Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.CCO.N.[Li]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2CCN(C)CC2)cc1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C[C@@H]2CCCN2)CC1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a flame dried 3 neck 250 mL round bottom flask fitted with dry ice condenser, ammonia (50 mL) was condensed at −78° C. using an acetone bath. 1-Methyl-4-({(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-2-yl}methyl)piperazine (2.562 g, 7.790 mmol) dissolved in THF (40 mL), EtOH (2 mL) and NH3 (40 mL) was transferred via syringe into the reaction vessel. Lithium (0.500 g, 72.000 mmol) was added by small pieces into the stirred solution. Acetone bath was then removed and the reaction was allowed to reflux for 2 hours and then warmed up to rt. The reaction was quenched with H2O (50 mL) basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The aqueous layer was re-extracted with CH2Cl2/MeOH (90/10) and the combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as a yellow oil (1.300 g, 93% ). NMR (400 Mz, DMSO-d6): consistent. Reference: (Tetrahedron, 43(14), 3289, 1987).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]([CH3:12])[N:5]=2)[CH2:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([CH3:12])[C:7]=1[C:9]([OH:11])=[O:10]
Reactant: Cn1nc(C2CC2)cc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1nc(C2CC2)c(Br)c1C(=O)O

Procedure:
A solution, cooled to 0° C., of 100 mg (0.60 mmol) of 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid in 5 ml of acetic acid is admixed with 173 mg (1.08 mmol) of bromine and afterstirred overnight at room temperature. Acetic acid and bromine are drawn off on a rotary evaporator and the solid residue is washed with cyclohexane and a small amount of diethyl ether. This gives 69.0 mg of 4-bromo-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (47%) as a yellowish solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][N:58]=2)=[CH:47][CH:46]=1>>[CH3:44][C:45]1[C:50]2[O:51][CH2:52][C:53]3([CH2:55][CH2:54]3)[C:49]=2[C:48]([O:56][C:57]2[N:58]=[CH:59][C:60]([NH:63][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:61][N:62]=2)=[CH:47][CH:46]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(Oc2ncc(N)cn2)c2c1OCC21CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (45 mg, 0.222 mmol) in dry DMF (1 ml) DIPEA (870, 0.5 mmol) and then HATU (80 mg, 0.21 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-amine (Intermediate 162, 50 mg, 0.185 mmol) was then added and the reaction mixture was stirred for 6 hours at room temperature. The reaction was quenched with water (2 ml) diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 90:10 to cyclohexane/ethyl acetate 60:40 as eluents affording the title compound (45 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Cl[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:24][C:23]([F:26])([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(NCc2ccc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 130 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
{[2-(Trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 100 mg, 0.467 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (Intermediate 26, 128 mg, 0.700 mmol) and potassium carbonate (142 mg, 1.027 mmol) were dissolved in DMSO (1 mL). The reaction mixture was stirred in the microwave for 1 hour at 130° C. The LC/MS showed product. The reaction mixture was poured into water and the product was extracted with ethyl acetate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure. Purification was done by MDAP. The most pure fractions were combined and diluted with DCM and washed with aqueous sodium bicarbonate. Traces of water were removed with a phase separator. The solvent was removed under reduced pressure to give the title compound (20 mg);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:17][CH3:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:17][CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCCCc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1ccc(OCc2ccccc2)c(OC)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of ethyl 5-(4-hydroxy-3-methoxyphenyl)pentanoate (27.92 g), benzyl bromide (20.82 g), potassium carbonate (22.9 g) and N,N-dimethylformamide (DMF) (140 ml) was stirred for 15 hours at 90° C. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:6, v/v), was obtained ethyl 5-(4-benzyloxy-3-methoxyphenyl)pentanoate (31.64 g, 84%),
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:29])(=O)=O>C(Cl)Cl>[Cl:29][CH2:14][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Temperature: 25 °C

Procedure:
To a mixture of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (1.52 g, 5.89 mmole) and triethyl amine (1.64 mL, 11.78 mmole) in DCM (100 mL) at 0° C., is injected methanesulfonyl chloride (0.91 mL, 11.78 mmole) dropwise. The reaction is kept at 0° C. for an hour and warmed up to room temperature for an hour. The reaction mixture is concentrated on rota vapor, and the resulting residue is purified on a silica gel column, eluting with 0-15% ethyl acetate in hexane and concentrated to provide the titled compound as off-white solid.
Reaction SMILES: [H-].[Na+].ClC1C=C(O)C=CC=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[CH:12]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. m-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2CL2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-m-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g, white needles, m.p. 152°-153° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:11].[Na+].[OH-].[Na+]>C(#N)C.O.OO>[CH3:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]([OH:11])=[O:8]
Reactant: O=P([O-])(O)O
Reactant: Cc1cc(C=O)c(C)s1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 261.8 %

Procedure:
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5-dimethylthiophene (11.2 g) was added. The mixture was stirred at 100° C. for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,5-dimethyl-3-thiophenecarbaldehyde (1.41 g). 2,5-Dimethyl-3-thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added dropwise. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[F:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cccc(F)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(F)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (46.0 μL, 0.26 mmol) was added to 8-fluoro-3-carboxy-coumarin (50.3 mg, 0.24 mmol) and HATU (100.5 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.0 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: BrCCCCCCCc1ccccc1
Reaction time: 0.01 h
Yield: 147.6 %

