Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH2:55].COCC(O)C>>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:44]=[CH:43][C:42]=1[NH:55][C:18]1[N:17]=[CH:16][C:15]2=[CH:14][CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]2[N:19]=1
Reactant: COc1cc(CN2CCN(C)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(CN2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C
Yield: 30 %

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (89 mg, 0.20 mmol), N,N-Diisopropylethylamine (0.0757 mL, 0.435 mmol), 2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 1-Methoxy-2-propanol (0.71 mL) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in CAN. The collected fraction afforded N-(2-{2-[2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide as a yellow solid (32 mg, 30%). LCMS (E/I+) 536.16 (M+H). NMR 1H (DMSO-d6)-8.99 (s, 1H), 8.04 (d, 1H, J=8.09 Hz), 7.95-8.01 (m, 1H), 7.79 (s, 1H), 7.62-7.70 (m, 1H), 7.51-7.59 (m, 2H), 7.06 (s, 1H), 7.02 (d, 1H, J=4.66 Hz), 7.00 (d, 1H, J=4.66 Hz), 6.86 (d, 1H, J=8.22 Hz), 3.88 (s, 3H), 3.20-3.80 (m, 10H), 3.08 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=O)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.P(Cl)(Cl)(Cl)=O.CO/N=C1/C2C(C)=NC(N)=NC=2C[C@@H](C2C=CC(F)=CC=2C2C(F)=NC=CC=2)C/1>C(#N)C>[N:22]1([C:11]2[C:5]3[C:4]([CH3:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=3[CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[N:10]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CO/N=C1\C[C@H](c2ccc(F)cc2-c2cccnc2F)Cc2nc(N)nc(C)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc(N)nc2c1C(n1nnc3ccccc31)=N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 75 °C

Procedure:
In a 2-neck round-bottomed flask, under a blanket of nitrogen was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (106a, 1.00 g, 2.85 mmol), 1H-benzo[d][1,2,3]triazole (106b, 0.678 g, 5.70 mmol) and anhydrous acetonitrile (14 mL). Phosphoryl trichloride (0.796 mL, 8.54 mmol) was added slowly to the mixture and the reaction was heated in 75° C. oil bath for 18 hours. By LC/MS about 7-10% of compound 1 remained unreacted. The reaction mixture was concentrated, then diluted with 80 mL of ethyl acetate and the resulting mixture was added slowly to 40 mL of saturated sodium bicarbonate. The layers were partitioned. The aqueous layer was washed one more time with 40 mL of ethyl acetate. The organic layers combined, washed with brine, dried over sodium sulfate, and concentrated to a yellow-light brown solid, 1.72 g, contained about 0.37 g of excess benzotriazole. The crude material was taken on to the next step without purification. MS (ES) [M+H] calc'd for C20H15BrFN7, 452. found, 452.3-454.3. 1H NMR (400 MHz, CHLOROFORM-d) 61.96 (s, 3H), 2.74 (dd, J=16.42, 14.91 Hz, 1H), 3.13 (dd, J=16.55, 4.17 Hz, 1H), 5.20 (dd, J=14.91, 4.04 Hz, 1H), 5.69 (s, 2H), 7.03-7.12 (m, 1H), 7.38 (dd, J=8.21, 2.65 Hz, 1H), 7.47-7.52 (m, 1H), 7.56-7.63 (m, 1H), 7.74 (dd, J=8.84, 6.06 Hz, 1H), 8.16 (d, J=9.35 Hz, 2H).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>O>[F:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into a warm (55° C.) mixture of Ag2O (13.5 g, 58.4 mmol), NaOH (19.5 g, 487 mmol) and water (200 mL) was added 2-fluoro-4-methoxybenzaldehyde (15 g, 97.4 mmol). The mixture was stirred for 1 h, filtered off and the precipitated solids were washed with hot water (10 mL). The filtrate was added slowly into cold (0° C.) HCl (5N) with vigorous stirring. The precipitated solid was filtered, washed with water and dried to give a white solid (13.6 g, 82% yield, m.p. 194–196° C.); MS m/e 169 (M−H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].S(O[CH2:22][CH2:23][S:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:4]1([CH2:3][CH2:2][O:1][CH2:22][CH2:23][S:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H](SCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 69.8 %

