Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[H-].[Na+:10]>O1CCOCC1>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O-:7])=[CH:1][CH:2]=1.[Na+:10]
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: [O-]c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The general experimental procedure for the synthesis of polymers of types III and type VII was as follows: Sodium p-bromophenoxide was prepared by adding a solution of p-bromophenol in dioxane (100 mL of dioxane was usually employed) to a stirred suspension of a molar excess of sodium hydride and dioxane (100 mL). After 4 hours, the reaction mixture was heated to reflux and filtered. The filtrate was added to a stirred solution of poly(dichlorophosphazene) in dioxane (150 mL). The reaction mixture was stirred for 4-8 hours at 25° C. and was then added to a solution of sodium phenoxide prepared in a similar manner to the preparation of sodium p-bromophenoxide, in boiling dioxane (250 mL). The reaction mixtures were refluxed for 168 hours and concentrated by rotoevaporation, and the concentrate was added to water. The precipitate was collected, washed with ethanol, redissolved in hot tetrahydrofuran (THF) and precipitated into water. The reprecipitation procedure was carried out once from THF into water, from THF into ethanol, and from THF into pentane. The yields of the polymers represented by VII exceeded 50%. The preparation of polymer III was carried out by obtaining a solution of sodium p-bromophenoxide in dioxane, prepared by the method described above, was heated to reflux and filtered into a reaction vessel (three-necked, 1-L capacity). A solution of poly(dichlorophosphazene) in dioxane (150 mL) was added dropwise to the sodium p-bromophenoxide solution at reflux. The reaction mixture was heated at reflux for 168 hours and concentrated by rotoevaportion, and the concentrate was added to water. The precipitate was washed with ethanol and an unsuccessful attempt was made to dissolve the polymer in tetrahydrofuran. The polymer was recovered from tetrahydrofuran by filtration and then dissolved in boiling dioxane. The hot solution was filtered and reprecipitated into water. The recovered polymer was redissolved in boiling dioxane and reprecipitated once again into water. The polymer was further reprecipitated from dioxane into ethanol and then from dioxane into pentane. The yield of III was 30%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([C:15](OC)=[O:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].C([Al+]C(C)C)(C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][OH:16])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COC(=O)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Agent: CC(C)[Al+]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: OCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.3 %

Procedure:
280 mg of methyl 1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropanecarboxylate (step 1) was dissolved in 5 ml of dry toluene and the solution was cooled to −78° C. under argon. 2 ml of diisopropylaluminium hydride (1.2 N in toluene) was slowly added and the solution was allowed to warm up to ambient temperature. The mixture was stirred 45 min, then cooled to 0° C. and a saturated solution of ammonium chloride was added followed by 1N hydrochloric acid. The mixture was extracted with diethyl ether, the organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure giving an oil which solidified on standing. Thus, 220 mg of [1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropyl]methanol was obtained. 1H-NMR (CDCl3): 8.71 ppm (s, 1H), 7.92 ppm (s, 1H), 3.84 ppm (d, 2H), 1.85 ppm (t, 1H), 1.12 ppm (m, 2H), 1.07 ppm (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccccc2)nc1OCc1ccccc1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 55 %

