Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.C(OC([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[NH2:40][CH2:41][CH2:42][C:43]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:44]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), N-(tert-butoxycarbonyl)-β-alanine (0.27 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride 0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 1% to methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with hexane:dichloromethane (5:1) yielded the tert-butoxycarbonyl derivative of the title compound as a waxy off-white solid (0.34 g). This protected derivative was dissolved in methylene chloride (5 ml) and trifluoroacetic acid (10 ml) was added. The resulting light yellow solution was stirred at room temp. for 1 hour, then concentrated in vacuo. The residue was suspended in dioxane (20 ml), and treated with 4M HCl in dioxane (2 ml). The resulting thick suspension was stirred for 10 minutes, diluted with ether, and filtered to yield the hydrochloride salt of the title compound as a hygroscopic yellow solid (0.30 g), mp68–75° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:41])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 36.7 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 0.575 mmol) in toluene (5 mL) and DME (5 mL) was added Lawesson reagent (0.372 g, 0.920 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 36.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.90 (d, J=8.8 Hz, 1H), 6.67 (brs, 1H), 6.38 (m, 1H), 6.31 (s, 1H), 4.85 (d, J=15.2 Hz, 2H), 4.14 (m, 4H), 3.87 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.59 (s, 3H), 1.42 (s, 9H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: CC[N:3](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][C:21]1[S:47][C:24]2[NH:25][C:26]([C:28]([NH:30][CH:31]3[CH2:40][C:39]4[C:34](=[CH:35]C=[CH:37][CH:38]=4)[N:33](CC(O)CO)[C:32]3=[O:46])=[O:29])=[CH:27][C:23]=2[CH:22]=1.ClC1SC2NC(C(NC3CC4C(=CC=CC=4)N(CC4ON=C(C)N=4)C3=O)=O)=CC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:20][C:21]1[S:47][C:24]2[NH:25][C:26]([C:28]([NH:30][CH:31]3[CH2:40][C:39]4[C:34](=[CH:35][N:3]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:46])=[O:29])=[CH:27][C:23]=2[CH:22]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cc1noc(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1Cc2ccncc2NC1=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
DIPEA (297 mg, 2.3 mmol), HOBT (128 mg, 0.95 mmol), 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9, 154 mg., 0.767 mmol) and 3-amino-3,4-dihydro-1,7-naphthyridin-2(1H)-one (Method 28, 300 mg, 0.767 mmol) were suspended in DCM (10 mL). EDCI (183 mg, 0.95 mmol) was then added and the reaction mixture stirred at ambient temperature for 2 hrs. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (2×25 mL) and brine (25 mL), dried (MgSO4) and evaporated under reduced pressure to give a light brown solid which was washed with methanol (20 mL) and dried to give the title compound (45 mg, 17%).
Reaction SMILES: [C:1]([NH:6][NH2:7])(=O)[CH:2]([CH3:4])[CH3:3].CNC.[CH3:11][C:12]#N.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:21]=[C:22]([NH2:24])[CH:23]=1)=[O:17]>C(O)(=O)C>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:21]=[C:22]([N:24]2[C:11]([CH3:12])=[N:7][N:6]=[C:1]2[CH:2]([CH3:4])[CH3:3])[CH:23]=1)=[O:17]
Reactant: CC(C)C(=O)NN
Reactant: CC#N
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: CNC
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2c(C)nnc2C(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Isobutyric acid hydrazide (55 mg, 5.34 mmol) and 1,1-dimethoxy-ethyl)-dimethyl-amine (774 mg, 5.81 mmol) were added to 6 mL CH3CN and the mixture was heated to 50° C. and stirred for 30 minutes. 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.0 g, 4.15 mmol) was added, followed by 6 mL of acetic acid. The reaction mixture was heated to 120° C. and stirred for five hours, then cooled to room temperature. Solvent was removed under reduced pressure and the residue was purified via flash chromatography to give 400 mg (30%) of 5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a white powder.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([C:17]([F:20])([F:19])[F:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([C:17]([F:20])([F:19])[F:18])[C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Product: CCC(CC)c1ccc(C(F)(F)F)c2nc(Cl)n(C)c12
Temperature: 110 °C
Yield: 91 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1-methyl-4-(trifluoro-methyl)-1,3-dihydro-2H-benzimidazol-2-one (310 mg, 1.08 mmol) and phosphoryl chloride (5 ml) was heated at 110° C. for 1 h and concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 300 mg (0.99 mmol, 91%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.N[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O.C1(C)C(C)=CC=CC=1.C1C2C(=CC=CC=2)C=C[N:25]=1>O>[C:9]1([C:3]2[C:4]([NH:25][C:1](=[O:7])[CH:2]=2)=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1O
