Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1)[CH3:42]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M140) (0.34 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (239 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>CO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH:3]([C:2]([CH3:1])([CH3:21])[CH2:6][OH:5])[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[O:23][CH3:22])=[O:7])=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Solvent: CO
Product: COc1ccc(CNC(=O)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C(C)(C)CO)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A suspension comprised of (±)-4-(4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile (81.55 g; 272.5 mmol), 2,4-dimethoxybenzylamine (50.40 g; 295.4 mmol), and methanol (300 mL) was stirred at ambient temperature under a nitrogen atmosphere overnight. The suspension became a clear solution. The reaction mixture was concentrated in vacuo to afford a cloudy orange oil (145 g.) The oil was triturated with diethyl ether (500 mL) over a steam bath to gentle boiling. The flask was removed from the steam bath as a solid began to slowly form. The oil was scratched with a spatula which accelerated solid formation and the solids were collected by vacuum filtration to afford 107.25 g of an off-white amorphous solid. The mother liquor was concentrated in vacuo to give 28.35 g of a crude red-brown oil. This oil was purified by flash silica column chromatography (Isco Fraction Collector with Biotage 65i 330 g silica cartridge.) Elution with a gradient (98:2 v/v hexanes-ethyl acetate to 100% ethyl acetate over 1 hour, 12 minutes, 18×150 mm tubes, each filled to 27 mL mark in 30 seconds) afforded 20 g of a light-yellow solid. The material was recrystallized from diethyl ether to afford 9.659 g of a white crystalline solid; 1H-NMR (400 MHz; CDCl3) δ 7.61 (d, 1H, J=8.8 Hz), 7.24 (d, 1H, J=2.5 Hz), 7.07 (d, 1H, J=8.2 Hz), 6.94 (dd, 1H, J=8.8, 2.5 Hz), 6.58 (t, 1 H, J=5.6 Hz), 6.37 (dd, 1H, J=8.4, 2.5 Hz), 6.28 (d, 1H, J=2.4 Hz), 4.52 (s, 1H), 4.37-4.25 (m, 2H), 3.78 (s, 3H), 3.58 (s, 3H), 3.50 (d, 1H, J=11.7 Hz), 3.42 (d, 1H, J=11.7 Hz), 1.09 (s, 3H), 0.97 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ −62.70 (s, 3F); MS (APCl+) 467.3 (M+1,100); (APCl−) 465.2 (M−1, 14), 186.0 (100).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13](=[O:30])[CH2:14][C@H:15]([NH:26]C(=O)O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[F:25])[CH2:4][C:3]1=[O:31].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:26][C@H:15]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])[CH2:14][C:13]([N:5]1[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:31])[CH2:4]1)=[O:30]
Reactant: CN1C(=O)CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)O)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 2 [3-(1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-(R)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tart-butyl ester (90 mg 0.18 mmol) in dry DCM (5 mL), was added trifluoroacetic acid (0.55 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After completion of the reaction, as confirmed by TLC, excess of TFA and DCM were evaporated in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 76%) as a white solid
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7](Cl)[N:6]=1)=[O:4].[CH3:14][N:15]1[C:19]([CH3:20])=[C:18](B(O)O)[C:17]([CH3:24])=[N:16]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([C:18]2[C:17]([CH3:24])=[N:16][N:15]([CH3:14])[C:19]=2[CH3:20])[N:6]=1)=[O:4]
Reactant: Cc1nn(C)c(C)c1B(O)O
Reactant: COC(=O)c1ccc(C#N)c(Cl)n1
Product: COC(=O)c1ccc(C#N)c(-c2c(C)nn(C)c2C)n1

Procedure:
The title compound may be prepared from 6-chloro-5-cyano-pyridine-2-carboxylic acid methyl ester by reaction with 1,3,5-trimethylpyrazol-4-ylboronic acid under Suzuki reaction conditions as described in the previous examples.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11]>CS(C)=O.C(=O)([O-])[O-]>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
An IgG fraction of affinity-purified rabbit anti-p19 antibody is fluoresceinated as follows: Thirty micrograms of FITC isomer II (20 μL of a 3.0 mg/mL solution in DMSO) is added to 1 mg of antibody in 125 μL of 0.27M carbonate buffer, pH 9.3. The mixture is incubated for 30 minutes at 37° C., after which free (unconjugated) fluorescein is separated from fluoresceinated antibody by gel filtration on Sephadex G25 equilibrated in 50 mM sodium phosphate, 0.5M NaCl, and 0.1% azide.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[CH:18]([OH:22])[CH2:19][C:20]#[CH:21]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]#[C:20][CH2:19][CH:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[OH:22]
Reactant: C#CCC(O)c1cnc2ccccc2n1
Reactant: Ic1ccccn1
Product: OC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (72 mg, 0.35 mmol) and 1-quinoxalin-2-yl-but-3-yn-1-ol (70 mg, 0.35 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2 to DCM/MeOH 9:1) to yield 60 mg (0.22 mmol, 62%) of 4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:10]3[CH2:21][N:20](C(OC(C)(C)C)=O)[C:19]([CH3:30])([CH3:29])[C:11]=3[N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[ClH:33]>O1CCOCC1>[ClH:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]3[CH2:21][NH:20][C:19]([CH3:29])([CH3:30])[C:11]=3[N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)NC2
Yield: 98 %

