Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH3:2])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc(-c2ccc(-c3ccc(C)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.7 ml (21.7 mmol) of TMP are initially introduced at −15° C. in 10 ml of diethyl ether, and 13.0 ml (20.7 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min, a solution of 6.8 g (19.6 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 50 ml of diethyl ether is added. When the addition is complete, the batch is warmed to RT and stirred for 90 min. The solution is cooled to −70° C., and 6.0 ml (96.4 mmol) of methyl iodide are added. The reaction mixture is warmed to RT and stirred for 20 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 92° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:39][CH2:40][CH2:41][C:42]1([OH:45])[CH2:44][CH2:43]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:45][C:42]1([CH2:41][CH2:40][CH2:39][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)cn2)CC1
Yield: 64.9 %

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1-dicarboxamide (300 mg, 0.682 mmol), 3-(1-hydroxycyclopropyl)-propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (668 mg, 2.05 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (3:1 (v/v) EtOAc/n-hexane) to give the title compound as a white solid (238.5 mg, 65%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:32])[C@@H:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]([CH3:33])[N:9]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C>[Pd].CO>[CH3:33][N:10]1[C:11]([NH:13][C:14](=[O:32])[C@@H:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=2)=[N:9]1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a 100 ml flask was added 1.4 g of 17.8.A, 500 mg of Pd on carbon, 150 ml of MeOH and 520 μl of diisopropylethylamine. The air was removed from the flask and replaced with hydrogen gas. This process was repeated four more times and then the reaction was stirred at room temperature for 2 hours, at which time the reaction was filtered over a bed of celite. The solvent was then removed and the crude was purified with a silica gel column (eluting with 2-5% MeOH in DCM) to give 800 mg of (S)-tert-butyl 2-(1-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.8.B as a solid. (Rf silica=0.27 in 5% MeOH in DCM).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:32][N:31]=1>>[Cl:29][C:30]1[CH:35]=[C:34]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:37]=2)[CH:33]=[CH:32][N:31]=1
Reactant: NC(=NO)c1ccnc(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccnc(Cl)c3)no2)C1

Procedure:
600 mg (1.49 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 281 mg (1.64 mmol, 1.1 eq.) of 2-chloro-N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 315 mg (39% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:42])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.18 mmol) of the compound from Example 99 were introduced into 25 ml of dichloromethane at 0° C., 43 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 65 mg (84% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[Br:1][CH:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(COCc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(c1ccccc1)C(Br)OCc1ccccc1
Reaction time: 2 h

Procedure:
Bromine (1.4 g, 8.8 mmol) is added dropwise with stirring to a solution of 2-benzyloxy-acetophenone (2.0 g, 8.8 mmol) in dry ether (30 ml) at room temperature. After stirring for additional 2 h the solution is washed with water and dried over sodium sulfate. Evaporation of the filtered solution yields the title compound. 1H-NMR (CDCl3, 400 MHz): 7.83-7.81 (m, 1H); 7.49-7.38 (m, 6H); 7.06-7.00 (m, 2H); 5.18 (s, 2H), 4.52 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[N:19]=[C:18]3[N:9]([C:10](SC#N)=[N:11][C:12]4[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=43)[N:8]=2)=[CH:4][CH:3]=1.[NH3:24]>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:19]=[C:18]3[N:9]([C:10](=[NH:24])[NH:11][C:12]4[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=43)[N:8]=2)=[CH:4][CH:3]=1
Reactant: N#CSc1nc2ccc(Cl)cc2c2nc(-c3ccc(Br)o3)nn12
Reactant: N
Solvent: C1CCOC1
Product: N=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccc(Br)o3)nn12

Procedure:
To a solution of 4.9 g of 2-(5-bromo-2-furyl)-9-chloro-5-thiocyanato[1,2,4]triazolo[1,5-c]quinazoline in 80 cc of tetrahydrofuran is added gaseous ammonia under ice cooling over 1.3 hr. The precipitate which forms is collected washed with tetrahydrofuran, recrystallized from N,N-dimethyl acetamide and dried under high vacuum at 100° to afford pure 2-(5-bromo-2-furyl)-9-chloro-5-imino-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline, mp 282°-283°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(Oc2ccc(I)cc2)n1
Yield: 88.7 %