Reactant: O=C1C=CC(=O)O1
Reactant: c1ccc2cnccc2c1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C=C(c2ccccc2)C(=O)N1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Maleic anhydride polymer (product of Polyscience Co.) and aminophenol were put respectively in amounts of 5 g together with 100 mL of xylene into a 3-neck round flask into which nitrogen had been filled. Then an agitation was carried out for 30 minutes at the room temperature. Then 2.9 g of isoquinoline was put, and the temperature was raised slowly up to 150 degrees C., so that a reaction would occur. Thus the reaction was carried out for 3 hours while the formed water was slowly discharged. Then the reaction was terminated, and the temperature was lowered to the room temperature. Then the solution was put into 500 mL of methanol to capture the precipitate. Then the precipitate was filtered, and was vacuum-dried at 100 degrees C., thereby obtaining polyhydroxy phenylmaleimide.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[S:6](=[O:9])([OH:8])[O-:7].[Na+:10]>>[Na+:10].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6]([O-:9])(=[O:8])=[O:7]
Reactant: O=S([O-])O
Reactant: ClCC1CO1
Agent: [Na+]
Product: O=S(=O)([O-])CC(O)CCl
Temperature: 80 °C

Procedure:
Epichlorohydrin (one mole, 93 g) is slowly added to an aqueous solution of one mole sodium bisulfite (104 g in about 120 ml water) while maintaining the temperature at about 80° C. The epichlorohydrin is added dropwise over about three hours, and after addition is complete, the mixture is stirred for an additional hour. After the mixture cools to about 20° C., the solids of 3-chloro-2-hydroxypropylsulfonic acid sodium salt formed from the reaction are filtered and analyzed by Nuclear Magnetic Resonance (NMR). The ISC spectra shows peaks at 69.99 ppm, 56.97 ppm, and 51.18 ppm from TMS (tetramethyl silane) and the proton spectrum shows, three groups of peaks centering at 2.95, 3.58 and 4.17 ppm (from TMS), in a 2:2:1 ratio respectively, consistent with the structure of CHPS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:18])([F:19])/[CH:16]=[CH:17]/[C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(I)cc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-fluoro-4-iodo-benzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[Cl-:7].[CH2:8]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][CH3:11]
Reactant: c1ccncc1
Reactant: CCCCCl
Product: CCCC[n+]1ccccc1
Product: [Cl-]
Reaction time: 48 h

Procedure:
Pyridine and excessive amount of chloro-n-butane (molar ratio: 1/1.05) were reacted at 70° C. with stirring for 48 hours. Excessive of reactants were removed by rotary evaporation, thereby N-butylpyridinium chloride was obtained. The obtained N-butylpyridinium chloride was further added into an aqueous solution with excessive amount of potassium hexafluorophosphate (molar ratio: 1/1.1) and stirred for 24 hours. After settlement, a product was separated from the reactant solution. After liquid separation, the product was washed with water until no chlorine ion was detected by a silver nitrate solution (0.1 mol/L). A product of N-butylpyridinium hexafluorophosphate was obtained after removing methylene dichloride in the product by rotary evaporation and drying.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CS(O)(=O)=O.[CH:41]1[CH:46]=[CH:45][C:44]([CH2:47][O:48][C:49](Cl)=[O:50])=[CH:43][CH:42]=1.C(O[K])(C)=O>O.C(O)C.C(COC)OC>[NH2:3][CH2:2][CH2:1][NH:4][C:49](=[O:50])[O:48][CH2:47][C:44]1[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Yield: 50.9 %

Procedure:
Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL) containing bromocresol green as an indicator. Methane sulfonic acid (2.8 g, 31 mmol) in water (3.0 mL) is added until a blue to pale yellow color transition is just achieved. The solution is diluted with ethanol (8.0 mL) and vigorously stirred. To the mixture was added the solution of Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/v aqueous AcOK (10 mL) at 20° C. simultaneously to maintain the pale yellow-green color of the indicator. After the additions are complete the mixture was stirred (RT, 1 h) and concentrated at low temperature under vacuum to removed the volatiles. The residue was shaken with water (20 mL) and filtered. The filtrate was then washed with toluene (3×50 mL), basified with excess 40% aqueous NaOH and extracted with toluene (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and evaporated to give benzyl 2-aminoethylcarbamate as an oil (1.65 g, 51%). Mass calculated for C10H14N2O2=194.23; found: [M−H]+=193.3.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]2[CH:10]=[CH:11][NH:12][C:13]=2[CH:14]=1.Cl.