Procedure:
5-tert-Butyl 1-ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (2.5 g, 5.59 mmol) was dissolved in dioxane (50 ml) and treated with HCl 4M in dioxane (28 ml, 20 eq). After 2 hours at 40° C. (TLC: CH2Cl2/MeOH 90/10) the reaction mixture was concentrated and the residue was treated with diethyl ether, filtered to afford the title compound (2.09 g) as a solid in 98% yield.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:64]([C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)=[N+:65]=[N-:66]
Reactant: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a stirred mixture of tert-butyl (2S,4R)-4-hydroxy-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (3.00 g, 11.6 mmol, step 2 of Example 9) in tetrahydrofuran (50 mL) were added triphenylphosphine (4.55 g, 17.4 mmol) and diethyl azodicarboxylate solution (50% in toluene, 7.56 mL, 17.36 mmol) at room temperature. After stirring for 15 min, diphenyl phosphoryl azide (3.74 mL, 17.36 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 40 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.53 g (77%) of the title compound as a pale yellow oil.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14]>CO>[CH3:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[N:3][C:4]=2[N:5]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: CC(=O)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2ccc(-c3cccs3)nc2n1
Reaction time: 20 h
Yield: 17 %

Procedure:
1 ml of 40% strength by weight aqueous potassium hydroxide solution was added to a suspension of 2.0 g (14.6 mmol) of 4-amino-5-formyl-2-methylpyrimidine and 1.93 g. (15.3 mmol) of 2-acetylthiophene in 25 ml of methanol. The reaction mixture was then stirred for 20 hours at 20°-25° C. after which the solvent was removed After the residue had been taken up in dichloromethane, the organic phase was washed with water, dried and evaporated down. Yield: 17%; mp.: 175°-180° C.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[NH:5][N:6]=1.[CH3:10]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[N:5]([CH3:10])[N:6]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2c1CCC2
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 3-iodo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (305 mg, 1.3 mmol) in THF (8.51 mL) at 0° C. was added KOtBu 1M in THF (1.82 mL, 1.82 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale yellow solution then added MeI (259 mg, 114 μL, 1.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the more polar desired 3-iodo-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (177 mg, 714 μmol, 55%) as a white solid. MS (M+H)+=249; 1H NMR (CDCl3) δ: 3.78 (s, 30H), 2.68-2.79 (m, 20H), 2.51-2.58 (m, 4H). The regisomeric product, 3-iodo-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole, (125 mg, 504 μmol, 39%) was also obtained as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH:23](=O)[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C>C(O)C.O>[O:28]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:23]=[C:19]1[C:20](=[O:21])[C:4]2([CH3:3])[CH:17]([CH:16]3[CH:7]([CH2:6][CH2:5]2)[C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[CH2:14][CH2:15]3)[CH2:18]1
Reactant: O=Cc1ccco1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccco1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (2.704 g, 10 mmol) and furfuraldehyde (2 mL, ca. 20 mmol) in ethanol (40 mL). The resulting dark brown solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added. After a few minutes the product started to precipitate. The precipitation was completed by addition of more water (ca. 10 mL). The yellow solid was filtered off, washed with water, dissolved in chloroform and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was crystallised from ethyl acetate/hexane. Yield: 3.24 g (93%) light yellow crystals. 1H-NMR (CDCl3, 400 MHz) δ: 0.97 (s, 3H, —CH3), 1.42-1.76 (m, 5H), 2.00-2.20 (m, 2H), 2.22-2.35 (m, 1H), 2.36-2.51 (m, 2H), 2.82-3.00 (m, 2H), 3.14 (ddd, J=15.2, 6.6, 1.6 Hz, 1H), 5.08 (s, 1H, —OH),6.52 (dd, J=3.1, 1.6 Hz, 1H),6.62 (d, J=2.7 Hz, 1H),6.64-6.70 (m, 2H),7.16 (d, J=8.2 Hz, 1H), 7.22-7.27 (m, 1H), 7.57 (d, J=1.6 Hz, 1H). LRMS (FAB+): 349.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-])=[O:21])=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:36]([C:38]1[C:46]2[C:45]([NH2:47])=[CH:44][CH:43]=[CH:42][C:41]=2[N:40]([CH2:48][C:49]2[CH:53]=[CH:52][N:51]([CH3:54])[N:50]=2)[N:39]=1)[CH3:37]>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH2:36]([C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][C:45]=2[NH:47][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:21])[N:40]([CH2:48][C:49]2[CH:53]=[CH:52][N:51]([CH3:54])[N:50]=2)[N:39]=1)[CH3:37]
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: CCc1nn(Cc2ccn(C)n2)c2cccc(N)c12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1nn(Cc2ccn(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a suspension of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (94.0 mg, 0.294 mmol) (Example 56, step A) in NMP (4 mL) was added 2,4,6-trichlorobenzoyl chloride (45.9 μL, 0.294 mmol). The reaction mixture was stirred for 30 minutes. 3-Ethyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (50 mg, 0.196 mmol) was added and the mixture was heated at 87° C. for 3 hours. The mixture was cooled to ambient temperature and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc. The organic phase was washed with water and brine, concentrated under reduced pressure and the residue was triturated with Et2O to give the final product (71 mg). MS (ES+APCI) m/z=542 (M+H).
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:28]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (192 mg, 0.41 mmol, 1.00 equiv, 90%) in methanol (10 mL), a solution of sodium hydroxide (80 mg, 2.00 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 80 mg (47%) of 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13]C1CCCCO1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: Fc1c(COC2CCCCO2)ccc2c1CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCc1ccc2c(c1F)CCCC2