Procedure:
Using [3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.79 g) synthesized in Example 66(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.68 g, 55%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[F:1][C:2]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1F
Product: Nc1ccc(S(=O)(=O)O)cc1F
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
2-Fluoroaniline (40 g, 0.36 mol) was added dropwise to a stirred solution of concentrated sulphuric acid (60 ml) and the mixture heated to 190° C. for 15 h. The reaction mixture was then cooled to room temperature and poured slowly onto a stirred solution of ice-water. After stirring for 15 mins the mixture was filtered to yield a solid, 2-fluoro-4-sulphoaniline (41 g). NMR: 7.05 (t, 1H), 7.20-7.30 (m, 2H), 8.1 (br s, 3H); MS: 190 (M−H)−. The 2-fluoro-4-sulphoaniline (41 g) was dissolved in acetic anhydride (70 ml) and stirred in an ice bath. Triethylamine (22 g, 0.22 mol) was added very slowly with vigorous stirring (and concomittant release of heat). The reaction mixture was left to stir for 14 h, at which point a solid formed; this was filtered to yield the title compound (39 g, 0.12 mol). MS: 232.
Reaction SMILES: O.NN.[N:4]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][N:27]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:22][CH2:21]3)[N:14]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1>CCO>[NH2:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[N:14]=[C:13]([N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:6]=[N:5]3)[CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Hydrazine monohydrate (0.28 mL, 2.7 eq) was added to a solution of trans-2-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-isoindole-1,3-dione (976 mg, 1 equivalent) in EtOH (60 mL). The reaction mixture was stirred overnight at 70° C., a second aliquot of hydrazine monohydrate (0.22 mL, 2.0 eq) was then added and the mixture was stirred at reflux for 7 hours. The solvent was then evaporated under reduced pressure, the residue was dissolved in a mixture of isopropanol and chloroform and it was acidified until pH 3 by the addition of HCl (1 M). The organic phase was washed 3 times with water. The aqueous phase was basified to pH 8-9 by the addition of NaOH (1 M) and it was extracted 5 times with a mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. This acid/base extraction procedure was repeated 3 times in order to remove phthalazinone. trans-(4-Aminomethyl-cyclohexyl)-(4-benzotriazol-1-yl-pyrimidin-2-yl)-amine was obtained in 71% purity (450 mg, 65% yield). 1H NMR (400 MHz, CD3OD) δ ppm 8.53-8.85 (1 H, bd), 8.40 (1 H, d, J=5.50 Hz), 8.09 (1 H, d, J=8.31 Hz), 7.67 (1 H, m), 7.53 (1 H, m), 7.39 (1 H, d, J=5.50 Hz), 3.76-3.89 (1 H, m), 2.60 (2 H, d, J=6.60 Hz), 2.11-2.28 (2 H, m), 1.88-2.02 (2 H, m), 1.08-1.54 (5 H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH2:28][CH:29](OC)OC)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH2:25][CH2:26][OH:27])[CH3:24])=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>CN(C)C=O.O>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:28]=[CH:29][N:16]([C:17]4[CH:22]=[CH:21][C:20]([N:23]([CH2:25][CH2:26][OH:27])[CH3:24])=[CH:19][CH:18]=4)[C:14]3=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(CN(C(=O)Nc1ccc(N(C)CCO)cc1)c1ccc(OC2CCCC2)cc1)OC
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCO)c1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1
Reaction time: 48 h

Procedure:
A solution of 1-(4-cyclopentyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-{4-[(2-hydroxyethyl)methylamino]phenyl}urea (0.4 g) in dimethyl-formamide (6 mL) was mixed with trifluoroacetic acid (2 mL) and left to stand for 48 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and sodium carbonate solution, dried and concentrated. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+), was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][N:5]([CH:29]([CH3:31])[CH3:30])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24](OC)[O:25]C)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[I-].[Na+].ClC([SiH3])(Cl)Cl>C(#N)C>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]([CH:29]([CH3:31])[CH3:30])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([CH:24]=[O:25])[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(NC(=O)N(Cc3c(F)cccc3F)C(C)C)cc2)CC1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)N(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1

