Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrC[C:21]1[CH:26]=[CH:25][CH:24]=C[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[CH:25][CH:26]=[CH:21][N:22]=2)[CH:3]=1
Reactant: BrCc1ccccn1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(Br)cc1NCc1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 1 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give the title compound (336 mg, 68%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1B(O)O
Product: C=CC(=O)Nc1ccccc1B(O)O

Procedure:
2-Acrylamido-phenylboronic acid (“2-APB”) was synthesised by reacting 2-aminophenylboronic acid with an excess of acryloyl chloride in an aqueous alkaline solution. The product was extracted in acetone and dried using a rotary evaporator. The structure of 2-APB was confirmed using NMR. The purity was shown to be greater than 90%.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:28][C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)[CH:22]=[CH:23][CH:24]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.34 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (138 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (123 mg, 80.0%) as a white solid: MS (ESI) M+1=470.2.
Reaction SMILES: [OH-:1].[Mg+2:2].[OH-].[C:4](=[O:6])=[O:5]>O>[C:4](=[O:1])([OH:6])[O-:5].[Mg+2:2].[C:4](=[O:1])([OH:6])[O-:5]
Reactant: O=C=O
Reactant: [OH-]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O

Procedure:
The calcium oxide powder is digested by water at liquid to solid ratio of 2.5:1 (calculated by the weight of water and calcium oxide) for 60 mins at 80° C. to get calcium hydroxide slurry, and then brine is added by Ca/Mg molar ratio of 1.2:1 for a 60 minutes reaction at 25° C. to get magnesium hydroxide slurry which is then filtered to get magnesium hydroxide cake. The magnesium hydroxide cake is mixed with water at liquid to solid ratio of 50:1 (calculated by the weight of water and magnesia), and then carbon dioxide gas is introduced into it to carbonize continuously at 20° C. Aqueous solution of magnesium bicarbonate (MgO: 18.6 g/L, Fe: 1.7 ppm, Al: 0.3 ppm) is obtained after filtration.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[S:31]([CH3:30])(=[O:33])=[O:32])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3ccccc3S(C)(=O)=O)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 2-methylsulfonylphenylboronic acid.
Reaction SMILES: CN1C=CN=C1.[OH:7][CH2:8][CH:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:7][CH2:8][CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC(CO)CO1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
N-methylimidazole (360 ml, 4.5 mmol, 1.5 eq) is added to a cooled suspension of 4-(hydroxymethyl)-1,3-oxazolidin-2-one a90 (0.35 g, 3 mmol, 1 eq) in dichloromethane (20 ml). p-Toluenesulfonyl chloride a40 (0.63 g, 3.3 mmol, 1.1 eq) in dichloromethane (5 ml) is then added, dropwise. The mixture is stirred at 0° C. for 5 hours then at room temperature for 24 hours. The mixture is then quenched under vigorous stirring with 0.5 ml of water and taken up in chloroform (100 ml). The organic phase is washed with a saturated aqueous solution of sodium hydrogenocarbonate (2×25 ml), with a 1N solution of hydrochloric acid (2×25 ml), with brine, and is dried over magnesium sulfate. The organic layer is concentrated in vacuo to afford 0.61 g of (2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate a91 as a white solid.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@H:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[NH2:23])[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:23][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:32])([F:33])[F:34])[CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 41 was prepared following general synthesis scheme 8 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) was reacted with (S)-2-(azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethanamine dihydrochloride to give the title compound as a off-white solid. LC/MS [451 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.20 (s, 1H), 9.01 (d, 1H), 8.56 (d, 1H), 8.39 (dd, 1H), 8.20 (d, 1H), 8.05 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 5.38 (t, 1H), 3.11 (ddd, 5H), 2.84 (dd, 1H), 1.93 (p, 2H). IC50 p70S6K: 1.6 nM, Akt: 11 nM
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>ClCCl>[OH:31][CH2:30][C:29]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:33])[CH3:32]
Reactant: O=C(O)c1cc(I)cc(C(F)(F)F)c1
Reactant: CC(C)(N)CO
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1cc(I)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)benzoic acid (2.32 g) and triethylamine (1.13 ml) in dichloromethane (20 ml) was added dropwise a solution of ethyl chloroformate (1.4 ml) in dichloromethane (2.0 ml) over 10 minutes at −30° C., and the mixture was stirred at −30° C. for 1 hour. 2-Amino-2-methyl-1-propanol was added dropwise to the mixture over 5 minutes at −30° C., and the mixture was stirred at −30° C. for 30 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous ammonium chloride solution at 0° C., and extracted with dichloromethane (X2). The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine, and then dried over magnesium sulfate, evaporated, and purified with column chromatography (silica gel, ethyl acetate:hexane=20:80) to give N-(2-hydroxy-1,1-dimethylethyl)-3-iodo-5-(trifluoromethyl)benzamide (2.10 g) as an oil.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[CH:12]1([NH:18][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)NC1CCCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Benzoyl isothiocyanate (19.4 g, 118.9 mmol) was dissolved in dichloromethane and cooled to 0° C. Cyclohexylamine (13 g, 131.1 mmol) was added dropwise. Then the reaction was stirred at room temperature for 2 h. The mixture was washed with water, dried over sodium sulfate. Concentration under vaccum gave the title compound as a pale white solid in quantitative yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OC1CCNCC1
Product: OC1CCN(Cc2cccc(Br)n2)CC1

Procedure:
10] To 4-hydroxypiperidine (143 mg, 1.41 mmol) was added a solution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) to give 2-bromo-6-[(4-hydroxypiperidyl)methyl]-pyridine as a white -solid. MS m/z: 271.0 (M+H). Calc'd for C11H15BrN2O—271.15.
Reaction SMILES: [OH:1][CH:2]1[C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:7]2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]2=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH:16]=[C:7]2[CH2:6]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: OC1CCNCc2cc3ccccc3nc21
Product: CCOC(=O)OC1CCN(C(=O)OCC)Cc2cc3ccccc3nc21
Yield: 80 %

Procedure:
5-(Ethoxy-carbonyloxy)-2,3,4,5-tetrahydro-1H-2-azepino [4,3-b]quinoline-carboxylic acid ethyl ester was prepared from 5-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26](O)=[O:27])[CH:19]=[CH:18]2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@H:25]([CH3:29])[C:26]([O:1][N:2]1[C:3](=[O:12])[C:4]3[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=3[C:6]1=[O:7])=[O:27])[CH:19]=[CH:18]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)ON3C(=O)c4ccccc4C3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of N-hydroxyphthalimide (7.1 g, 43.4 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 10 g, 43.4 mmol) and N,N-dimethylaminopyridine (DMAP, 5.3 g, 43.4 mmol) in CH2Cl2 (70 mL) and DMF (30 mL) at 0° C. was treated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (8.3 g, 43.4 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 16 hours and the solvent was evaporated under vacuum. The residue was then dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was chromatographed on silica gel eluting with EtOAc:hexane (1:1) to give the title compound (7.6 g, 47% yield) as a white solid. Mp 110-112° C. 1H NMR (300 MHz, d6-DMSO) δ 7.80-8.06 (m, 7H), 7.50 (dd, J=1.7 and 8.5 Hz, 1H), 7.32-7.37 (m, 1H), 7.20 (dd, J=2.5 and 9.0 Hz, 1H), 4.50 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ 171.2, 161.8, 157.5, 153.0, 135.5, 133.6, 133.5, 129.3, 128.4, 128.2, 127.3, 126.1, 126.0, 124.0, 119.0, 105.8, 55.2, 41.8, 18.6. Mass spectrum (API-TIS) m/z 376 (MH+), 393 (MNH4+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: NC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(N)=O
Yield: 88 %

