Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.S(=O)(=O)(O)O.[CH:18](=O)[CH:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:19]1([CH:18]([C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2]([CH3:1])([CH3:12])[CH2:3][S:4][C:5]=3[CH:11]=2)[C:10]2[CH:9]=[CH:8][C:6]3[NH:7][C:2]([CH3:12])([CH3:1])[CH2:3][S:4][C:5]=3[CH:11]=2)[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1
Reactant: O=CC1C=CCCC1
Reactant: CC1(C)CSc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CSc2cc(C(c3ccc4c(c3)SCC(C)(C)N4)C3CC=CCC3)ccc2N1

Procedure:
90 g (0.5 mole) of 3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazine, 500 ml of toluene, 3.2 g of concentrated sulphuric acid and 27.5 g (0.25 mole) of tetrahydrobenzaldehyde are refluxed for 5 hours, washed with water, the organic phase dried and the solvent removed in vacuo. Unreacted 3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazine is distilled off under a high vacuum, leaving as residue 1-cyclohex-3-enyl-1,1-di-(3,3-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-7-yl)-methane in the form of a dark brown brittle resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C([OH:24])C>O>[C:15]([C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([NH2:14])=[O:24])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)cc1

Procedure:
The process of Example 2 was followed, starting with 3.7 g. of ethyl 1-(4-chlorophenyl)-5-cyano-4-pyrazolecarboxylate and 2 g. of sodium hydroxide in 60 ml. of denatured ethanol and 60 ml. of water to obtain 2.3 g. of the desired product, m.p. 249°-250° . The elemental analysis was as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29]>C(Cl)Cl>[ClH:29].[NH2:21][C@@H:19]([CH3:20])[CH2:18][O:17][C:15]1[N:16]=[C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](COc1cccc(Nc2cc(Br)cn(C)c2=O)n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](N)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 107b (550 mg, 1.21 mmol) in DCM (10 mL) was treated with HCl (4 M in dioxone, 3 mL, 12 mmol). The reaction mixture was stirred at rt for 2 h and quenched with sat. Na2CO3, extracted with DCM. The combined extracts were dried over Na2SO4, filtered and concentrated to give 107c (400 mg, 1.03 mmol) as brown solid. MS-ESI: [M+H]+ 352.9
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNc1ccc2c(/C=C/c3ccccc3)cccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 3 mL dimethylformamide. Styrene (79 mg, 0.760 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphine (14 mg, 0.046 mmol) and palladium(II)acetate (5 mg, 0.022 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 2 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a light yellow solid (142 mg, 67%),
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61](Cl)(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])(=[O:63])=[O:62])=[CH:57][CH:56]=1)([O-:54])=[O:53]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 51% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 70 ml of ethyl acetate. A solution (35 ml) of benzenesulfonic acid (1.852 g) in isopropanol is added slowly and drop-wisely. The solid precipitated is filtered under suction to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[OH:31])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)ccc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)ccc2O)c1-c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 57.8 %

