Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>C1COCC1.O>[CH2:29]([N:5]1[CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][C:2]([CH3:28])([CH3:1])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:12])=[O:13])=[C:6]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at ° C. was added 0.128 mL (1.07 mmol) of benzyl bromide followed by 0.034 g (0.86 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction was allowed to warm to room temperature after 30 min and stirred for an additional 30 min before being quenched with water. The quenched reaction was diluted with five volumes of water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 70% hexanes/AcOEt to give 0.39 g (93%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.27 (s, 3H), 1.52 (s, 3H), 1.93-2.05 (m, 2H), 2.27 (s, 3H), 3.83 (d, J=15.8 Hz, 1H), 4.18-4.30 (m, 3H), 5.51 (d, J=15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd, J=8.2, 12.1 Hz, 4H), 7.17 (d, J=6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH3:13])[S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[NH3:16]>>[CH:1]1([N:7]([CH3:13])[S:8]([CH2:11][CH2:12][NH2:16])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CS(=O)(=O)N(C)C1CCCCC1
Reactant: N
Solvent: CO
Product: CN(C1CCCCC1)S(=O)(=O)CCN

Procedure:
Ethenesulfonic acid cyclohexyl-methyl-amide (0.0167 mol) was reacted with a mixture of methanol/ammonia (10 mL) in an autoclave for 16 hours at room temperature, and then the solvent was evaporated. The residue was purified by column chromatography (eluent: 90:10 CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:30])=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: COc1cnc(Nc2ccc(C(=O)O)cc2)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Nc2ccc(C(=O)N3CCOCC3)cc2)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-methoxypyrimidin-2-ylamino)benzoic acid (25 mg, 0.058 mmol), morpholine (5.0 μL, 0.058 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (31 mg, 0.069 mmol) in N,N-dimethylformamide (0.4 mL) was added N,N-diisopropylethylamine (24 μL, 0.14 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture. LCMS (M+H) 502.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2ncc(C=O)s2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ncc(CO)s2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To a suspension of 1-[(3,4-dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 5) (1.2 g, 30 mmol), in a mixture of DCM/MeOH, was added sodium borohydride (130 mg). The reaction was stirred at room temperature for 1 hour. After evaporation, the residue was poured in a mixture of water/concentrated HCl solution and extracted with ethyl acetate. A solid was formed and filtered. The filtrate was dried over sodium sulphate and evaporated in vacuo. The combined solids were recrystallised from acetonitrile to give the title compound as a yellow solid (0.8 g, 67%). HRMS calculated for C15H13Cl2N5O2S (M+H)+ 398.0245, found: 398.0205, Rt: 2.59 min. MP: 170.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[CH2:10]Br.[C:12]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[I:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][N:31]([C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2
Reactant: BrCc1ccc(I)cc1CBr
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of the product of Step B (0.34 g; 0.87 mmol) hydrochloride salt of tritylamine (0.22 g; 0.87 mmol) and N,N-diisopropylethylamine (DIPEA) (0.49 ml; 2.8 mmol) in anhydrous DMF (3 ml) was stirred for 2 h at 60° C. under N2. After removing the solvent in vacuo, the residue was diluted to 15 ml with ethyl acetate (EtOAc) and washed with, H2O, brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc, 8:2) to give pure title compound (0.2 g; 48%) as colourless heavy syrup. 1H-NMR (CDCl3) 3.86 (s, 2H); 3.87 (s, 2H); 6.81-7.57 (m, 18H).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH3:22][C:23]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:36][O:37][CH3:38])[CH:34]=[O:35]>CCOCC>[CH3:38][O:37][N:36]=[C:33]([C:34]1[O:35][CH:12]=[N:11][CH:10]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:24]1[CH:39]=[C:40]([CH3:43])[CH:41]=[CH:42][C:23]=1[CH3:22]
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: CON=C(c1cnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 44.6 %