Procedure:
In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethoxypyrimidine (192 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethoxypyrimidine (322 mg).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([Sn:13](Br)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>CCOCC>[CH2:11]([Sn:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1)[CH3:12]
Reactant: c1cocn1
Reactant: CC[Sn](Br)(CC)CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1ncco1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6M, 11 mL, 17.38 mmol) was added to a solution of oxazole (1.0 g, 14.48 mmol) in anhydrous ether (20 mL) stirred at −78° C. under nitrogen. After 5 min, triethylstannyl bromide (2.07 g, 7.24 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oily residue (1.0 g), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 0.87 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (181 mg, 1.0 equiv), K2CO3 (303 mg, 2.5 equiv.) and triphenylphosphine (45 mg. 0.2 equiv) were weighed in air and added in a flame-dried flask. Bis(dibenzylidenacetone)palladium (25 mg, 0.05 equiv) was added and the flask was closed by a septum. Dioxane (6 mL) was added and the mixture was stirred for 18 h (TLC control) at 90° C. The catalyst was filtered off and washed with EtOAc, the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 1/3 to 1/2) to give 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (0.57 mmol, 66%) as a white solid. ESI-MS: m/z 300 [M+H]+, rt: 4.97 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:9])=[CH:11]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ccccc3c2=O)nc1
Yield: 35.1 %

Procedure:
Experimental conditions analogous to those described for Example 1 step 3 were used with 68 mg (0.257 mmol) of 3-(5-Methyl-pyridine-2-carbonyl)-1H-quinolin-4-one, 77.2 mg (0.309 mmol) of 3-bromobenzyl bromide, 12.4 mg (0.309 mmol, 60% dispersion in oil), and 1 mL of DMF. The crude product was purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 39.1 mg of 1-(3-Bromo-benzyl)-3-(5-methyl-pyridine-2-carbonyl)-1H-quinolin-4-one as a white solid. LC-MSD, m/z for C23H17BrN2O2 [M+H]: 433.05 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([C:12]([F:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[O-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([O:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:22])[C:12]([F:21])([C:13]([F:15])([F:14])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: [O-]C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)OCc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl bromide, 10.62 g (0.0621 mol), was added dropwise to a solution of 27.5 g (0.069 mol) of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propoxide (prepared as in Example 7) in 50 mL of acetonitrile at 25°. The reaction mixture was stirred for 2 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give benzyl 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propyl ether as a colorless liquid: bp 86°-87° (36 mm); 19F NMR (CDCl3) δ-73.9 ppm (t, d, J=9, 6 Hz, 6F), -79.2 ppm (d, septet, J=9, 9 Hz, 2F), and -187.7 ppm (t, septet, J=9, 6 Hz, 1F). Anal. Calcd. for C11H7F9O: C, 40.50; H, 2.16. Found: C, 40.69; H, 2.29.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:16]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>CN(C)C=O>[Cl:24][C:23]1[C:16]([S:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Cl)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a suspension of 112.1 g of potassium-t-butoxide in 1000 mL of dimethylformamide under a nitrogen atmosphere, 124.3 g of benzylmercaptan was added dropwise while maintaining the reaction temperature at 20°-25° C. with an ice-water bath. After stirring at 25° C. for 1.5 hours, a solution of 175 g of 2,3-dichlorobenzaldehyde dissolved in 750 mL of N,N-dimethylformamide was added dropwise, while maintaining the reaction temperature at 25°-40° with a water bath. After stirring at 25° C. for 12 hours, the reaction mixture was poured onto excess ice water to yield a precipitate. The suspension was filtered, and the isolated solid was washed with water, suction-dried and finally dried in vacuo at 40° C. overnight to afford 201 g of the title compound as a light yellow solid; m.p. 65°-68° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:6]2=[CH:5][N:4]=1.[Br:21]N1C(=O)CCC1=O.O>O1CCCC1>[Br:21][C:5]1[N:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:7]2[CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:11][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(cnc2C(F)(F)F)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11a (370 mg, 1.27 mmol) was dissolved in 30 mL of tetrahydrofuran, followed by addition of N-bromosuccinimide (453 mg, 2.54 mmol) under −78° C. After stirring for 1 hour, the reaction mixture was heated to room temperature and reacted for 12 hours. The reaction mixture was added with 50 mL of H2O, extracted with ethyl acetate (60 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (510 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Reaction SMILES: C1COCC1.O=C1C2C(=CC=CC=2)C(=O)[N:8]1[CH:17]1[CH2:30][C:20]2[NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][C:27]=3[C:19]=2[CH2:18]1.O.NN>C(O)C>[NH2:8][CH:17]1[CH2:30][C:20]2[NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][C:27]=3[C:19]=2[CH2:18]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N)C3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a three neck round bottomed flask, equipped with a mechanical stirrer, prepare a mixture of THF (3100 ml) and ethanol (550 ml). To this mixture add crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (170 g, 0.52 mol) and stir for 15 min. Add hydrazine hydrate (90 ml, 1.9 mol) and stir the mixture at room temperature for 16 h. Check by LC/MS to confirm that no starting material remains. Filter the crude reaction in vacuo and wash the solid with THF (2×200 mL). Collect the mother liquors and remove the solvent under vacuum. Purify by silica gel filtration (1.5″ high, very wide SiO2 pad) using (2 M NH3/MeOH)/CH2Cl2 (3-10%). Collect the fractions containing product and remove the solvent. Add acetonitrile (180 ml) and reflux the mixture for 15 min and then cool to room temperature. Collect a brown solid by filtration and dry in vacuo overnight at 40° C. to give the racemic title compound, 55 g (60%). GC-MS: 198 (M+), 196 (M−);
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.CO.O>CN1C(=O)CCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:1](=[O:2])[NH:21][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Br)cc1N
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 100 °C