[OH2:20]>>[Br:5][C:6]1[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]2[C:10]([CH:11]=[O:20])=[N:1][NH:12][C:13]=2[CH:14]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of sodium nitrite (68.4 g, 991.3 mmol) in water (1425 mL) was added methyl 6-bromo-1H-indole-4-carboxylate (20.64 g, 81.25 mmol) at RT and the mixture stirred for 15 min at RT. To the mixture was added 6N HCl (159.6 mL) slowly dropwise over a period of 1 h and the reaction mixture was then stirred at room temperature for 48 h. The reaction mixture was extracted with 10% THF in ethyl acetate (5×500 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to ⅓ volume and cooled in freezer for 4 h. Precipitated solids were filtered and washed with cold ethyl acetate and dried under high vacuum to afford the title compound as an off white solid (13.7 g, 59.6%). 1H NMR (DMSO-d6, 400 MHz): δ 3.905 (s, 3H), 7.754 (s, 1H), 8.183 (s, 1H), 10.274 (s, 1H), 14.563 (brs, 1H). LCMS (ES+): 281.06 [M−H] ion present.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 96%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.S(Cl)([Cl:18])=O>>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:18])=[O:8])[O:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
5 g (0.23 mole) of 4,5-methylenedioxy-2-nitrobenzoic acid are suspended in 50 ml of thionyl chloride and refluxed for 2 hours. The solution obtained is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of 50 ml of petroleum ether. The crystals are spun and recrystallized in ether.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:47])([F:46])[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][C:37]([F:46])([F:47])[F:36])[CH2:45][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: FC(F)(F)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(F)(F)F)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3,3,3-trifluoro-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(3,3,3-trifluoro-propyl)-piperazine (example 16i) in an analogous manner as described in example 25. LR-MS: 675.4 [(M+H)+]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 74.9 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.3 g (7.4 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 1.7 g (11 mmol) of 4-chlorophenylboronic acid. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3) and subsequent recrystallization from ethyl acetate/hexane gave 1.90 g (74%) of 1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 180.2°-180.6° C.; NMR (CDCl3) δ 3.06 (s, 3H), 7.04 (d, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.38-7.51 (m, 4H), 7.81 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 342 (34), 228 (100); HRMS Calc'd for C19H15ClO2S: 342.0481. Found: 342.0484. Anal. Calc'd for C19H15ClO2S: C, 66.56; H, 4.41; Cl, 10.34. Found: C, 66.45; H, 4.48; Cl, 10.63.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 2a) in 20 ml of DMSO was stirred at room temperature for 24 h. The mixture was poured onto 200 ml of water and extracted twice with 100 ml of diethyl ether. The organic layers were extracted twice with 50 ml of water. The combined aqueous layers were acidified hydrochloric acid. The resulting fine suspension was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. The residue was dried under high vacuum to give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.92 min, [M+1]+=416.20, [M−1]−=414.24.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][CH2:37][NH:38][C:39]([CH3:51])([CH3:50])[CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=1)=O)(C)(C)C.C(OC(CCNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:45][C:44]1[CH:48]=[CH:49][C:41]([CH2:40][C:39]([NH:38][CH2:37][CH3:36])([CH3:51])[CH3:50])=[CH:42][CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCCC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCCC(=O)OC(C)(C)C)cc2)c1
Product: CCNC(C)(C)Cc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 43.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoic acid (125 mg) according to analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (94 mg) was used according to an analogous synthetic method to the above-mentioned Example 215 and Example 337 to provide the title compound (55 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[S:15](=[O:17])=[O:16].[ClH:18]>O.C(O)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:15]([Cl:18])(=[O:17])=[O:16])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: O=S=O
Reactant: Cl
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
100 g of para-amino acetophenone are dissolved in 124 ml of concentrated hydrochloric acid and the mixture is cooled to 0° C. A solution of 55.2 g of sodium nitrite in 90 ml of water are then added in keeping the temperature at 0° C. After 1 h of stirring, the solution obtained is added dropwise to a solution of 23 g of cupric chloride in 600 ml of glacial acetic acid saturated with sulphur dioxide. After stirring for 1 h at ambient temperature, the reaction mixture is poured into 2 l of ice-water mixture, then filtered off. The orange solid obtained is washed with water, then with pentane.