Procedure:
To a solution of 0.21 g of 1-(2-hydroxyethyl)pyrrolidine in 5 ml of dimethylformamide, 0.076 g of NaH (60% dispersion in mineral oil) were added and the mixture was kept at reflux for 2 hrs, then 0.35 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of dimethylformamide was added, the mixture was kept at reflux temperature for 4 hrs and 5 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.22 g of the title compound (I-bz) as a white pasty solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1>>[Cl:12][C:13]1[C:14]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:24])([F:23])[F:25])[C:19]([C:26]([OH:28])=[O:27])=[CH:18][C:17]=2[CH:31]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethyl)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 230.9-232.0° C. 1H NMR (acetone-d6 /300 MHz) 7.93 (s, 1H), 7.77 (m, 3H), 7.27 (d, 2H, J=8.7 Hz), 6.86 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -62.8 (s, 3F), -79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 437 (M-H). ESHRMS m/z 437.0008 (M-H, Calc'd 437.0015). Anal. Calc'd for C18H9ClF6O4 : C, 49.28; H, 2.07; Cl, 8.08. Found: C, 49.25; H, 2.08; Cl, 8.24.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:13]1[CH2:12][C:11](=[O:15])[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:14]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCCCCCC1=CC(Br)CC1=O
Temperature: 5 °C

Procedure:
A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl) cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5°C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λMeOHmax. = 225 mμ (8850); νmax. = 1705 (carbonyl groups) and 1625. cm-1 (olefin group).
Reaction SMILES: [I:1]I.I(O)(=O)(=O)=O.S(=O)(=O)(O)O.[CH2:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)(=O)C.O>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][C:24]([I:1])=[CH:25][C:20]=1[O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCOc1ccccc1OCCCCCC
Reactant: II
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(I)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 213.7 %

Procedure:
69.3 g (253 mmol) of iodine, 32.8 g (144 mmol) of periodic acid, 150 mL of distilled water and 22.5 mL of concentrated sulfuric acid were added to 750 mL of glacial acetic acid and stirred for 5 minutes at room temperature followed by the addition of 80.00 g (287 mmol) of 1,2-dihexyloxybenzene and stirring for 24 hours at 40° C. The resulting reaction mixture was cooled to room temperature, washed with aqueous KOH solution (1 M, 1.5 L) and 3 L of distilled water, and then extracted with 800 mL of chloroform. The organic phase was dried with MgSO4 followed by distilling off the solvent. The residue was purified by column chromatography followed by distilling to obtain 218.6 g of a light brown liquid.
Reaction SMILES: [CH3:1][C@@:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C@@:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanoate (1.22 g, 3.48 mmol, 1 eq) in THF-H2O (15 mL:15 mL) was added LiOH (0.258 g, 10.4 mmol, 3 eq). The mixture was allowed to stir at RT overnight. The mixture was acidified with 1M HCl and extracted with EtOAc. The organic layers were combined, dried (MgSO4), filtered and concentrated to give (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (0.855 g, 76 yield). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.86 (s, 1H), 7.53 (d, J=7.4 Hz, 2H), 7.32 (t, J=7.7 Hz, 2H), 7.15 (s, 1H), 4.35-4.23 (m, 1H), 4.20-4.08 (m, 1H), 3.11 (s, 3H), 2.71-2.57 (m, 1H), 2.38-2.25 (m, 1H), 1.50 (s, 3H). LC-MS M+H+323.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.CC1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(O)=O)=CN=1.[F:47][C:48]([F:52])([F:51])[CH2:49][NH2:50]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:50][CH2:49][C:48]([F:52])([F:51])[F:47])=[O:20]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)ccn1
Agent: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCC(F)(F)F)ccn1
Yield: 51 %

Procedure:
As described for example 8b, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid (78 mg, 0.3 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using 2,2,2-trifluoroethylamine instead of methylamine, to the title compound (49 mg, 51%) which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:51])[C:24](=[O:50])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:21][C:18]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:11][C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:24]([N:23]([CH3:51])[CH3:22])=[O:50])=[CH:30][CH:29]=4)=[CH:40][CH:39]=3)=[N:3]2)=[CH:8][CH:7]=1)([CH3:20])[CH3:19]
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(C)(O)c1ccc2c(N3CCOCC3)nc(Cl)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(C(C)(C)O)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 4.9 %

