Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[C:12][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]#[CH:12])=[CH:4][N:3]=1
Reactant: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.8 grams (0.012 mole) of 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine and 1.8 grams (0.012 mole)of potassium carbonate in 100 mL of methanol is stirred at ambient temperature for one hour. The reaction mixture is then concentrated under reduced pressure to a residue. The residue is taken up in about 150 mL of water, and the solution is extracted with two 250 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-ethynylpyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1>>[F:23][C:24]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[N:12]=[N:13][CH:14]=3)[CH:5]=[CH:6][C:7]=2[F:8])[C:27]([C:28]#[N:29])=[CH:26][CH:25]=1
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CC1(C)OB(c2cc(F)ccc2C#N)OC1(C)C
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-benzonitrile by the method of Example 12 to give 5,2′-difluoro-5′-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]biphenyl-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 6.99-7.11 (2H, m), 7.27-7.34 (2H, m), 7.47 (1H, t, J 9.4 Hz), 7.87 (1H, dd, J 5.5, 8.6 Hz), 8.30-8.41 (3H, m), 9.66 (1H, s); m/z (ES+) 407.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[CH:24]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1csc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (87 mg), (5-bromo-3-thienyl)methanol (119 mg) and tributylphosphine (188 mg) in THF (4 ml) was added 1,1′-(azodicarbonyl)dipiperidine (234 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then cooled to room temperature, concentrated, and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (38 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=O.P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\[Cl:25])/[C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1cc2nccnc2s1
Product: Cc1ccc([N+](=O)[O-])cc1/N=C(\Cl)c1cc2nccnc2s1
Yield: 111.9 %

Procedure:
A solution of N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 1.273 mmol) in phosphorus oxychloride (15 mL, 161 mmol) was stirred at 105° C. for 7 h. POCl3 was evaporated to dryness and co evaporated with toluene. Triturating with acetonitrile gave crude (Z)—N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl chloride 76 (474 mg, 112%) which was used without further purification. (m/z)=333 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:11]([CH3:13])=[CH:12]2
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2[nH]1
Temperature: -55 °C
Reaction time: 1 h

Procedure:
27.0 g of 2-bromonitrobenzene are placed in 400 ml of THF. The mixture is placed under nitrogen and cooled to −55° C. and then 800 ml of isopropenylmagnesium bromide at 0.5 M in THF are added dropwise. The mixture is left with stirring for 1 hour and then poured into saturated NH4Cl solution. It is extracted with ether, the extract is evaporated and then the residue is taken up in DCM. It is washed with saturated NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica, eluting with an AcOEt/cyclohexane (1/9; v/v) mixture. This gives 10.7 g of the expected compound.
Reaction SMILES: [CH:1]([N:4]([C:16](=[O:35])/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:20]=1)[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].BrC[CH2:44][O:45][CH3:46]>CC(C)=O>[CH:1]([N:4]([C:16](=[O:35])/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH:20]=1)[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:44][O:45][CH3:46])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: COc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100.0 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), 1-bromo-2-methoxyethane (0.024 ml, 0.26 mmol) was added drop-wise. The reaction mixture was refluxed at 60° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3: methanol=65:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-(2-methoxyethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (66.4 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([O:15]C)=[O:14])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.1 %

Procedure:
Methyl N-(tert-butoxycarbonyl)-O-methyl-D-serinate (2.0 g, 85.7 mmol) was dissolved in tetrahydrofuran (40 ml) and water (20 ml) and lithium hydroxide mono hydrate (1.8 g, 42.9 mmol) added. The mixture was stirred for 4 hours at room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran and then acidified by the addition of concentrated hydrochloric acid. The solution was extracted with ethyl acetate (three times). The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-O-methyl-D-serine (1.9 g, 100%) as a colourless oil; 1H NMR spectrum: (DMSO d6) 1.37 (s, 9H), 3.23 (s, 3H), 3.53 (m, 2H), 4.18 (m, 1H), 6.87 (d, 1H), 12.60 (brs, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([OH:14])(C)([CH3:12])[CH3:11].[CH3:15]C(C)([O-])C.[K+].O>C1COCC1>[N:1]1([C@@H:11]([CH3:15])[C@@H:10]([CH3:12])[OH:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](C)n1cnc2ccccc21
Temperature: 60 °C
Yield: 84 %

Procedure:
Benzimidazole (950 mg, 8.0 mmol) in THF was added to tert-butanol (20 mL) and THF (2.5 mL) containing potassium tert-butoxide (900 mg, 8.0 mmol). 2R,3R-butene oxide (500 mg, ˜1 equiv) was added. The reaction was heated in a sealed tube at 60° C. for 2 days. After cooling to room temperature, the reaction was poured into water, extracted with ethyl acetate, washed with 1.0N sodium hydroxide, then brine. To give (1R,2S)-2-benzimidazol-1-yl-1-methyl-propanol 1.27 g (84%) as a yellow oil. MS (APCI) m/z 191.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH2:26][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:24])([CH2:20][CH2:21]3)[O:16][CH2:15]4)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)cc1
Temperature: 120 °C
Yield: 68.8 %