Procedure:
To a solution of ethyl 5-(2-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxamide (25 mg, 4.7×10−2 mmol) in DCM (5 ml) at 0° C., 1M BCl3 in DCM (0.15 ml) was added. The resulting cloudy yellow solution was then stirred at 0° C. for 15 minutes and room temperature 3 to 4 hours until it became clear. After that, the solution was quenched by MeOH (1 ml). Sat. NaHCO3 (1 ml) was then added and extracted with EtOAc (2×2 ml) and dried. After the solvent was filtered and evaporated, the crude oil was purified by preparative TLC (EtOAc:MeOH/50:1), yielded 12 mg solids. 1H NMR (d4-MeOD) δ=7.60 (2H, d); 7.50-7.30 (1H+1H+1H, m); 7.00 (2H, d); 3.70 (4H, m); 3.60 (2H, s); 3.50 (2H, q); 2.60 (4H, m) and 1.25 (3H, t). LCMS: (M+1)+=442.2 (RT=3.54 min.)
Reaction SMILES: [CH:1]1([N:4]([C:19]2[N:24]=[C:23]([S:25][C:26]#[N:27])[C:22]([N+:28]([O-])=O)=[CH:21][N:20]=2)[C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.CN1CCCC1=O.O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:27][C:26]1[S:25][C:23]2[N:24]=[C:19]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]3[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=3)[N:20]=[CH:21][C:22]=2[N:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc([N+](=O)[O-])c(SC#N)n2)C2CC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc3nc(N)sc3n2)C2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
To a solution of the above-mentioned crude product of tert-butyl {3-[cyclopropyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate in ethanol (60 mL)/1-methylpyrrolidin-2-one (15 mL)/water (10 mL) were added reduced iron (4.29 g, 76.9 mmol) and calcium chloride (8.53 g, 76.9 mmol), and the mixture was stirred at 100° C. for 5 hr, and at room temperature for 2 days. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water (200 mL), and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate and hexane to give the title compound (2.37 g, 39%) as a gray solid.
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7](#[N:9])[CH3:8].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=1)[CH2:8][C:7]#[N:9]
Reactant: CC#N
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(O)c1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of t-BuO−K+ (68.5 g, 614 mmol) in THF, cooled to −50° C., was added acetonitrile (30.3 mL, 540 mmol), dropwise over a period of 5 min. The resulting mixture was stirred at −50° C. for 30 min following which a solution of 3-hydroxybenzaldehyde (21.2) (30.0 g, 244 mmol) in THF was added slowly, over a period of 10 min. This was then allowed to warm to 0° C. and stirred for another 3 h during which the reaction was complete. The reaction was quenched by slow addition of ice-water followed by extraction with EtOAc. The combined organics were washed with water, brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 3-hydroxy-3-(3-hydroxyphenyl)propanenitrile (21.16) as yellow oil which was purified by flash column chromatography (0 to 20% EtOAc hexanes gradient). Yield (25.0 g, 62%); 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H), 4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C:11]1[C:15]([Br:16])=[C:14]([CH3:17])[O:13][N:12]=1>N1C=CC=CC=1>[Br:16][C:15]1[C:11]([NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[N:12][O:13][C:14]=1[CH3:17]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1onc(N)c1Br
Solvent: c1ccncc1
Product: Cc1onc(NS(=O)(=O)c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Thiophene-2-sulfonyl chloride (183 mg, 1 mmol) was added to a solution of 3-amino-4-bromo-5-methylisoxazole (177 mg, 1 mmol) in dry pyridine (0.5 ml). The reaction mixture was stirred at room temperature for 3 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (3×10 ml), brine (10 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which was solidified at −20° C. and then purified by recrystallization from ethyl acetate/hexanes, to give the pure product (51% yield) as a tan solid, m.p. 156-158° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:10])[C:8]=1[I:9])[NH2:5].O.[N:12]([O-])=O.[Na+]>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:12])[CH:6]=[C:7]([I:10])[C:8]=1[I:9]
Reactant: O=N[O-]
Reactant: Nc1cc(I)c(I)c(I)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)c(I)c(I)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Triiodoaniline was obtained by the procedure of L. Kalb (L. Kalb et al., Über substituierte Indol-2-carbonsäure-8-propionsäuren and einige jodierte Bensolderivate, Chem. Ber. 59 (1926) 1860-1870). 4 g (8.5 mmol) of 3,4,5-triiodoaniline were stirred with the solution of 2.3 mL of concentrated hydrochloric acid and 2.3 mL of water. The mixture was cooled to about −10° C. and the equivalent quantity of 2.5 M solution of NaNO2 was added dropwise with intensive stirring. The reaction mixture was continued stirring for 30 min at −10° C. Next, the cooled solution of 5.75 g (25.5 mmol) of SnCl2-2H2O in 6 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water to yield 4.7 g of 3,4,5-triiodophenylhydrazine, as a double salt with tin chloride, which was used for following step without additional treatment or purification. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 10.14 (2H, broad s, NH2), 8.46 (1H, s, NH), 7.5 (2H., s, arom.).
Reaction SMILES: N=C=N.[OH:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:7][CH2:6]1.C1CCC(NCC(F)=C2CCCCC2)CC1.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:4][CH:5]1[C:14]2=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:10]=[C:9]2[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:37])[CH2:7][CH2:6]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CCC3O)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: FC(CNC1CCCCC1)=C1CCCCC1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)NS(C)(=O)=O)CCC3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of polymer supported carbodiimide (1.36 mmol/g, 60 mg, 0.082 mmol) in DCM (dry) at RT (2 ml) under nitrogen was treated with (R or S)-7-(8-Hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid ([prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028 Example 9.8a)(25 mg, 0.054 mmol), methanesulfonamide (5.17 mg, 0.054 mmol) followed by DMAP (6.65 mg, 0.054 mmol). The resulting orange suspension was stirred at RT overnight under an atmosphere of nitrogen. The reaction mixture was diluted with DCM (20 ml) and washed with 10% aqueous citric acid solution (20 ml×2), passing the organic portion through a phase separating column. The organic filtrate was concentrated under reduced pressure. Purification of the crude material by chromatography on silica eluting with EtOAc/iso-hexane followed by further purification by SFC (Chiralpak AD 250×10 mm; 30% IPA) afforded the titled compound;
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][C:23]([CH3:29])([CH3:28])[CH2:22][C:21]3([CH3:31])[CH3:30])=[O:17])=[CH:11][CH:10]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][C:23]([CH3:29])([CH3:28])[CH2:22][C:21]3([CH3:31])[CH3:30])=[O:17])=[CH:13][CH:14]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(C)(C)c2cc(C(=O)Oc3ccc(CC(=O)O)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(tert-butoxycarbonylmethyl)phenyl ester (Compound 45, 0.1 g, 0.23 mmol) was treated with 5 mL of trifluoroacetic acid and stirred at ambient temperature for 1 h. The trifluoroacetic acid was distilled off under reduced pressure and the residue was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound as a white solid (0.045 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1.[Na]>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:41])[F:42])=[CH:37][CH:36]=4)=[O:40])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Agent: [Na]
Solvent: CN(C)C=O
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
250 mg (0.65 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine were dissolved in 10 ml of dry dimethylformamide and 92 μl of p-trifluoromethyl-phenylisocyanate were added. The reaction was stirred at room temperature overnight, poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic phase was then dried over sodium sulphate and evaporated. The residue was purified by flash-chromatography on a silica gel column CH2C12-CH3COCH3; from 9/1 to 8/2), giving 234 mg (63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:37]#[C:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:37]#[C:38][C:39]3[CH:44]=[N:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(C#CBr)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.5 %