Procedure:
p-Toluenesulfonylmethylisocyanide (0.23 g, 1.2 mmol), potassium carbonate (0.18 g, 1.3 mmol) and methanol (2 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.30 g, 1 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl oxazol-5-yl ketone O-methyloxime (0.15 g, 44.6%) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1>>[CH3:30][C:19]1[O:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[CH:12][CH:13]=2)=[N:21][C:20]=1[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH3:29]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: OB(O)c1cncnc1
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 5-pyrimidine boronic acid (178 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 40 mg (40%). MS (m/e) 349.3 (M+1)
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20]C2CCCCO2)[C:10]=1[C:27]([OH:29])=[O:28])(=[O:8])=[O:7])(C)C.Cl>CC(C)=O>[NH2:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][OH:20])[C:10]=1[C:27]([OH:29])=[O:28])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1c(C(=O)O)n(CCOC2CCCCO2)c2ccccc12
Agent: Cl
Solvent: CC(C)=O
Product: NS(=O)(=O)c1c(C(=O)O)n(CCO)c2ccccc12
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To 50 mL acetone plus 1.80 g (4.2 mmol) of 3-[[(1,1-dimethylethyl)amino]sulfonyl]-1-[2-(tetrahydro-2-pyranyloxy)ethyl]1H-indole-2-carboxylic acid was added 4.2 mL 1N HCl and the mixture was stirred overnight. Acetone was then evaporated and the residue extracted with ethyl acetate three times. The organic layer was washed once with brine, dried (Na2SO4) and stripped to dryness. The residue was then taken up in trifluoroacetic acid (20 mL) then evaporated in vacuo after several hours at room temperature. The residue was triturated and collected with ethyl ether to afford 1.37 g of the title compound, m.p. 145°-146° C. dec.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[S:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:2](=[O:8])[C:3](=[O:5])[N:22]([CH:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]2=[S:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(NC(=S)Nc1ccc(C(C)(C)C)cc1)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(C(C)(C)C)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Ethyl chlorooxoacetate (0.46 mL, 4.10 mmol) was added to a stirring solution of the above thiourea (0.80 g, 2.74 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.61 g (64%) of 1-(4-tert-butyl-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 208.9–209.5° C.; 1H NMR (DMSO-d6): δ 7.52 (d, 2H), 7.40 (d, 2H), 4.85 (q, 1H), 1.48 (d, 3H), 1.30 (s, 9H), 1.00 (s, 9H); IR (KBr): 3505, 2930, 1780 cm1; MS (m/z) 346 (M+).
Reaction SMILES: [CH2:1]([C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:9]([OH:13])[CH2:10][NH:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(C)C>[CH2:1]([C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C@H:9]([OH:13])[CH2:10][NH:11][N:12]=[C:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNN
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNN=C1CCCC1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
A solution of tert-butyl N-[(1S,2R)-1-benzyl-3-hydrazino-2-hydroxypropyl]carbamate (500 mg, 1.695 mmol) in 5 mL of isopropanol under Argon was treated with cyclopentanone (180 μL, 2.034 mmol). After stirring for approximately 18 hours, the reaction solvent was removed in vacuo and the residue was triturated with diethylether. The slurry was filtered and the solid was dried under high vacuum to provide tert-butyl N-[(1S,2R)-1-benzyl-3-(2-cyclopentylidenhydrazino)-2-hydroxypropyl]carbamate (85 mg, 14%) as a white solid. H1-NMR (chloroform-D3) 1.34 (s, 9H), 1.54 (b, 2H), 1.73 (m, 2H), 1.83 (m, 2H), 2.22 (m, 2H), 2.35 (m, 2H), 2.90 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 3.38 (m, 1H), 3.64 (bm, 1H), 3.84 (bm, 1H), 4.52 (m, 1H), 7.25 (m, 5H). MS(APCI): 361(M+Na).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.Cl[C:33]([O:35][CH2:36][CH2:37]Cl)=[O:34].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:6]5[CH2:37][CH2:36][O:35][C:33]5=[O:34])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N2CCOC2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.5 %

Procedure:
To a 6 ml tetrahydrofuran solution of 150 mg (0.425 mmol) of the compound obtained in Example 44, 79 μl (0.765 mmol) of 2-chloroethyl chloroformate and triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Further, 30 μl (0.29 mmol) of 2-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To a 2 ml ethanol solution of the residue, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 116 mg (65%) of the captioned compound.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2cccn2)nc1
Solvent: ClCCl
Product: ClCc1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of alcohol (III) (10.5 g, 59.9 mmol) in CH2Cl2 (150 ml), SOCl2 (36 g, 22 ml, 299.6 mmol) was added and the resulting reaction mixture was stirred at room temperature for a period of between 12 to 18 hours. The excess SOCl2 was quenched with saturated aqueous NaHCO3. The resulting mixture was extracted with CH2Cl2 and washed with brine. Removal of solvent gave a compound of formulae (11.15 g, 95% yield) as a white solid. MS-ESI=194.06, 196.06, 1H NMR (ppm): 8.59(H3′, d), 8.43(H6, d), 8.03(H2, d), 7.89(H3, dd), 7.78(H5′, s), 6.50(H4′, t), 4.65(—CH2-).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]([CH3:33])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 135 °C
Yield: 46 %

