Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-acetamido-5-bromobenzotrifluoride (665 mg, 2.436 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.4 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 700 mg (90%) of crude 2-acetamido-5-bromo-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to offer 610 mg (78.8%) of pure compound as white needles. Mp: 193°-5° C., 1H NMR (CDCl3): δ 2.250 (s, 3H), 7.346 (s, 1H), 8.039 (s, 1H); 8.247 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:37])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M70) (0.32 g, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off white solid (120 mg, 48%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42]C1C=CC=CC=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]C=1S(Cl)(=O)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:51]=[CH:52][C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:49]=1)(=[O:40])=[O:41])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc4ccccc4c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 53 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 2-naphthalenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 53% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(=O)C(C)C)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise isobutyryl chloride (0.6 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off, washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.2 g) having the following physical properties.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=[O:3])[CH3:2].O.[NH2:30][NH2:31].[OH-].[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
A solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21g) and hydrazine hydrate (0.12 ml) in glacial acetic acid (5 ml) was heated under reflux of 16 hours. Evaporation of the reaction mixture under reduced pressure gave a glassy residue to which was added sodium hydroxide solution (2N, 10 ml). The resulting solution was extracted well with chloroform, the combined organic phases washed with water, dried and evaporated to give a white brittle residue which was recrystallised from isopropanol/ether to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid (0.16g, 80% m.p. 102°-109° C; M+, 376, M 376).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[Cl:18][C:19]1[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:22]1[S:23][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)s1
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)s1
Yield: 29 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-chlorothiophen-2 carbaldehyde in 29% yield as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:11][N:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[CH2:17][CH2:18][NH2:19].C(N(C(C)C)CC)(C)C.[CH2:29]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:29]([C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:19][CH2:18][CH2:17][C:8]2[C:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:10][NH:11][C:7]=2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)(=[O:42])=[O:41])=[CH:38][CH:39]=1)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NCCc1c(-c2cccs2)n[nH]c1-c1cnccn1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2cnccn2)cc1
Reaction time: 3 h
Yield: 30580.7 %

Procedure:
A mixture of the 2-(5-Pyrazin-2-yl-3-thiophen-2-yl-1H-pyrazol-4-yl)-ethylamine 1D (7 mg, 25.8 μmol), diisopropylethylamine (9.0 μl, 51.6 μmol) and 4-n-pentylbenzenesulfonyl chloride (7.0 mg, 28.3 μmol) in dichloromethane (1 mL) was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product dissolved in methanol (2 ml) and was purified by prep-HPLC. Removal of the solvent in vacuo provided the title compound (3.8 g mg, 41% yield). MS m/e 481; HPLC retention time 3.54 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:40]=[CH:41][CH:42]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([O:37]CC)=[O:36])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH:40]=[CH:41][CH:42]=3)[O:20][C:21]3[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:24]=[N:23][C:22]=3[C:35]([OH:37])=[O:36])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2nnc(C(=O)O)c2Oc2cccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
Ethyl 5-{3-{3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy}phenoxy}-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate, (8.00 g, 0.013 mole) was dissolved in ethanol, (150 ml) and water (50 ml) and sodium hydroxide (0.520 g, 0.013 mole) dissolved in water (5 ml) was added. The solution was stirred at room temperature for 5 hours. The reaction was neutralized with dilute hydrochloric acid and excess ethanol evaporated in vacuo. The aqueous solution was extracted with EtOAc, (three times), then chloroform (three times), and the organic extracts combined, dried (MgSO4), and evaporated in vacuo to a pale yellow foam. Trituration with diethyl ether gave a white solid which was filtered off and dried in vacuo to yield 92% of the title compound, mp (EtOH) 100°-2° C. (dec). νmax (mull) 1515, 1590, 1615, 3390 cm-1 δ(DMSOd6) 1.81 (2H, m, CH2), 2.50 (10H, m, piperazinyl+ CH2), 3.45 (2H, s, CH2N--) 3.70 (3H, s, OCH3), 3.89 (2H, t, J 6 Hz, OCH2), 4.75 (1H, bs, OH, exchangeable D2O), 5.35 (2H, s, N--CH2), 6.40 (2H, m, aromatics), 6.67 (1H, dd, J2, 8 Hz, aromatic), 7.00 (4H, ABq, Δν 84 Hz, J 9 Hz, C6H4OCH3), 7.19 (1H, t, J 8 Hz, aromatic) 7.32 (4H, ABq, Δν 17 Hz, J 8.5 Hz, --C6H4 --Cl). Mass spec. Observed mass 547.2342, theoretical mass 547.2350 (C31H34ClN5O5 --CO2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Temperature: 100 °C

