Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.043 mmol) in Acetonitrile (0.5 mL) was treated with 4-fluorobenzyl chloride (0.025 mL, 0.213 mmol) and Cs2CO3 (69 mg, 0.213 mmol) and then stirred at 70° C. for 2 hours. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(4-fluorobenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate as pale a yellow solid which was used with no further purification. LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].[CH3:26][NH:27][CH:28]([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH:28]([N:27]([CH3:26])[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: CNC(C)C
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), N-methylisopropylamine (0.58 ml), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[6-{2-[isopropyl(methyl)amino]ethoxy}-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.135 g); Mass Spectrum: M+H+ 396.
Reaction SMILES: Br[C@@:2]1([C:14](=[O:16])[CH3:15])[C@:10]2([CH3:11])[C@H:5](/[C:6](=[CH:12]/[Br:13])/[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[Br:13]/[CH:12]=[C:6]1\[CH2:7][CH2:8][CH2:9][C@@:10]2([CH3:11])[C@H:5]\1[CH2:4][CH:3]=[C:2]2[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)[C@@]1(Br)CC[C@H]2/C(=C/Br)CCC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
1-{(E,1R,3aS,7aS)-1-bromo-4-(bromomethylene)-octahydro-7a-methyl-1H-indene-1-yl}ethanone (Compound 12: 100 mg, 0.369 mmol) was dissolved in dimethylformamide (1.6 ml), and lithium bromide (35.8 mg, 0.412 mmol) and lithium carbonate (27.4 mg, 0.371 mmol) were added thereto. The resulting mixture was heated to 100° C. and stirred for 3 hours. After cooling the reaction solution to room temperature, water was added thereto, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated to obtain a crude product. The product was purified by flash column chromatography to obtain 1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanone (71.6 mg, 94.0%) as a white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([CH3:32])=[CH:34][CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2)C3)cc1

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 4-methylbenzylamine (2.2 eq.) in the manner of Example 68, m.p. 174-176° C. MS [(+)ESI, m/z]: 500 [M+H]+ Anal. Calcd for C29H26CIN3O3: C, 69.66; H, 5.24; N, 8.40. Found: C, 69.56; H, 5.35; N, 8.37.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1(C#N)CCCC1.C1([Li])C=CC=CC=1.C(OCCCC)CCC.[BH4-].[Na+].[NH2:35][CH:36]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:37]1(N(C)C)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.CO>[NH2:35][CH:36]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:37]1([CH2:1][NH:2][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: CN(Cc1ccccc1)C1(C#N)CCCC1
Agent: [BH4-]
Agent: [Li]c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: NC(c1ccccc1)C1(CNCc2ccccc2)CCCC1
Yield: 47 %

Procedure:
The title compound (3.90 g; 47%) was prepared from 1-[methyl(phenylmethyl)amino]cyclopentanecarbonitrile D28 (6.0 g; 28 mmol) and phenyllithium in di-n-butylether (16.21 ml of 1.9M solution; 30.8 mmol) in THF (60 ml), followed by reaction with sodium borohydride (3.2 g; 84 mmol) in methanol (60 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS), API+: Found 295 (MH+). C20H26N2 requires 294. Ret. time 2.12 min.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CS(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([Br:11])=[CH:6][C:5]=1[O:12][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: Oc1cc(Br)c(O)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCOc1cc(Br)c(OCCCCCC)cc1Br
Reaction time: 1 h