Procedure:
To a 50 mL round bottom flask, 2-(2-chloro-4-morpholino-quinazolin-7-yl) propan-2-ol (0.08 g, 0.00026 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (0.128 g, 0.000312 mol), cesium carbonate (0.169 g, 0.00052 mol), DMF (3 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.009 g, 0.000013 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 10% MeOH in chloroform. The compound was further purified by prep TLC using 10% MeOH in chloroform to obtain the title compound [0.007 g, 5%]. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.97 (s, 1H), 8.44 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.8 Hz, 3H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 3.83 (brs, 4H), 3.81 (brs, 4H), 2.96 (s, 6H), 1.52 (s, 6H). LC-MS (ESI): Calculated mass: 554.2; Observed mass: 555.1 (RT: 0.17 min).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[Cl:19][C:20]([Cl:41])([Cl:40])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)[N:22]=1.O>CN(C=O)C>[CH2:1]([S:3][C:4]1[N:8]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:23]3[N:22]=[C:21]([C:20]([Cl:40])([Cl:19])[Cl:41])[O:25][N:24]=3)=[CH:33][CH:34]=2)[C:7]2=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (3 g) in DMF (20 ml) was added sodium hydride (60%, oil) (0.56 g), and the mixture was stirred for 10 minutes. To the ice-cooling mixture was added [2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl bromide (6.1 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow syrupy product (4.15 g, 58%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[C:17]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[NH:22][N:21]=3)[CH:16]=[CH:15][C:14]=2[F:31])[C:6]1=[O:32].CO.[NH3:36]>>[F:31][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][N:21]=2)=[CH:18][C:13]=1[N:7]1[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]([NH2:36])=[O:2])[C:6]1=[O:32]
Reactant: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1(C)C
Reactant: N
Solvent: CO
Product: CC1(C)C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(N)=O
Temperature: 60 °C

Procedure:
{3-[2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid methyl ester (0.025 g, 0.055 mmol) was dissolved in solution of 7N ammonia in methanol (3 ml, 21 mmol) and heated in a sealed tube at 60° C. for 18 hours. The resultant solution was concentrated in vacuo and submitted for preparative HPLC purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1.B>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CCc1ccc(C(=O)NCc2ccc(F)cc2F)cc1
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(CNCc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol) was dissolved in freshly distilled THF (220 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched at 0° C. by careful addition of 10% HCl (11 mL) and the mixture was stirred at room temperature for three hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and aqueous 2 M K2CO3 (200 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.56 g (94%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=4)[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)OC)cc2)nc1Cl
Yield: 70.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (2 mL), methyl 4-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.31 g of the title compound as a light yellow solid (70%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:34]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:34]([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:35]1
Reactant: OCC1CCNC1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCC(CO)C2)c(C(=O)O)c1
Yield: 25 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and rac-pyrrolidin-3-yl-methanol and obtained in 25% yield. MS (m/e): 313.0 MH− (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:29]#[C:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3]1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(C#Cc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (19 mg, 15%); 1H NMR δ (CDCl3): 7.66-7.55 (m, 5H), 6.64 (s, 1H), 3.98 (s, 3H), LCMS m/z: 250.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc(OC)c1OC

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,4,5-trimethoxybenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20]>>[OH:18][CH:17]([CH2:19][OH:20])[CH2:16][NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN
Reactant: OCC1CO1
Product: CCCCCCCCCCCCCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetradecylamine (28.80 g, 0.13 mole) was heated to 85° C. Glycidol (10.00 g, 0.13 mole) was added dropwise. The reaction solution was heated under nitrogen for 3 hours and then was stirred overnight at room temperature. A white solid was obtained (crude yield=38.45 g). The solid was recrystalized from hot hexane (yield=12.2 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Br)nc1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)C(C)(C)c1ccc(Br)nc1
Yield: 93 %

Procedure:
Prepared in a similar manner to Example 35a from 2-(6-Bromopyridin-3-yl)-2-methylpropanoic acid (example 40b) and isobutyl amine. Yield: 93%. MS+H (300).