Procedure:
A mixture of 0.67 g (1 equivalent) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equivalent) of sodium iodide and 15 ml of 2M dimethylamine in tetrahydrofuran was heated at 135° C. for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated to give 0.50 g. The crude product was purified by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethylamine 6:4:0.1) to give 0.312 g (46%) of pure product. MP 218-219° C. mass spectrum (electrospray m/e): M+H=402.9.
Reaction SMILES: [K].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].S(OC)(O[CH3:21])(=O)=O.[OH-].[K+]>C(C(C)=O)C.O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N

Procedure:
A reaction vessel containing 30 ml of water and 60 ml of methyl ethyl ketone is charged with 16.15 g of the dry potassium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid. With stirring, the mixture is heated to 72°-74° C. and 9.45 g of dimethyl sulfate are added dropwise at the same temperature to the resultant suspension, while keeping the pH at 6-8 by the gradual addition of 30% potassium hydroxide solution. The reaction mixture is kept under reflux for 2 hours and the aqueous layer is then separated. The organic layer is completely evaporated, affording 12.4 g of methyl 3,4,5,6-tetrachloro-2-cyanobenzoate with a melting point of 82°-83° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([NH2:19])[CH2:15][N+:16]([O-:18])=[O:17]>N1C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][N+:16]([O-:18])=[O:17]
Reactant: NC(C[N+](=O)[O-])c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Reaction time: 1 h

Procedure:
At RT, 182 μl (2.35 mmol) of methanesulphonyl chloride were added to a solution of 300 mg (about 93% pure, 1.18 mmol) of the compound of Example 25A in 7.2 ml of pyridine, and the mixture was stirred for 1 h. The pyridine was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. This gave 221 mg (65% of theory) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:26])([N:14]2[C:25]3[C:17](=[CH:18][N:19]=[C:20]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[N:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:26][C:11]1([N:14]2[C:25]3[C:17](=[CH:18][N:19]=[C:20]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[N:16]=[N:15]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(n2nnc3cnc4[nH]ccc4c32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCNCC1
Reaction time: 1.5 h
Yield: 101 %

Procedure:
A mixture of 4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidine-1-carboxylic acid tert butyl ester (200 mg, 0.56 mmol) in DCM/TFA was stirred for 1.5 hours. The solvent was evaporated under vacuum and the resulting residue purified by column chromatography using an Isolute® SCX-2 column (gradient: 0 to 50% [2M NH3 in methanol] in DCM) to afford 145 mg (100%) of 1-(4-methyl-piperidin-4-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method I, ESI): RT=0.32 & 1.58 min, m+H=257.3; 1H NMR (400 MHz, DMSO) δ: 12.41 (s, 1H), 9.04 (s, 1H), 7.62 (d, 1H), 7.04 (m, 1H), 2.90 (m, 2H), 2.79 (m, 2H), 2.70 (m, 2H), 2.05 (m, 2H), 1.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: OC(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.91 g), 3-bromo-1,1,1-trifluoropropan-2-ol (1.2 mL), cesium carbonate (3.8 g) and N,N-dimethylacetamide (20 mL) was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 65%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][CH2:53][C:54]([CH3:59])([CH:56]1[CH2:58][CH2:57]1)[OH:55]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:52][CH2:53][C:54]([CH:56]1[CH2:58][CH2:57]1)([OH:55])[CH3:59])=[O:9]
Reactant: CC(O)(CN)C1CC1
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (1.1 g, 3.0 mmol) was dissolved in DMF (25 mL). To the solution was added TBTU (1.06 g, 3.3 mmol), N,N-diisopropylethyl amine (2.54 mL, 15 mmol) and α-(aminomethyl)-α-methyl-cyclopropanemethanol (0.38 g, 3.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (20 mL), washed with sodium hydroxide solution (0.5 N) and brine. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, heptane/ethyl acetate) to give the title compound (0.38 g) as a light yellow solid, MS (ISP) 462.9, 464.9 (M−H)+.