Procedure:
To a stirring solution of 47.6 (0.75 g, 2.8 mmol) in EtOH (25 mL) at 23° C., is added PPTS (catalytic). The mixture is stirred until TLC confirms consumption of the starting material. The mixture is concentrated in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford alcohol 47.7.
Reaction SMILES: [Li][NH2:2].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:12])[CH3:11].Cl.C([O-])(O)=O.[Na+]>COCCOC>[CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:2])([CH3:12])[CH3:11]
Reactant: CC(C)c1ccccc1Br
Reactant: [Li]N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccccc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
(CyPF-t-Bu)PdCl2 (73.0 mg, 100 mmol), LiNH2 (2.30 g, 100 mmol) and 1-Bromo-2-i-propylbenzene (1.99 g, 100 mmol) were weighed into a 100 mL round bottom flask with a stirring bar. DME (20.0 mL) was then added. The flask was sealed with a cap and wrapped tightly with electrical tape. The reaction mixture was stirred for 24 h at 90° C. The reaction mixture was allowed to cool to room temperature before pouring into ice water (50.0 mL). To this mixture was added aqueous HCl (100 mL, 1.0 M). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHCO3 (50.0 mL). After extraction with CH2Cl2 (3×50.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by column chromatography, eluting with hexane/ethyl acetate (70/30) to give 1.11 g (82%) of 2-i-propylaniline as a solid.
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:12][S:13]([OH:16])(=[O:15])=[O:14].O1CCOCC1.Cl>O.O1CCOCC1>[CH3:12][S:13]([O-:16])(=[O:15])=[O:14].[CH2:2]([N+:6]1[CH:10]=[CH:9][N:8]([CH3:11])[CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CS(=O)(=O)O
Agent: CCCC[n+]1ccn(C)c1
Agent: Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)[O-]

Procedure:
Analogously to Example 1, 26.5 g (0.152 mol) of 1-butyl-3-methylimidazolium chloride are reacted with 21.4 g of approx. 70% aqueous methanesulfonic acid, CH3SO3H. 100 ml of 1,4-dioxane are subsequently added, and 107 ml of HCl-containing water/dioxane azeotrope are distilled off at atmospheric pressure (85-101° C.). After 18 additional azeotropic distillations with 100 ml of 1,4-dioxane each time and drying of the distillation residue under reduced pressure at 1.3 Pa and 80° C., 1-butyl-3-methylimidazolium methylsulfonate is obtained. The yield is approximately quantitative.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.Br[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:27][C:28](=[O:30])[CH3:29])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)CBr
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCC(C)=O
Yield: 63 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 10 ml of methyl ethyl ketone, and 0.15 g (1.10 mmol) of bromoacetone as a reaction reagent (XII) and 0.30 g (2.20 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.29 g (yield 63%) of 4-methoxy-5-methyl-6-(5-acetylmethyloxy-1-ethylpyrazol-4-yl) carbonylthiochroman-1, 1-dioxide (Compound No. 59) as an end compound which comes under the general formula (XI). Table 20 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]=O.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CO.C(Cl)Cl.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:14]#[N:2]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1c[nH]c2ccc(Br)cc12
Yield: 78.1 %

Procedure:
Hydroxylamine hydrochloride (4.5 g, 66 mmol) is add to a mixture of 5-bromoindole-3-carbaldehyde (14.7 g, 66 mmol, reference example 74) and methanol (100 mL). After 1 hour toluene (80 mL) and THF (30 mL) are added and the reaction concentrated. Additional toluene (80 mL) is added and the reaction is azeotroped again. The mixture is dissolved in toluene (200 mL) and thionyl chloride (12 mL, 165 mmol) added causing a mild exotherm. The reaction is placed in a 70° C. bath and heated for 45 minutes. The reaction is then cooled and azeotroped with a mixture of CH2Cl2 and THF. The crude reaction mixture is dissolved in a mixture of methanol and CH2Cl2, adsorbed to silica gel and extracted with CH2Cl2 to provide 11.4 g of 5-bromoindole-3-carbonitrile. An analytically pure sample is obtained by recrystallization from toluene: (reddish needles) m.p. 189-191; 1H NMR (300 MHz, DMSO-d6) d 12.38 (bs, 1H), 8.30 (d, J=3.0 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.6 Hz, 1H); MS (EI) m/z 220 (M+, Br).