Procedure:
To a mixture of methyl 2-(4-(4′-amino-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (0.323 g, 0.918 mmol) in toluene (35 ml) was added benzyl alcohol (2.377 ml, 22.95 mmol), titanium(IV) isopropoxide (0.807 ml, 2.75 mmol) and 4 A molecular sieves (5 g, 0.918 mmol). The reaction mixture was heated at 120° C. for 48 hours. The resulting mixture was taken up in EtOAc and filtered. The filtrate was subsequently washed with water, then brine. The organic portion dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound after drying (270 mg, yield 68.8% yield). LC/MS, ESI-MS(+) m/z 428.1, RT 1.59 (Condition R).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([OH:72])=O)[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44].[NH2:73][C:74]1[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=1>C1COCC1>[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([NH:73][C:74]4[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=4)=[O:72])[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44]
Reactant: Nc1ccncc1
Reactant: CCc1ccc(C2CC(c3nc(C(=O)O)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C2CC(c3nc(C(=O)Nc4ccncc4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.9 %

Procedure:
145 mg (0.279 mmol) of PYBOP and 169 mg (1.304 mmol) of N,N-diisopropylethylamine were added to a mixture of 80 mg (0.186 mmol) of the compound from Example 143A in 0.5 ml of THF. The reaction mixture was stirred at room temperature for 40 minutes. 21 mg (0.223 mmol) of 4-aminopyridine were then added, and stirring of the mixture at RT was continued overnight. For work-up, the solvent was evaporated and the residue was taken up in ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Diastereomer separation of the cis/trans isomer mixture according to Method 12C gave 14 mg of the title compound (cis isomer) and 23 mg of the trans isomer.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[C:30]1([B:36]([OH:38])[OH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>O>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[C:30]1([B:36]([O-:38])[O-:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccccc1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: Cc1ccccc1
Solvent: O
Product: [O-]B([O-])c1ccccc1
Temperature: 2.5 °C

Procedure:
A suspension of lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated with agitation under a nitrogen atmosphere. A reflux temperature of 100-105° C. was maintained for 55 minutes as water was collected and separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50° C. The concentrated solution was treated with hexanes (3.15 L) between 40-50° C. The resulting suspension was cooled to 0-5° C. for 2 hours and the product was filtered and washed with 0-5° C. hexanes (350 mL). The product was dried at 35-40° C. under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].C([N:21]1[CH:25]=[CH:24]N=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]2([C:46]([C:48]2([CH2:63][C:64]([O:66][CH3:67])=[O:65])[CH2:53][CH2:52][CH2:51][CH2:50][CH:49]2[C:54]2[CH:59]=[CH:58][C:57]([NH:60][CH3:61])=[C:56]([NH2:62])[CH:55]=2)=[O:47])[CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:30]=[CH:31][C:32]=1[NH:33][CH3:34]>O1CCCC1>[C:25]([C:24]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]([NH:62][C:56]2[CH:55]=[C:54]([CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:48]3([C:46]([C:36]3([CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]3[C:29]3[CH:30]=[CH:31][C:32]([NH:33][CH3:34])=[C:27]([NH:26][C:11](=[O:13])[CH2:10][O:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:28]=3)=[O:47])[CH2:63][C:64]([O:66][CH3:67])=[O:65])[CH:59]=[CH:58][C:57]=2[NH:60][CH3:61])=[O:13])=[CH:5][CH:4]=1)#[N:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Reactant: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(N)c2)cc1N
Solvent: C1CCOC1
Product: CNc1ccc(C2CCCCC2(CC(=O)OC)C(=O)C2(CC(=O)OC)CCCCC2c2ccc(NC)c(NC(=O)COc3ccc(C#N)cc3)c2)cc1NC(=O)COc1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
620 mg (3.5 mMol) of 4-cyanophenyloxyacetic acid and 570 mg (3.5 mMol) of 1,1'-carbonyl-diimidazole were refluxed in 50 ml of tetrahydrofuran for 15 minutes. Then 1.0 g (3.28 mMol) of 3-amino-4-methylaminophenyl-(1-methoxycarbonylmethyl-cyclohex-1-yl)-ketone were added and the mixture was boiled for a further 4 hours. Then the solvent was evaporated off and the crude product thus obtained was purified by column chromatography (150 g silica gel; eluant: dichloromethane with 0 to 2% ethanol). Yield: 1.4 g (93% of theory), C26H29N3O5 (463.5) Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1)
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([C:14]([OH:16])=O)[C@H:11]([CH2:17][CH3:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:19]([C:21]1[N:22]=[C:23]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=1)[NH2:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.[Si](O[C@H]1C[C@H](C(NNC2N=C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C3=NC=2)=O)[C@H](CC)C1)(C(C)(C)C)(C)C>[Si:1]([O:8][CH:9]1[CH2:13][CH:12]([C:14]([NH:20][NH:19][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:24]3=[N:25][CH:26]=2)=[O:16])[CH:11]([CH2:17][CH3:18])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCC1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic acid (1.62 g, 5.96 mmol) in DCM (60 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D, 1.86 g, 6.13 mmol), HATU (2.38 g, 6.26 mmol) and TEA (3.32 mL, 23.8 mmol). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction mixture was diluted with DCM (200 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-30% EtOAc in DCM to give a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethyl-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentanecarbohydrazide (2.64 g, 79%) as a brown solid: LC/MS (Table 1, Method b) Rt=3.20 min; MS m/z: 558 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][C:6]1C=C([Si](C)(C)C)[O:9][CH:10]=1)([OH:3])=[O:2].C1C(I)=C([OH:33])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.C[C:62]([CH3:64])=[O:63]>>[C:1]([CH:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][C:6]1[CH:10]([OH:9])[O:33][C:62](=[O:63])[CH:64]=1)([OH:3])=[O:2]
Reactant: CCCCCCCCCCCC(Cc1coc([Si](C)(C)C)c1)C(=O)O
Reactant: CC(C)=O
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=O
Product: CCCCCCCCCCCC(CC1=CC(=O)OC1O)C(=O)O

