Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:19][N:20]([CH:22]=[C:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][C:13]1=[O:15])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: COc1ccccc1C1CC(=O)C(=CN(C)C)C(=O)C1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (386 mg, 1.77 mmol), example 1/a, and N,N-dimethylformamide dimethylacetal (2 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was run at 100° C. for 2 h, after which the solvent was removed by evaporation under reduced pressure to produce the title compound as a brown oil. The title compound was used without further purification in the next step.
Reaction SMILES: [C:1]1(=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH3:19]>[Pd]>[CH2:9]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1)[CH2:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:18][CH3:19]
Reactant: CCO
Reactant: c1ccc(N=C2CCCc3ccccc32)cc1
Agent: [Pd]
Product: CCCCCCCCCCCCc1ccc(NC2CCCc3ccccc32)cc1

Procedure:
N-(1,2,3,4-tetrahydronaphthylidene) aniline (XXVI) (38 g) prepared as described in example XXXIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. The crude product was crystallized from ethanol to give 1-(p-dodecylanilino)-1,2,3,4-tetrahydronaphthalene (XXVII). XXVII had a melting point of 34° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]1([C@@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([N:31]3[C@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:34][O:33][C:32]3=[O:35])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cn3)CC2)c(C)c1
Yield: 20.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 21 and (R)-(−)-4-phenyloxazolidin-2-one (326 mg), the title compound (183 mg) was obtained.
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:6].[NH4+].[Cl-]>C(OCC)C>[F:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:5]([OH:6])([CH3:1])[CH3:4]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(C)(C)O)c(F)c1
Yield: 80.9 %

Procedure:
17.75 g (0.125 mole) methyliodide are dissolved in diethylether and the resulting solution is added dropwise with stirring to 3.04 g magnesium chips in 15 ml anhydrous ether. The mixture is then heated under reflux for 30 minutes, followed by the dropwise addition with stirring of a solution of 16.82 g (0.1 mole) 2-fluoro-4-methoxy-acetophenone in diethylether. After heating under reflux for 2 hours, the reaction mixture is cooled, poured onto ice and the corresponding deposit dissolved by addition of aqueous NH4Cl solution. The ether phase is separated off, the aqueous phase is extracted with ether, the combined ether phases are washed with aqueous solutions of NaHSO3, NaHCO3 and then with pure water, dried over Na2SO4 and the ether removed. Distillation of the residual oil in a high vacuum gives 14.9 g 2-(2-fluoro-4-methoxyphenyl)-2-propanol.
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([NH2:21])=[N:18][N:17]=2)[CH2:12][CH2:11]1>C(#N)C.CN(C=O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([NH:21][C:7]([NH2:6])=[S:8])=[N:18][N:17]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)N=C=S
Reactant: CN1CCN(c2nnc(N)s2)CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(c2nnc(NC(N)=S)s2)CC1
Temperature: 80 °C

Procedure:
Ethoxycarbonylisothiocyanate (0.346 ml, 2.96 mmol) is added dropwise to a stirred suspension of 5-(4-Methyl-piperazin-1-yl)-[1,3,4]thiadiazol-2-ylamine (63b) (0.59 g, 2.96 mmol) in acetonitrile (15 ml) and DMF (5 ml). The reaction is heated at 80° C. for 7 h followed by removal of the solvent. The residue heated in 2M aqueous NaOH (80 ml) at reflux for 30 minutes. After cooling to room temperature the solution is neutralised by addition of 6M aqueous HCl and the titled product is removed by filtration and dried under vacuum.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH:22]1([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:34]4[C:42]5[C:37](=[N:38][C:39]([C:43]6[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[CH:44]=6)=[CH:40][CH:41]=5)[N:36]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:35]=4)[CH:31]=3)[C:26]2=[O:59])[CH2:24][CH2:23]1>C(#N)C>[CH:22]1([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:34]4[C:42]5[C:37](=[N:38][C:39]([C:43]6[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:44]=6[F:21])=[CH:40][CH:41]=5)[N:36]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:35]=4)[CH:31]=3)[C:26]2=[O:59])[CH2:23][CH2:24]1
Reactant: COc1cc(OC)cc(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (0.21 g, 0.59 mmol) was added to a stirring solution of 2-cyclopropyl-5-[6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one (0.15 g, 0.29 mmol) in acetonitrile (3 mL). The mixture was stirred at r.t. for 2 h. Then it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M+H)+=529.2.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C1CCN2C(=NCCC2)CC1.[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:37][CH2:38]Br)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:40])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(SCCNC(=O)OC(C)(C)C)nc2ccccc21
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a solution of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 1.31 g, 4.97 mmol) in dry THF (2.6 ml) cooled to 0° C. is added a solution of DBU (756.6 mg, 742.5 μl, 0.47 mmol) in dry THF (1 ml). This yields a paste that is diluted with dry THF (2.5 ml). A solution of (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.17 g, 5.22 mmol) in dry THF (2.6 ml) is then added and the resulting mixture is allowed to stir for 2 h. The solvent is removed under reduced pressure and saturated aqueous KH2PO4 solution (50 ml) is added. The product is extracted with AcOEt (150 ml), the organic phase is washed once with water and once with brine and dried over Na2SO4. The solvent is removed in vacuo and the crude mixture is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:12), yielding the title compound (1.41 g) in 69% as a colourless oil: tR=2.35 min (LC-2), ESI-MS (pos.): m/z 408.27 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[F:31][C:32]([F:38])([F:37])/[CH:33]=[CH:34]/[C:35]#[N:36].N12CCCN=C1CCCCC2>C(#N)C>[C:35]([CH2:34][CH:33]([N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1)[C:32]([F:38])([F:37])[F:31])#[N:36]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Reactant: N#C/C=C/C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#CCC(n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1)C(F)(F)F
Temperature: 80 °C