Procedure:
To a solution of 7-phenyl-1-heptanol (29.1 g, 151.3 mmol) in 800 mL CH2Cl2 at room temperature was added CBr4 (60.2 g, 181.6 mmol) then triphenylphosphine (47.6 g, 181.6 mmol). After 30 s, the reaction had turned a light green color. TLC indicated that the reaction was complete at this point. The solvent was removed in vacuo to give a greenish-white semisolid. To this material was added 10% EtOAc: 90% Hexanes and the resulting suspension was filtered through a pad of silica gel washing well with the same solvent system. There yielded 57 g of a colorless oil as the desired bromide and triphenylphosphine oxide. This oil was then flash chromatographed (Hexanes) to yield 38.6 g, 100% of the bromide as a colorless oil. 1H NMR (CDCl3) δ 1.30–1.49 (m, 6H); 1.60 (quintet, J=8.18 Hz, 2H); 2.60 (t, J=8.18 Hz, 2H); 3.39 (t, J=8.18 Hz, 2H); 7.13–7.20 (m, 3H); 7.21–7.31 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6](=[N:33][OH:34])[C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([O:27][CH3:28])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: c1ccncc1
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 12 (0.01 mmol, 1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyridine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H22FNO5 [M+H]+: 448.2, [M−H]−: 446.2.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: OCCCCl
Product: O=Cc1ccccc1OCCCO

Procedure:
Synthesized from salicylaldehyde and 3-chloropropanol as described in Example XXIXb.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NCc1ccccc1Cl
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccccc1CNCCCOc1ccc(-c2csc3ccccc23)cc1
Yield: 78.3 %

Procedure:
Combine 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene (0.200 g, 0.576 mmol), 2-chlorobenzylamine (0.326 g, 2.30 mmol), potassium carbonate (0.200 g, 1.45 mmol) and acetonitrile (4.0 ml) and heat (75° C.) overnight. Cool reaction to room temperature, filter through a Waters Sep-Pak 1 g Silica cartridge (ethyl acetate) and concentrate (in vacuo). Purify the crude product by column (silica) chromatography with a graded solvent mixture of 40% ethyl acetate in dichloromethane to 100% ethyl acetate. Concentrate the appropriate fractions, dissolve in dichloromethane and re-evaporate under a stream of nitrogen. Dry sample under vacuum (0.5 mm Hg, 50° C.) overnight to obtain the title compound as a light amber oil (0.184 g, 78% Yield). Purity by LC/MS=98%, [M+H]+=408.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C@@H:2]([NH:1][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (350 mg, 0.750 mmol) according to the procedure for Preparation XIX using Boc-L-Tic-OH (220 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (450 mg, 1.5 mmol), HOAT (100 mg, 0.764 mmol), and DMF (5 mL) (590 mg crude). MS (ESI, pos. ion) m/z: 730 (M+H), (ESI, neg. ion) m/z: 728 (M−H). Calc'd for C35H41Cl2N5O6S: 729.22.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:41]([CH3:43])[CH3:42])[N:38]=[CH:37][N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[O:34][C:35]1[CH:40]=[C:39]([N:41]([CH3:43])[CH3:42])[N:38]=[CH:37][N:36]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2cc(N(C)C)ncn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1cc(Oc2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (110 mg) is dissolved in ethanol (5 ml) and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(6-dimethylamino-pyrimidin-4-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (107 mg). MS (m/z): 719 [M+H]+
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:13]=1[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC>[CH2:21]([N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12](=[O:14])[C:13]2=[CH:1][CH:2]=[CH:3][N:4]12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c2ccccc2[nH]n2cccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2ccccc2n(Cc2ccccc2)n2cccc12
Yield: 58.8 %

Procedure:
A stirred slurry containing pyrrolo[1,2-b]cinnolin-10(5H)-one (4.0 g) and potassium carbonate (11.2 g) in 100 ml of 2-butanone was treated with benzyl bromide (4.0 g) and the mixture was stirred at 60°. After 4 h the mixture was quenched with 700 ml of H2O and extracted with two 150 ml portions of dichloromethane. These organic extracts were dried over MgSO4, filtered and concentrated to a green oil. This oil was purified by flash chromatography (silica, dichloromethane) to a yellow solid which was recrystallized from dichloromethane to give 3.5 g of bright yellow crystals, mp 146°-148°.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35](=[O:47])[CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2
Reactant: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of N-{5-[(1S)-2-methoxy-1-methylethoxy]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (80 mg) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (16 mg) under ice-cooling, and the mixture was stirred for 30 min. Aqueous sodium thiosulfate solution was added, and the mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized (acetone-hexane-diisopropyl ether) to give the title compound (37.5 mg, yield 46%) as a colorless solid. melting point 175-176° C.
Reaction SMILES: [OH:1]O.[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[OH-].[Na+].CO>O>[NH2:3][C:4]1[C:5]([C:14]([NH2:15])=[O:1])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: N#Cc1ncc(C(F)(F)F)cc1N
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ncc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of a 30% aqueous hydrogen peroxide solution was added to a mixture of 100 mg of 3-amino-2-cyano-5-trifluoromethylpyridine, 2 ml of a 10% aqueous sodium hydroxide solution and 6 ml of methanol, under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 100 mg of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide.