H), 3.32 (dt, J=3.1, 11.9 Hz, 1H), 3.24 (s, 1H), 2.74-2.51 (m, 2H), 1.89 (ddd, J=7.3, 9.3, 14.0 Hz, 1H), 1.60-1.47 (m, 1H), 0.94 (t, J=7.4 Hz, 3H); m/z (ESI, +ve ion) 503.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.679 μM; GK-GKRP EC50 (LC MS/MS)=1.37 μM.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH:19]=[C:18]([CH2:21][NH:22][C:23](=[O:38])[C:24]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[NH:15]1[CH2:16][CH:17]=[C:18]([CH2:21][NH:22][C:23](=[O:38])[C:24]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=C(NCC1=CCN(Cc2ccccc2)CC1)C(O)(c1ccccc1)C1CCCCC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NCC1=CCNCC1)C(O)(c1ccccc1)C1CCCCC1
Yield: 16.1 %

Procedure:
A solution of 1-chloroethyl chloroformate (0.53 ml) in methylene chloride (5 ml) was added dropwise to a solution of N-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (1.50 g) in methylene chloride (25 ml) below 7° C. After being refluxed for 1 hour, the reaction mixture was evaporated in vacuo. To the residue was added methanol (20 ml) and the mixture was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo, and to the residue was added 1N aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of 2-propanol and ethanol to give N-(1,2,3,6-tetrahydropyridin-4-yl)methyl-2-cyclohexyl-2-hydroxy-2-phenylacetamide (0.19 g).
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:16]([N:20]=[N:21][C:22](Cl)([CH3:32])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])([CH3:19])([CH3:18])[CH3:17]>O.CCCCC>[C:16]([N:20]=[N:21][C:22]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH3:32])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCC
Solvent: CO
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)Sc1ccc(C(C)(C)C)cc1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a stirred solution of 36.2 grams (0.55 moles) of 85% potassium hydroxide in 200 ml. of methanol in a 2 liter jacketed reactor was added with cooling 91.5 grams (0.55 moles) of para-t-butylthiophenol. After the addition was complete the reaction was stirred for 20 minutes. Then a solution of approximately 138.25 grams (0.5 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in step B) in 1000 ml. of pentane was added over a 20 minute period, holding the temperature at 10°-20° C by circulating cold water through the reactor jacket. After the addition was complete the reaction was stirred for an hour at 15°-20° C, a 600 ml. portion of water added and the reaction stirred until the salts dissolved. The pentane layer was separated, washed with water, 5% HCl, water, dried over anhydrous Na2SO4, filtered and the pentane evaporated to leave 167 g. (83% yield) of n-butyl 4-t-butylazo-4-(p-t-butylthiophenoxy)valerate.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((4-methyl-piperazin-1-yl)-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol 5:1) C29H30N4O3
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:8][C:7]2=[O:32].[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:42])[C:39]=1[CH:40]=O.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Cl:42])[C:39]=1[CH:40]=[C:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:12][CH:11]=2)[C:7](=[O:32])[O:8]1
Reactant: COc1ccc2c(c1)C(=O)OC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Reaction time: 8 h

Procedure:
A suspension under N2 of (5-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)triphenyl-phosphonium bromide (74 g, 0.134 mole), prepared as described in example 36, and 3,5-dichloro-pyridin-4-carbaldehyde (23.6 g, 0.134 mole) in CH2Cl2 (500 ml) was dropwise added with triethylamine (18.5 ml, 0.134 mole), adjusting the temperature with a water bath. The mixture was stirred overnight, then cooled and treated with 5% HCl. The phases were separated and the acidic one was extracted with CH2Cl2, washed with H2O/NaCl, discoloured with charcoal, anhydrified and concentrated at high vacuum. There were obtained 85.4 g of a crude which was used as such in the subsequent step. A sample of the crude was purified by flash chromatography (eluent: hexane/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: NC1CCOCC1
Solvent: CN1CCCC1=O
Product: O=C1Nc2nc(NC3CCOCC3)ncc2CN1c1ccccc1Cl
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Sulfone 9.1 (0.205 g, 0.494 mmol) in 5 mL 1-methyl-2-pyrrolidinone was combined with 4-aminotetrahydropyran (0.100 g, 0.988 mmol). The reaction was stirred at 100° C. for 24 hours and purified by column chromatography on silica gel using 3-7% methanol/dichloromethane as eluant. The column fractions containing product were combined and concentrated in vacuo to a give the title compound as a brown gum which was redissolved in methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave 0.026 g of the hydrochloride salt 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [N+](=[C:3](P(=O)(OCC)OCC)C(=O)C)=[N-].[CH2:15]([C:17]1[N:18]([CH2:30][CH2:31][CH2:32][CH:33]=O)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:15]([C:17]1[N:18]([CH2:30][CH2:31][CH2:32][C:33]#[CH:3])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:29]=1)[CH3:16]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCCn1c(CC)nc2cnc3ccccc3c21
Yield: 80.1 %