Procedure:
A mixture of 4-(2-carboxytridecyl)-2-trimethylsilylfuran (46.3 mg, 0.126 mmol) and Rose Bengal (5 mg) in acetone (10 ml) was exposed to singlet oxygen at -78° for 2 hours. The residue, after solvent removal, was purified by preparative TLC (20×20 cm, 500μ silica plate; developed with 10% MeOH/CHCl3 containing a few drops of acetic acid). The title compound was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[C:12](=[CH2:15])[CH2:13][CH2:14][C:3]=12.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C(O)(C)C>O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:16])[CH:12]([CH2:15][N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH3:17])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1ncc[nH]1
Reactant: C=C1CCc2c(C)c3ccccc3n2C1=O
Solvent: CC(C)O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cn1ccnc1C)CC2
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-methylenepyrido[1,2-a]indol-6(7H)-one (142 mg), 2-methylimidazole (180 mg), isopropyl alcohol (1 ml) and water (0.4 ml) was heated at 100° C. for 3 hours. The reaction mixture was purified by a procedure analogous to that of Example 74 to give 8,9-dihydro-10-methyl-7-[(2-methyl-1H-imidazol-1-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (60 mg).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][Si:7]([CH3:21])([CH3:20])[CH2:8][CH2:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1)=[O:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:11]([O-:12])(=[O:10])[CH3:13].[CH3:6][Si:7]([CH3:21])([CH3:20])[CH2:8][CH2:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14]1)=[O:12]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)CCOC(=O)C1CCCC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCC(C(=O)OCC[Si](C)(C)C)C1
Product: CC(=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 1.6 M n-butyllithium in hexanes (14.0 mL, 22.4 mmol) was added to a heterogeneous mixture of methyltriphenylphosphonium bromide (8.02 g, 22.4 mmol) in tetrahydrofuran (50 mL) at −10° C. After stirring for 30 min at −10° C., the yellow slurry was cooled to −78° C. and 3-oxo-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (3.41 mg, 14.1 mmol) in tetrahydrofuran (20 mL) was added. After stirring for 10 min at −78° C., the dry ice/acetone bath was removed and the heterogeneous mixture was stirred for 3 h, during which time the solution warmed to ambient temperature. The heterogeneous mixture was concentrated and the residue was flash chromatographed with 99:1, 49:1, 24:1, and 23:2 hexanes:etheyl acetate as the eluant to yield 3.38 g (100% yield) of 3-methylene-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester as a clear oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[N:15]=[N:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:18]=2[CH3:19])=O)[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1>C(#N)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][N:17]2[C:18]([CH3:19])=[C:14]([CH2:12][NH:11][C:5]3[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=3)[N:15]=[N:16]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: Cc1c(C(=O)Nc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: Cc1c(CNc2cc(CO)cc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Yield: 5 %

Procedure:
This compound was obtained as a by product of the reduction of dimethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-benzenedicarboxylate (Intermediate 14) in the preparation of N-[3,5-bis(hydroxymethyl)phenyl]-1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 52). It was obtained as a white solid (5%) via recrystallisation from acetonitrile. HRMS calculated for C19H20Cl2N4O2 (M+H)+407.1042. found: 407.1022, Rt: 2.40 min. MP: 120° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[N:11][N:10]=[C:9]2[CH3:18])=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:9]([CH3:18])=[N:10][N:11]=[C:12]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])=[CH:5][CH:4]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc([C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2)n1Cc1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
(R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole hydrochloride (58 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4-chlorophenyl isocyanate (0.031 ml, 0.2 mmol) and N,N-diisopropylethylamine-(0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (methanol/dichloromethane gradient, 0-15% methanol) afforded the desired product as a white amorphous solid (75.1 mg, 87%).