Procedure:
A suspension of KOH powder (10.47 g, 186.6 mmol) in dried DMSO (360 mL) was degassed under vigorous stirring for 1 h. 2,5-dibromo-1,4-dihydroxybenzene (5 g, 18.66 mol) and 1-bromohexane (5.8 mL, 41.06 mmol) were added and stirred for 12 h. The solution was concentrated and precipitated in water, filtered, washed with methanol. The product was recrystallized in ethanol, dried in vacuo (4.518 g, 55.5%). 1H NMR(300 MHz, CDCl3): δ 7.08 (s, 2H), 3.95 (t, 4H), 1.8 (m, 4H), 1.49 (m, 4H). 1.37 (m, 8H), 0.9 (t, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC=CC=1.C([Li])(C)(C)C.C1C[O:35][CH2:34]C1>O.CN(C)C=O.CCCCC>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:4]1[CH:9]=[CH:8][C:7]([CH:34]=[O:35])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCOC1CCCCO1)c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CCN(CCOC1CCCCO1)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
Water content in 45.1 g (0.14 mol) of N-ethyl-N-[2-(tetrahydropyran-2-yl)oxyethyl]-4-bromoaniline was removed by azeotropic distillation carried out twice with toluene, followed by dissolution in 390 ml of anhydrous THF in an atmosphere of argon. The solution obtained was cooled to -78° C., and 195 ml (2.2-fold equivalent weight) of t-butyllithium (1.55M, an n-pentane solution) was dropwise added thereto, followed by stirring for 45 minutes. To the resulting reaction solution, 23 ml of N,N-dimethylformamide (hereinafter "DMF") was added, and the mixture obtained was stirred at room temperature for 5 hours. Thereafter, 100 ml of water was added to the resulting solution, which was then extracted with chloroform (100 ml×3). The organic layer obtained was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing system: hexane/ethyl acetate=2/1) to obtain 35.0 g of N-ethyl-N-[2-(tetrahydropyran-2-yl)oxyethyl]-4-formylaniline (yield: 92%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:12][O-:13].[Na+].CO>O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
100 g (0.445 mol) of 4-(trifluoromethyl)bromobenzene, 120 g (2.22 mol) of sodium methoxide, and 300 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150° C. under tight sealing. The resulting reaction mixture was poured into water, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 49 g (0.278 mol) of 4-(trifluoromethyl)anisole (yield: 62.6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl(3R,4R)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:31][CH:32]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Reaction time: 16 h

Procedure:
The title B compound, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (98 mg, 0.34 mmol) and (4-hydroxymethylphenyl)carbamic acid t-butyl ester (153 mg, 0.68 mmol) and triphenylphosphine (180 mg, 0.68 mmol) are dissolved in THF (10 mL) with stirring under argon atmosphere. The reaction is cooled in an ice/water bath and diethyl azodicarboxylate (0.107 mL, 0.68 mmol) dissolved in THF (0.107 mL) is added dropwise. After 16 h, the solvent is evaporated and the residue is taken up in a minimal amount of CH2Cl2 and chromatographed on silica gel with a gradient from 1 to 5% EtOAc in CH2Cl2 over 15 min to give {4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-carbamic acid t-butyl ester as an oil: [M+NH4]+=509.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])[CH3:31])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36][C:37](=O)C>>[CH:30]1([N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:18]4[CH:19]=[C:20]5[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=4)[NH:14][CH:13]=[C:12]5[CH:9]4[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]4)[CH:22]=3)[CH2:26]2)[CH2:31][CH2:37][CH2:36][CH2:32]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Reactant: CC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C4CCCC4)C5)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting cyclopentanone (17 mg, 0.198 mmol) for 2-propanone to afford 4.8 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Na].COC([CH2:8][CH2:9][N:10]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][CH2:12][C:13]([O:15]C)=O)=O.Cl>C1C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:10]2[CH2:9][CH2:8][C:13](=[O:15])[CH2:12][CH2:11]2)[CH:19]=1
Reactant: COC(=O)CCN(CCC(=O)OC)Cc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1CCN(Cc2cccnc2)CC1
Yield: 71.3 %

Procedure:
72 Grams of sodium hydride (50% dispersion in oil) were added to 1.5 liters of sodium dried benzene and the suspension formed was refluxed. 137.61 grams of 3-[N,N-di(2-methoxycarbonylethyl)aminomethyl]pyridine were added dropwise to the refluxing sodium hydride suspension in benzene and the solution was heated for a further 21/2 hours. 500 Milliliters of concentrated hydrochloric acid was added carefully. The mixture was filtered, separated and the acid layer combined with a further 200 milliliters of concentrated hydrochloric acid and refluxed for 18 hours. Solid sodium carbonate was added till the solution had a pH of 8. The mixture was filtered and the solution treated with benzene. The benzene extracts were combined, dried over magnesium sulphate and the solvent was evaporated to give 66.58 grams of N-(3-pyridylmethyl)-4-piperidone.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[N:24][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)nc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[6-(trifluoromethyl)-3-pyridyl]benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].N#N.Br[C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)[N:37]=2)[CH:33]=[N:34][CH:35]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:30]3[CH:35]=[N:34][CH:33]=[C:32]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[N:37]=4)[CH:31]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(B(O)O)cc2)CC1
Reactant: Brc1cncc(-c2ccnc(-c3ccccn3)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4ccnc(-c5ccccn5)n4)c3)cc2)CC1
Temperature: 25 °C