Procedure:
Under anhydrous conditions, a solution of 1-(2,6-difluoro-benzyl)-3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-1-isopropyl-urea (0.32 g, 0.6 mmol), sodium iodide (0.228 g, 1.5 mmol), and trichloromethylsilane (0.143 mL, 1.2 mmol) in acetonitrile (2.5 mL) was stirred at ambient temperature for 15 minutes. The reaction mixture was quenched with water and partitioned with methylene chloride. The organic phase was washed with Na2S2O3 dilute solution and dried (Na2SO4). Removal of solvent afforded the crude product which was used directly in the next step without characterization.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[N:9]([CH2:13][C:14]3([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:8]2=[O:21])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25]>CO.[Pd]>[OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([CH2:13][C:14]3([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:8]2=[O:21])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC1(CN2C(=O)SC(=Cc3ccc(O)c(C(F)(F)F)c3)C2=O)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CC1(CN2C(=O)SC(Cc3ccc(O)c(C(F)(F)F)c3)C2=O)CCCCC1
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of compound 12 (20 mg) and Pd—C (40 mg) in methanol (5 mL) was stirred under hydrogen (50 psi) overnight, filtered, and concentrated to dryness under vacuum. The residue was purified by silica gel flash chromatography and re-crystallized with ethyl acetate-hexane (1:8), giving compound 20 (14 mg). 1H NMR (250 MHz, CDCl3) 0.81 (s, 3H), 1.16-1.59 (m, 10H), 3.13 (dd, 1H, J=9.3 Hz, 8.7 Hz), 3.45 (s, 2H), 3.51 (dd, 1H, J=9.3 Hz, 3.6 Hz), 4.44 (dd, 1H, J=3.6 Hz, 8.7 Hz), 5.53 (s, 1H), 6.92 (d, 1H, J=8.40 Hz), 7.33 (d, 1H, J=8.40 Hz), 7.39 (s, 1H), HRMS exact mass of (M+Na)+, 422.1170 amu; observed mass of (M+Na)+, 422.1173 amu.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C(N(CC)CC)C.Cl>ClCCl>[C:1]([OH:7])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:9])=[O:6].[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCC(=O)O
Reaction time: 0.67 h

Procedure:
One mole of glutaric anhydride and one mole of N-hydroxysuccinimide were treated in dichloromethane with 1.2 equivalents of triethylamine. This reaction was stirred for 40 minutes, acidified by the addition of 0.5 N hydrochloric acid (HCl) (aqueous), and then extracted with ethyl acetate to form mono N-hydroxysuccinimide glutarate. This glutarate was then combined with 5 moles of thionyl chloride and stirred at room temperature for three hours. The resulting reaction mixture was dried to remove volatiles, and thereby form N-hydroxysuccinimidyl glutaryl chloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[NH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28]>>[NH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc(C(N)=O)cc3)cc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 7-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinoline carboxylate (Ex V-17) and 4-(aminocarbonyl)-phenyl boronic acid according to the procedure described for I-VII-9. Tan solid; LC/MS (method A) 2.62 min; m/z 353 (M+H, 75%), 297 ([M−C4H8]+H, 100%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1)=[O:8]
Reactant: C1CNCCN1
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCNCC2)s1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate (1a) (5.00 g, 22.50 mmol) in acetonitrile (50 mL) were added piperazine 2 (2.32 g, 26.97 mmol) and potassium carbonate (6.22 g, 45.05 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 11 as a solid (4.10 g, 79.8%). HPLC: 92% (Rt=3.883 min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[NH2:38][CH2:39]C1C=CC(B(O)O)=CC=1>>[NH2:38][CH2:39][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: NCc1ccc(B(O)O)cc1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(CN)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (4-(aminomethyl)phenyl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=526, obsd.=526).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 88.2 %

Procedure:
A mixture of 2 g (11.59 mmol) of 2-chloro-4-methyl-5-nitropyridine, 1.41 g (11.59 mmol) of phenylboronic acid, 1.33 g (1.16 mmol) of tetrakis(triphenylphosphine)palladium and 4 g (28.97 mmol) of potassium carbonate suspended in 50 ml of degassed dioxane is refluxed for 12 hours. The mixture is then cooled, diluted with 50 ml of ethyl acetate, successively washed twice with 20 ml of water and then with 20 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluents: heptane/ethyl acetate) and then recrystallized from an isopropanol/isopropyl ether mixture. 2.19 g of a yellow solid are thus isolated, and are used without further purification in the following synthesis.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])([CH3:25])[CH2:22][O:23][CH3:24])[CH2:20][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:29]1([S:26]([C:21]([CH:19]2[CH2:20][C:9]3[NH:8][C:16]4[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=4[C:10]=3[CH2:18]2)([CH3:25])[CH2:22][O:23][CH3:24])(=[O:27])=[O:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COCC(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(C)(C1Cc2[nH]c3ccc(Cl)cc3c2C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.2 %