Procedure:
To the product of Step B (1.5 g) was added POCl3 (5 mL). The reaction was heated to 100° C. for 17 hours. After cooling to room temperature the excess POCl3 was removed in vacuo before the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel eluted with 10% EtOAc in hexane affording the title compound. HPLC/MS: 358.9 (M+1), 360.9 (M+3); Rt=4.07 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 84 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.50 (s, 3H), 2.89-3.09 (m, 4H), 3.68-3.88 (m, 4H), 4.14 (s, 3H), 6.99-7.78 (m, 7H), 7.76 (d, J=8.0 Hz, 1H),
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18](=[O:32])[C:19]3[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:21][C:20]=3[Cl:31])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:31][C:20]1[CH:21]=[C:22]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]([NH:17][CH2:16][C:15]1[CH:33]=[CH:34][C:12]([C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:5])[CH:11]=2)=[CH:13][CH:14]=1)=[O:32]
Reactant: COCCOc1cc(Cl)c(C(=O)NCc2ccc(-c3ccnc(OC(C)(C)C)c3)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc(Cl)c(C(=O)NCc2ccc(-c3cc[nH]c(=O)c3)cc2)c(Cl)c1

Procedure:
Compound N-(4-(2-tert-butoxypyridin-4-yl)benzyl)-2,6-dichloro-4-(2-methoxy ethoxy)benzamide was re-dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. after the reaction was done it was concentrated in vacuum and then purified by reverse phase chromatography to afford 2,6-dichloro-4-(2-methoxyethoxy)-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].Cl>C1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:2]([NH:1][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[C:3]([C:7]=1[CH3:17])[C:4]([OH:6])=[O:5])=[O:13])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)cc(NC(=O)C(C)C)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
To an ice-cooled mixture consisting of 500 mg of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 15 ml of benzene, and 0.3 ml of pyridine was added dropwise with stirring a solution of 323 mg of isobutyryl chloride in 2 ml of benzene. After completion of the addition, the reaction mixture was further stirred for 5 hours at room temperature, and then heated to reflux for one hour. After cooling, the mixture was shaken with dilute hydrochloric acid and the layers were separated. The slightly acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was recrystallized from ethyl ether/n-hexane to yield 523 mg of 5-ethoxycarbonyl-2-isobutyrylamino-4,6-dimethylbenzoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([S:25]([O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2.50 g (0.012 mol) of 3,5-di-tert-butylphenol and 1.27 g (0.013 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 1.62 g (0.013 mol) of ethanesulfonyl chloride over the course of 10 minutes at 5° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 3,5-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in ice water and following separation of the organic layer, was washed twice with saturated brine followed by drying with MgSO4 and concentrating to obtain 3.27 g (yield: 91%) of 3,5-di-tert-butylphenyl ethanesulfonate. A purified product crystallized with n-hexane (white crystals, melting point: 52° C.) was used in a battery test.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH:21][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate A, Step 7, 21 g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) were suspended in DMF (240 mL). Diisopropylethylamine (33.7 g, 260.4 mmol) and then PyBOP (51 g, 97.7 mmol) were added and the resulting mixture stirred with overhead stirring for 3 days at ambient temperature. At this time, the resultant precipitate was isolated by vacuum filtration. After repeated washing with EtOAc, the material was dried under vacuum with slight heating to yield the title compound (27.3 g, 98%): HPLC MS RT=1.09 min, MH+=481.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.32 (1H, s), 8.89 (1H, br m), 8.84 (1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27 (1H, d), 7.16 (6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t), 3.78 (3H, s).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl.[CH3:15]O>C(Cl)Cl>[I:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([O:9][CH3:15])=[O:8])[NH2:6]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1I)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccccc1I
Temperature: 25 °C
Yield: 94 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser were added 5.00 g of 2-iodo-L-phenylalanine.HCl and 100 mL of anhydrous MeOH. The mixture was stirred and acidified by bubbling HCl gas through for 3 min. A clear solution resulted which was heated at reflux for 5h. The solution was cooled to RT and concentrated in vacuo to dryness to give a white solid. The material was suspended in 120 mL of CH2Cl2 and washed with 5% aqueous NaHCO3 (4×80 mL). The CH2Cl2 solution was concentrated to a volume of 20 mL, diluted to 60 mL with ethyl ether and treated with 16 mL of 1M ethereal HCl. A white solid precipitated which was collected by vacuum filtration and dried in vacuo to afford 4.90 g (94%) of methyl 2-iodo-L-phenylalaninate.HCl m.p. 194-196° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH:32](=O)[CH3:33]>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:24][CH2:25][N:26]([CH2:32][CH3:33])[CH2:27][CH2:28]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC=O
Reactant: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCNCC3)nc2c(=O)[nH]1
Product: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(CC)CC3)nc2c(=O)[nH]1

Procedure:
The title compound was prepared by the method of example 51 using the title compound of example 118 and acetaldehyde.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]1([C:8]2[N:13]=[C:12]([C:14]([NH:16][C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[C:19](O)=[O:20])=[O:15])[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1>>[CH:1]1([NH:4][C:19]([C:18]2[CH:22]=[CH:23][N:24]=[CH:25][C:17]=2[NH:16][C:14]([C:12]2[C:11]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:10][CH:9]=[C:8]([CH:5]3[CH2:7][CH2:6]3)[N:13]=2)=[O:15])=[O:20])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NC1CC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 28 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclopropylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (28%) as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=O.[NH:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=[CH:17]1>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:16][CH:17]=1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: c1cnc2[nH]ccc2c1
Product: Cc1nn(-c2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12

Procedure:
3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridine P-0080 was synthesized in 2 steps from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 100 and 7-azaindole 1 as shown in Scheme 38.
Reaction SMILES: O1CCOCC1.[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[CH:13]=[C:14]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)[C:15]([F:18])=[N:16][CH:17]=1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
Reactant: CSc1nc(C)nc(Cl)n1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(C)nc(-c2cc(C3OCCO3)cnc2F)n1
Temperature: 90 °C
Yield: 48.3 %

Procedure:
1,4-Dioxane (16 mL) and water (3.3 mL) were added to a mixture of 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (0.715 g, 3.53 mmol), 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.682 g, 3.88 mmol), Pd(PPh3)4 (0.408 g, 0.353 mmol), and Na2CO3 (0.935 g, 8.82 mmol) and the suspension was heated at 90° C. for 2 h. After cooling, the mixture was filtered, washed with EtOAc (2×20 mL), and the combined organic phases were concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (hexanes to 30% ethyl acetate in hexanes) to give 2-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (0.5259 g, 1.706 mmol, 48.3% yield) as a white solid. LCMS (API-ES) m/z 309 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:33][CH2:32][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:32][CH2:33]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Product: CNc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-Chloro-pyridine-3-sulfonyl)-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (described in example 206) and methyl amine. Off-white solid. MS (ESI): 499.3 (MH+).