Procedure:
1,1′-Carbonyldiimidazole (2.1 g) in NMP (5 ml) was added to a solution of 4-bromo-o-phenylenediamine (CAS Reg. No. 1575-37-7, 2 g) in NMP (5 ml). The mixture was heated to 100° C. for 2 h and then allowed to cool to 60° C. MeOH (3 ml) was added, and the mixture was allowed to cool to room temperature. Water (50 ml) was added. The mixture was filtered. The residue was washed with isopropanol and then dried in vacuo to give the title compound (1.65 g) as a dark brown solid. MS (m/e, ISP neg. ion)=213.1 [M−H+].
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].Cl[CH2:14][C:15]1[N:16]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1.C(N(CC)CC)C>CN(C=O)C>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:14][C:15]1[N:16]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNS(C)(=O)=O)c12
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNS(C)(=O)=O)c12
Reaction time: 3 h

Procedure:
N-Hydroxyphthalimide (64 mg, 0.39 mmol) was added to a stirred solution of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}methanesulfonamide (100 mg, 0.26 mmol) in DMF (2.6 mL). Triethylamine (0.109 mL, 0.78 mmol) was added dropwise, causing the solution to turn red. After 3 hours, more N-hydroxyphthalimide and triethylamine (3 equivalents each) were added and stirring was continued overnight. The solvent was removed under reduced pressure. To the resulting oil was added ethyl acetate and water, which caused a yellow solid to form. The solid was isolated by filtration, washed with chloroform, and then was triturated with ethyl acetate and isolated by filtration to afford N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]methanesulfonamide as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([S:15][CH3:16])[CH:14]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][S:15][C:13]1[CH:14]=[C:9]([C:18]#[C:17][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[CH:10]=[N:11][CH:12]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: CSc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1cncc(C#Cc2cccc(C#N)c2)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
Add copper (I) iodide (20.0 mg, 0.18 mmol), bis(triphenylphosphine)palladium (II) dichloride (64.2 m g, 0.092 mmol) and triethylamine (1.03 mL, 7.32 mmol), to a solution of 3-bromo-5-methylsulfanylpyridine, (prepared as described in PREPARATION 29), (375 mg, 1.83 mmol) and 3-ethynylbenzonitrile, (prepared as described in PREPARATION 8), (465 mg, 3.66 mmol) in ethyl acetate (3 mL) and stir at 90° C. overnight. Cool to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes/ethyl acetate, to give the title compound (187 mg, 41%).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[F:18][CH2:19][C:20]1([CH:24]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][CH:30]=2)O)[CH2:23][O:22][CH2:21]1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:15]([CH:24]([C:20]1([CH2:19][F:18])[CH2:23][O:22][CH2:21]1)[C:26]1[O:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[N+:16]=[N-:17]
Reactant: Cc1ccc(C(O)C2(CF)COC2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N=[N+]=[N-])C2(CF)COC2)o1
Temperature: 0 °C
Reaction time: 15 h
Yield: 52.6 %

Procedure:
5.80 g (21 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 3.83 g (19 mmol, 1 eq) of (3-fluoromethyloxetan-3-yl)-(5-methylfuran-2-yl)methanol in 50 ml of toluene. The reaction medium was cooled to 0° C. and then 3.15 ml (21 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 15 hours. The (heterogeneous) reaction medium was treated with water and with ethyl acetate and then separated by settling out. The organic phase was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/200G, Spot II) eluted with heptane/ethyl acetate (91/9). 2.25 g of 2-[azido-(3-fluoromethyloxetan-3-yl)methyl]-5-methylfuran were obtained in the form of a yellow oil. Yield=53%. TLC SiO2/Heptane:EtOAc (80/20), developing with KMnO4.