Procedure:
A stirred solution of 4-(4-isopropylpiperazine-1-carbonyl)phenylboronic acid (Int. E) (1.2 eq, 53 mg) and 2M sodium carbonate solution (2 eq, 2 ml) in DME (1 ml) under an inert atmosphere of N2 is treated with 4-(5-bromo-pyridin-3-yl)-2-pyridin-2-yl-pyrimidine (Int. H) (1 eq, 50 mg) followed by PdCl2(dppf).DCM (0.1 eq, 13 mg). The mixture is heated using microwave radiation at 90° C. for 90 minutes and then allowed to cool to RT. The mixture is extracted with DCM and the organic extracts are washed with water. The solvent is removed in vacuo and the crude product is purified by reverse phase column chromatography (Isolute™ C18, 0-80% acetonitrile in water—0.1% TFA) and the appropriate fractions are combined and concentrated in vacuo. The residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+=465 as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([N:16]1C2C=CC=CC=2N=N1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:31]([C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:35]=1[NH2:36])(=O)[CH3:32].CN1CCOCC1.N>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:16]=[C:31]([CH3:32])[C:34]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:35]=2[NH:36][C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Reactant: CC(=O)c1cccc(C)c1N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine (14.11 g) in dry tetrahydrofuran (100 ml) were added oxalyl chloride (3.77 ml) and dimethylformamide (3 drops) under stirring at 0° C. in an ice-salt bath under nitrogen stream. After the mixture was stirred under the same conditions for 2 hours, a mixture of 2-acetyl-6-methylaniline (4.30 g) and N-methylmorpholine (8.74 g) in tetrahydrofuran (20 ml) was added dropwise for 20 minutes. After the addition was completed, the mixture was allowed to warm to ambient temperature with stirring. Tetrahydrofuran was removed in vacuo and the residue was dissolved in ethyl acetate. The mixture was washed with water twice and dried over magnesium sulfate. Removal of the solvent gave an intermediate product as an oil, to which was added 20% methanolic ammonia (75 ml) and stirred at ambient temperature overnight. The resultant precipitate was collected by filtration and washed with cold methanol and diisopropyl ether successively, and dried to give (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one as a white crystalline powder (6.17 g, 63.5%).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][C:6]3=[N:11]O)[CH:3]=[CH:2]1>CO.[Ni].O>[CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH2:11])[CH2:3][CH2:2]1
Reactant: ON=C1CC2CC1C1C=CCC21
Agent: [Ni]
Solvent: O
Solvent: CO
Product: NC1CC2CC1C1CCCC21
Reaction time: 20 h

Procedure:
2.2 g of 1,3a,4,6,7,7a-hexahydro-4,7-methanoinden-5-one oxime were dissolved in 50 ml of methanol, and about 10% Raney nickel, dissolved in 50% water, was added. The mixture was hydrogenated at 100 bar and 100° C. for 20 hours, the catalyst was then filtered off, and the solvent was evaporated under reduced pressure. The residue was taken up in ether and 6 N aqueous sodium hydroxide solution, the phases were separated, the aqueous phase was extracted three times with ether, the combined organic phases were dried with magnesium sulfate and filtered, and the filtrate was concentrated. This gave 1.8 g of a colorless oil which was purified by kugelrohr distillation. This gave 0.96 g of the desired amine as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([CH2:10][OH:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.O>[F:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])=[C:6]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=1
Reactant: OCc1cc(F)c(I)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a suspension of 8.86 mmol (5-fluoro-2-hydroxymethyl-4-iodo-phenyl)-methanol in 30 ml dichloromethane at 0° C. were added dropwise 22.2 mmol triethylamine and 19.5 mmol methanesulfonyl chloride. The mixture was stirred at 0° C. for 1 h, and then at room temperature for 5 h. The reaction mixture was diluted with water and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (67% yield) which was used in the next step without further purification.
Reaction SMILES: [Si]([C:5]#[CH:6])(C)(C)C.[CH3:7][C:8]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[C:9]1=O.CC[N+](S(/N=C(/OC)\[O-])(=O)=O)(CC)CC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:10]([C:9]1[C:8]([CH3:16])([CH3:7])[CH2:13][CH2:12][CH2:11][C:5]=1[CH3:6])#[CH:14]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)S(=O)(=O)/N=C(\[O-])OC
Agent: [F-]
Product: C#CC1=C(C)CCCC1(C)C

Procedure:
The prerequisite 2-ethynyl-1,3,3-trimethyl-1-cyclohexene was synthesized according to standard procedures by addition of the Li-derivative of TMS-acetylene to 2,2,6-trimethylcyclohexanone, dehydration by treatment with Burgess-reagent (methoxy-carbonylsulfamoyl-triethylammonium hydroxide, inner salt), and finally desilyation with tetrabutylammonium fluoride. It has to be used immediately due to its instability.