Procedure:
To a stirred solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.14 g, 0.00070 mol) and copper sulfate (0.017 g, 0.00007 mol) in toluene (4 mL) was added potassium carbonate (0.193 g, 0.0014 mol) and 1,10-phenanthroline (0.025 g, 0.000014 mol). The reaction mixture was stirred for 5 min at RT. A solution of 5-(bromoethynyl)-2-methylpyridine (0.150 g, 0.00077 mol) in toluene (2 mL) was added to the reaction mixture. After addition, the reaction mixture was stirred for 12 h at 80° C. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure, and the crude product was purified by column chromatography (4% MeOH:DCM as eluent on silica (100-200 mesh), diameter of column—5.0 cm, height of silica—approx. 5 inch). The product was further purified by preparative TLC to give the desired compound as a yellow colored oil (0.010 g, 4.5% yield). 2,8-Dimethyl-5-((6-methylpyridin-3-yl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.01 g, 0.0000317 mol) was dissolved in THF (1.0 mL).
Reaction SMILES: [Br:1]Br.Br.[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1>>[Br:1][C:6]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=1[CH3:4]
Reactant: BrBr
Reactant: Cc1ccc(C)cc1
Agent: Br
Product: Cc1ccc(C)c(Br)c1

Procedure:
This experiment was carried out in two successive steps. In the first stage the total p-xylene was divided into two parts and one-half of the p-xylene was added to the reaction vessel with the catalyst. The other half of the p-xylene and the bromine were then added simultaneously but in separate streams to the flask while maintaining the temperature of the reacting mixture at 20°-25°C. When the reaction was completed as evidenced by no further hydrogen bromide evolution, the resulting mixture was distilled. An initial fraction of monobromo-p-xylene was taken off at 75°-103° (9mm). The 2,5-dibromo-p-xylene was recovered by distillation at 122°-126° (10 mm) as a water-white liquid which solidified to a white, fused, crystalline mass.
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH3:12])[CH:11]=1.C(OO)(=O)C.[O-]S([O-])=O.[Na+].[Na+]>O>[CH3:5][C:6]1[CH:7]=[N+:8]([O-:3])[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cncc(C)c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c[n+]([O-])c1
Temperature: 50 °C

Procedure:
98 ml of glacial acetic acid were added dropwise, at 25° C., to 350 g of 3,5-dimethylpyridine. The mixture was heated to 50° C. and 870.3 g of 40% peracetic acid were metered in such that the temperature could be kept at 50° C. by cooling. About 1 hour after the addition of the peracetic acid had ended, the reaction mixture was cooled to 25° C. and 230 g of Na2SO3 in 1 1 of water were added dropwise, with cooling. After the excess peracetic acid had been destroyed (KI-starch test), 1330 ml of water were added, the mixture was rendered alkaline with 730 ml of 50% NaOH and the solution was extracted in several portions with a total of about 4500 ml of chloroform. The combined organic phases were dried with Na2SO4 and the solvent was evaporated off to about 740 ml.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:28]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[OH:34][CH2:33][C:32]([NH:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:18]([C:17]2[CH:16]=[N:15][N:11]3[C:12]([CH3:14])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29])([CH3:36])[CH3:35]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 514.5 [(M+H)+].