Procedure:
A mixture of (R)-1-Boc-3-methylpiperazine (100 mg, 0.50 mmol), 2-bromoacetamide (103 mg, 0.75 mmol), N,N-diisopropylethylamine (129 mg, 1.00 mmol) and sodium iodide (7.5 mg, 0.050 mmol) in acetonitrile (2.0 ml) was subjected to microwave irradiation at 100° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash chromatography eluting with ethyl acetate to 17% (v/v) methanol in ethyl acetate to afford (R)-2-(4-Boc-2-methylpiperazin-1-yl)acetamide (114 mg, 0.44 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:17]2([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1CCCCCC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCCCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (3.00 g, 12.6 mmol) in methanol (10 mL) was added cycloheptanone (1.63 mL, 13.8 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was stirred at a room temperature overnight. The generated precipitate was separated by a filtration and dried to give objective bis(3,5-di-t-butyl-4-hydroxyphenylthio)cycloheptane (yield 2.74 g and 76%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (400 mg, 1.94 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (523 mg, 2.33 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (18 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (102) as white solid (681 mg, 85%).
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])[C:9]1=[CH:15][C:16]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH:6]2[CH3:30].CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[N:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[N:17]([CH3:33])[C:18](=[O:19])[N:8]1[CH2:7][CH:6]2[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)C(C)Cn1c-2cc(Nc2c(C)cc(C)cc2C)nc1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(C)Cn1c-2cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Yield: 50.5 %

Procedure:
18 g of 6,7-dihydro-9,10-dimethoxy-2-mesitylamino-7-methyl-4H-pyrimido[6,1-a]isoquinolin-4-one are boiled under reflux in 1.5 l of acetone with 270 ml of methyl iodide in the presence of 90 g of potassium carbonate. The mixture is then filtered and the filtrate is evaporated. The residue is dissolved in chloroform and purified by chromatography on a silica gel column. There are obtained 9.4 g of pure 9,10-dimethoxy-3,7-dimethyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one, m.p. 156°-157° C. The corresponding hydrochloride of the compound melts at 224° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Cl:19][C:20]1[C:29]([CH2:30]Br)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[Cl:19][C:20]1[C:29]([CH2:30][O:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: Cn1nccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(COc2ccnn2C)c1Cl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
4.3 g (44 mmol) of 1-methyl-5-hydroxypyrazol, 9.1 g of potassium carbonate and 100 ml of tetrahydrofurane are heated at 65° C. for 1 h. 15 g (44 mmol) of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate and 150 ml of tetrahydrofurane are added to this mixture and heated at 40° C. for 4 h. This mixture is stirred for 12 h, freed from the solvent under reduced pressure, taken up in ethyl acetate, washed with sodium bicarbonate solution and water, dried and freed form the solvent. The crude product is purified over silica gel (eluent: cyclohexane/ethyl acetate=1/1). Yield: 7.6 g; m.p. 70° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Product: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1

Procedure:
In analogy to the procedure described in example 113H], [4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].C(N(CC)CC)C.[N+:19]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])([O-:21])=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[N+:19]([O-:21])=[O:20])=[O:7])#[N:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2ccccc2[N+](=O)[O-])c1
Reaction time: 24 h
Yield: 105.9 %

Procedure:
To a mixture of 3-cyanobenzoyl chloride (10.0 g, 60.4 mmol), triethylamine (12.6 mL, 90.6 mmol), and methylene chloride (120 mL) was added 2-nitroaniline (8.30 g, 60.4 mmol) followed by 4-(dimethylamino)pyridine (738 mg, 6.04 mmol). After stirring for 24 h, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexanes to 50% ethyl acetate/50% hexanes) yielded 17.1 g (99%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+]>Cl>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(C)c(O)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
The solution of 3-hydroxy-4-methylbenzoic acid (commercially available) in 32 mL hydrochloric acid (1.25M in methanol) was refluxed for 5 h. After cooling to room temperature the solution was poured on saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate and filtered to give the product as a white solid (99%) which was pure enough for the next step. MS (Turbo Spray): m/z=165.1 [M−H].