Procedure:
Diethyl 1-diazo-2-oxopropylphosphonate (9.6 g, 1.2 eq.) was added to a solution of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal (11.15 g, 41.7 mmol, 1 eq.) and potassium carbonate (11.6 g, 2 eq.) in methanol. The reaction mixture was stirred until analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was filtered and the filter cake was rinsed until clear. The filtrate was concentrated under reduced pressure to provide crude product as an oil. The oil was partitioned between dichloromethane (200 mL) and water (100 mL). The organic layer was washed sequentially with water and brine (2×100 mL) and then concentrated under reduced pressure to provide 8.8 g of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC([N:33]1[CH:37]=[C:36]([CH2:38]O)[CH:35]=[N:34]1)=O)(C)(C)C>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:38][C:36]2[CH:37]=[N:33][NH:34][CH:35]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Product: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Yield: 57.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g) and 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (2.4 g) as starting materials, N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxamide (2.9 g) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[C:46]([O:52][CH3:53])[C:42]=1[C:43]([NH2:45])=[O:44]>CC(N(C)C)=O>[CH3:53][O:52][C:46]1[CH:47]=[C:48]([O:50][CH3:51])[CH:49]=[C:41]2[C:42]=1[C:43](=[O:44])[NH:45][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]3[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14]3)=[CH:7][CH:8]=1)=[N:40]2
Reactant: O=Cc1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(=O)c5ccccc5)CC4)cc3)nc2c1
Temperature: 150 °C
Yield: 9.4 %

Procedure:
A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)benzamide (0.350 g, 1.10 mmol), NaHSO3 (0.180 g, 1.70 mmol) and p-TsOH (0.022 g, 0.11 mmol) and 2-amino-4,6-dimethoxybenzamide (0.223 g, 1.10 mmol) in DMA (10 mL) was heated at 150° C. overnight. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc and washed with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was purified by silica gel chromatography eluting with 10% to 50% CHCl3/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (0.050 g, 10%): 1H NMR (300 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.26 (d, J=7.4 Hz, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.83 (d, J=6.9 Hz, 2H), 7.44-7.49 (m, 3H), 7.05 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.93-4.17 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91-3.08 (m, 2H), 1.82-1.93 (m, 2H), 1.52-1.72 (m, 2H); APCI MS m/z 485 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(SCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of a 2-butanone solution containing 5.5 g of 4-nitrothiophenol and 28.3 g of 1,3-dibromopropane was added 9.0 g of anhydrous potassium carbonate, and the solution was then stirred for 30 minutes at room temperature.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[Br:22][CH:23](Br)[CH3:24]>C(O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([C:14]([CH2:24][CH2:23][Br:22])([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:4]([O:3][CH3:2])[C:9]=1[O:10][CH3:11]
Reactant: CCOC(=O)C(C#N)c1cc(OC)c(OC)c(OC)c1
Reactant: CC(Br)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)(CCBr)c1cc(OC)c(OC)c(OC)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
To dry ethanol (100 ml) under a nitrogen atmosphere was added sodium (4.2 gm, 0.18 mol). After the sodium had completely dissolved, ethyl 3,4,5-trimethoxy-α-cyanobenzeneacetate (50.0 g, 0.18 mol) in ethanol (70 ml) was added dropwise over 30 minutes. A slight exotherm was observed. The reaction was heated to 90° C. for 30 minutes, then added dropwise over 2 hours to a refluxing solution of dibromoethane (340.0 g, 1.8 mol) in ethanol (500 ml). The reaction was refluxed an additional 3 hours, then concentrated. The residue was taken up in water (300 ml) and extracted with ethyl acetate (2 ×500 ml). The combined organic layers were washed with brine (1×100 ml), dried (MgSO4) and concentrated to a solid. The solid was washed with hexane (2×200 ml) then recrystallized from hexane to give ethyl 3,4,5-trimethoxy-α-(2-bromoethyl)-α-cyanobenzeneacetate in 65% yield as a white solid, m.p. 76°-77° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[C:18]([O:21][C:22](=O)[CH3:23])(=O)[CH3:19].CC(OCC)(OCC)OCC>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:4]1=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2](=[O:1])/[C:3]/1=[C:18](\[O:21][CH2:22][CH3:23])/[CH3:19]
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Agent: CCOC(C)(OCC)OCC
Product: CCO/C(C)=C1\C(=O)N(c2ccccc2)N=C1CC(=O)OC
Reaction time: 8 h
Yield: 80 %

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-phenyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 1.85 g), acetic anhydride (1.00 ml) and MeC(OEt)3 (2.50 ml) was refluxed for 1 h. and left overnight at an ambient temperature. Resulting precipitate was collected by filtration and washed with ethyl ether (10 ml) in order to obtain crude product methyl[(4Z)-4-(1-ethoxyethylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g, 80% purity) in 50% yields. 1HNMR (400 MHz, CDCl3, ppm): 1.42 (3H, t, 7.1 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.76 (2H, s), 4.31 (2H, q, 6.9 Hz), 7.16 (1H, t, 7.2 Hz), 7.37 (2H, t, 7.6 Hz), 7.97 (2H, d, 8.0 Hz). MS (ESI+): 303.3; MS (ESI−): 301.2.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH2:28]([S:34][CH2:35][C:36](O)=[O:37])[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(OCC)(=O)C>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][C:36](=[O:37])[CH2:35][S:34][CH2:28][C:29]3[O:33][CH:32]=[CH:31][CH:30]=3)[N:11]=2)[N:13]=1)[NH2:20]
Reactant: O=C(O)CSCc1ccco1
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(N)=Nc1nc(-c2cccc(CNC(=O)CSCc3ccco3)n2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml), (furfurylthio)acetic acid (0.8 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 18 hours. The mixture was added to a mixture of ethyl acetate and water and the separated organic layer was dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-[6-(furfurylthio)acetylaminomethylpyridin-2-yl)thiazole (0.73 g).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[O:32][CH3:33])[OH:17])C1C=CC=CC=1.[CH3:38][O-:39].[Na+]>CO>[CH3:38][O:39][C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[O:32][CH3:33])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1OC

Procedure:
In analogy to the procedure described in example 48 e], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: B.C1COCC1.C1(C)C=CC=CC=1.[Br:14][C:15]1[C:16]([O:29][CH3:30])=[C:17]([C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1>CO>[Br:14][C:15]1[C:16]([O:29][CH3:30])=[C:17]([C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCC(=O)c1cccc(Br)c1OC
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC[C@H](O)c1cccc(Br)c1OC
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Under room temperature, a 1M borane THF solution (48 mL) was added to an R-CBS 1M toluene solution (120 mL). 1-(3-Bromo-2-methyloxyphenyl)heptane-1-one (7, 13 g) was added, and the mixture was stirred for 1 hour. Methanol was added, a solvent was distilled off, and the residue was purified by chromatography to obtain (S)-1-(3-bromo-2-methyloxyphenyl)heptane-1-ol (8, 12.86 g, yield 75%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O: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.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O: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
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2,3-dimethylphenylboronic acid (CAS RN 183158-34-1) and using gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless solid (81%). MS (ESI): m/z=453.140 [M+H]+.