Procedure:
52 mg (0.1 mmol) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester were dissolved in 4 mL CH2Cl2 at 0° C. Then, 1 mL of TFA was added dropwise and the temperature was slowly raised to RT and the reaction was stirred for 20 minutes. The reaction was quenched with a saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane 1:2) yielded 11 mg (26%) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole as a white powder, MS: 404 (MH|).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=2)=[CH:14][C:13]=1[F:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+].Cl>C(O)C.CO.CN(C)C=O.CCCCCC.C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)=[CH:14][C:13]=1[F:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: O=C(Nc1ccc(-c2ccnc(C(=O)O)c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Methyl 4-(4-benzyloxycarbonylamino-3-fluorophenyl)pyridine-2-carboxylate (1.02 g) was dissolved in a mixed solvent of ethanol (25 ml), methanol (50 ml) and N,N-dimethylformamide (7.5 ml), and then water (7.5 ml) was added. Lithium hydroxide monohydrate (185 mg) was added thereto at room temperature while stirring, followed by stirring at room temperature for 1.5 hrs. To the reaction mixture was added 1 N HCl (30 ml), followed by concentrating under a reduced pressure. To the resultant residue was added a mixed solvent of ethyl acetate (100 ml) and tetrahydrofuran (100 ml) to partition. The organic layer was washed with brine (50 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a solid, which was then suspended in a mixed solvent of diethyl ether (20 ml) and hexane (20 ml), filtered, and dried under aeration to provide the titled compound (846 mg, 86.1%) as a pale brown solid.
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:4].[OH-].[Na+].[N:12]1[C:19](Cl)=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14]>O>[Cl:14][C:13]1[N:12]=[C:19]([NH:9][C:3]([CH3:4])([CH3:2])[C:5]([CH3:8])([CH3:7])[CH3:6])[N:18]=[C:16]([NH:9][C:3]([CH3:4])([CH3:2])[C:5]([CH3:8])([CH3:7])[CH3:6])[N:15]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)C(C)(C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1

Procedure:
6.7 g. (0.044 mole) 2,3,3-trimethyl-2-butylamine hydrochloride and 3.4 g. (0.84 mole) NaOH in 20 ml. water are added to a stirred slurry of 3.6 g. (0.02 mole) cyanuric chloride in 150 ml. water. The reaction mixture is heated at reflux for 21/2 hours, cooled and filtered to give the product, a white solid, m.p. 129°-131° C., 6.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=CC(OCC)=O)=[CH:5]2.CC(C[AlH]CC(C)C)C.C1C[O:31]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[O:31])=[CH:5]2
Reactant: C1CCOC1
Reactant: CCOC(=O)C=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
ethyl 3-(5,6-dichloro-2indolyl)-2-propenoate (16.23 g, 57.1 mmol) was dissolved under nitrogen in dry THF (300 ml) cooled at -20° and 1M DIBAL in hexanes (115 ml, 115 ml) was added dropwise at -20° C. The reaction mixture was maintained at this temperature for 1 hour and then quenched with H2O. The mixture was warmed to RT, diluted with Et2O (200 ml) and filtered on a Celite pad, washing with 300 ml of Et2O. The dark-red solution was dried over MgSO4 and evaporated under vacuum to give pure title compound (13.8 g, 57.0 mmol, yield 99.8%).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)([CH3:7])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.CCN(CC)CC>C1C=CC=CC=1>[Cl:15][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:25]([SH:26])=[N:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CC(C)(C(=O)CN)c1ccc(Cl)c(Cl)c1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dichlorophenyl)-3-methylbutan-2-one hydrobromide (900 mg, 2.75 mmol), 4-fluorophenyl isothiocyanate (464 mg, 3.029 mmol), and Et3N (570 uL, 4.13 mmol) in dry benzene (20 mL) was heated at reflux 6 h. The reaction mixture was concentrated under reduced pressure, diluted with acetic acid (9 mL) and then heated at reflux 5 h. After cooling to room temperature and concentrating, the crude product was purified by flash column chromatography to afford 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (370 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 2H), 6.91 (m, 2H), 6.80 (m, 2H), 6.62 (m, 2H), 1.61 (s, 6H).