Procedure:
To a solution of N-{3-[5-(1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0458 mmol) in acetonitrile (1 mL) was added (2E)-4,4,4-trifluorobut-2-enenitrile (8.3 mg, 0.069 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (14 μL, 0.092 mmol). The solution was stirred and heated at 80° C. for several hours. The reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=522.1.
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].F[C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a 100 ml flask fitted with a magnetic stirrer and drying tube is added dimethyl sulfoxide (50 ml), anhydrous potassium carbonate (3.6 g, 0.026 mole) and 2-chloro-4-trifluoromethylphenol (4.8 L g, 0.024 mole). This mixture is stirred at room temperature overnight. 5-Fluoro-2-nitrobenzamide (4.5 g, 0.024 mole) is added rapidly and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture is poured into water (300 ml) and triturated with carbon tetrachloride (50 ml). The water and carbon tetrachloride insoluble solid is collected by filtration and dried under vacuum to afford 1.2 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide, mp 139°-43° C. Anal. Calcd. for C14H8ClF3N2O4 : C, 46.62; H, 2.23; Cl, 9.83; N, 7.76. Found: C, 45.77; H, 2.30; Cl, 10.62; N, 7.91.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C:33]1[CH:65]=[CH:64][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]2=[O:63])=[CH:35][CH:34]=1.[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75]O)=[O:72])([CH3:69])([CH3:68])[CH3:67]>C1C=CC=CC=1>[C:66]([O:70][C:71]([NH:73][C@H:74]([CH3:77])[CH2:75][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[N:40]([C:44]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:39]2=[O:63])=[CH:64][CH:65]=1)=[O:72])([CH3:69])([CH3:68])[CH3:67]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
13.2 g of diethyl azodicarboxylate were added dropwise to a solution of 20.7 g of triphenylphosphine in 300 ml of benzene and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 35.0 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in step (d) above] were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. 13.2 g of (R)-2-t-butoxycarbonylamino-1-propanol were added to the mixture, which was then allowed to stand overnight. At the end of this time, 40.9 g of triphenylphosphine, 23.68 ml of diethyl azodicarboxylate and 33 g of (R)-2-t-butoxycarbonylamino-1-propanol were added to the reaction mixture, in that order, in 3 or 4 separate portions, and the mixture was then stirred for 2 days. After this time, the benzene solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1: 3 by volume mixture of ethyl acetate and hexane as the eluent, to give 30 g of the title compound as crystals, melting at 153°-157° C.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[O:12][C:11]([C:13]2[C:17]([CH:18]=[N:19]O)=[CH:16][N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6]>C(Cl)(Cl)(Cl)Cl>[N+:5]([C:8]1[O:12][C:11]([C:13]2[C:17]([C:18]#[N:19])=[CH:16][N:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:14]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(-c2nn(-c3ccccc3)cc2C=NO)o1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Add 9.4 ml of thionyl chloride to a suspension of 32.6 g of finely-ground 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehydeoxime in 250 ml of carbon tetrachloride at 60° to 65° C. Stir the resulting admixture for 1.5 hours at this temperature and for 2 hours under reflux. Separate the formed precipitate by vacuum filtration at room temperature. Wash the filter residue (precipitate) with carbon tetrachloride and dry to obtain a 96% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][C:47]1[CH:52]=[CH:51][N:50]=[C:49]2[CH:53]=[CH:54][S:55][C:48]=12)[NH2:42].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:38][C:39]1[CH:40]=[C:41]([NH:42][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[O:16])=[O:15])[CH:43]=[CH:44][C:45]=1[O:46][C:47]1[CH:52]=[CH:51][N:50]=[C:49]2[CH:53]=[CH:54][S:55][C:48]=12
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C1CCN(c2ccc(F)cc2)C1=O
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (38 mg, 0.169 mmol), EDCI (88 mg, 0.461 mmol), and HOBt (62 mg, 0.461 mmol) in DMF (3 ml) was stirred at room temperature for 1 hour. 3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1, Step B; 40 mg, 0.154 mmol) was added followed by Et3N (0.064 mL, 0.461 mmol). After stirring for 2 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (3:1=Et2O:EtOAc to 1:3=Et2O:EtOAc) to afford 38 mg (53%) of the desired product. 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.45 (d, 1H), 7.92 (d, 1H), 7.85 (dd, 1H), 7.61 (m, 2H), 7.54 (d, 1H), 7.44 (m, 1H), 7.30 (t, 1H), 7.12 (m, 2H), 6.59 (d, 1H), 3.99 (m, 2H), 3.80 (dd, 1H), 2.67 (m, 1H), 2.52 (m, 1H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −117.6, −128.3. LRMS (ESI pos) m/e 466.1 (M+1).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]1([CH:15]([OH:18])[C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:17]=[C:16]([CH:15]([OH:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CC(O)c1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(C(O)c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 65 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 1-phenyl-2-propyn-1-ol to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 65% yield: mp 143-146° C. (methanol/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.49-7.28 (m, 10H), 6.19 (t, J=6.0 Hz, 1H), 6.07 (d, J=6.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 3.11 (d, J=3.0 Hz, 1H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.1, 152.4, 141.1, 137.4, 128.9, 128.8, 128.4, 127.9, 127.9, 126.4, 124.6, 119.0, 69.1, 44.3, 17.3; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: [Cl:1]C1C=CC(O)=C(C(C2C=C(F)C=CC=2O)(C)C)C=1.[C:20]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([N+:41]([O-:43])=[O:42])[C:35]=1[OH:44])([C:23]1[CH:28]=[C:27](F)[CH:26]=[C:25]([N+:30]([O-:32])=[O:31])[C:24]=1[OH:33])([CH3:22])[CH3:21]>>[Cl:1][C:27]1[CH:26]=[C:25]([N+:30]([O-:32])=[O:31])[C:24]([OH:33])=[C:23]([C:20]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([N+:41]([O-:43])=[O:42])[C:35]=2[OH:44])([CH3:22])[CH3:21])[CH:28]=1
Reactant: CC(C)(c1cc(F)cc([N+](=O)[O-])c1O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: CC(C)(c1cc(F)ccc1O)c1cc(Cl)ccc1O
Product: CC(C)(c1cc(F)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
2-(5-chloro-2-hydroxy-3-nitrophenyl)-2-(5-fluoro-2-hydroxy-3-nitrophenyl)propane (m.p. 160° C.) was prepared from 2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-hydroxyphenyl)propane following the method described in Example 3 for the preparation of 2,2'-isopropylidene bis(4-fluoro-6-nitrophenol).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])=[CH:26][CH:25]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To a suspension of NaH (0.49 g, 16.3 mmol, 80%) in THF (15 mL) at 0° C. was added diethyl malonate (2.61 g, 16.3 mmol). The mixture was stirred for 15 min and was then added dropwise to a refluxed mixture of (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.90 g, 13.6 mmol) in THF (25 mL), and the resulting solution was refluxed for 15 min. After evaporation of the solvent, the crude product was purified by flash chromatography (methanol/CH2Cl2, 1:100→2.5:100) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.18 g, 44%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: C[O-]
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Yield: 99.1 %

Procedure:
Sodium methoxide (28% methanol solution, 5.64 g) was added at room temperature to a methanol (120 mL) solution of 2,2′,3,4′-tetrafluorobiphenyl-4-carbaldehyde (4.95 g), and the mixture was heated to reflux for 16 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (5.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:36]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cnn(C)c5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 5-chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.073 g, 0.41 mmol) in CH2Cl2 (50 mL), was added Et3N (0.086 mL, 0.62 mmol) and the reaction stirred under nitrogen at room temperature for 1 hour. The residue was concentrated and purified by flash chromatography on silica gel, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a white solid (0.159 g, 76%). 1H NMR (500 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.80-3.87 (m, 6H), 3.63-3.80 (m, 4H), 3.38-3.44 (m, 4H). APCI MS m/z 509 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[C:6]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:7]1
Reactant: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cc(-c2cc3nccnc3[nH]2)c2cc(O)ccc21
Yield: 94.8 %

Procedure:
A mixture of 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [200 mg, Example 1(a)] hydrobromic acid (48%, 500 μl) and glacial acetic acid (3 mL) was heated under reflux for 14 hours. After cooling the mixture was neutralised by addition of saturated sodium bicarbonate solution. The resulting dark solid was filtered and then dried to give the title compound (180 mg) as a black solid, m.p. 289-290° C. MS: 264 (MH+).