Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in THF, 28 mL, 28 mmol) was slowly added to a solution of 5-bromoindole (5.00 g, 25.5 mmol) in THF (60 mL) at −78° C., under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 20 minutes, then triisopropylsilylchloride (5.7 mL, 26.8 mmol) was added. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to room temperature over a period of 1 hour. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl, diluted with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give a crude oil that was purified by flash chromatography (hexane 100%) providing 8.94 g (99% yield) of 5-bromo-1-triisopropylsilanyl-1H-indole as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH:19]=[CH:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH:20]=[CH:21][CH2:22][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: BrC=CCCBr
Product: Fc1ccc(-n2ccc3cc(OCC=CCBr)ccc32)cc1

Procedure:
In analogy to example 3.1, 1-(4-Fluoro-phenyl)-1H-indol-5-ol and 1,4-dibromobutene were converted to yield 5-(4-Bromo-but-2-enyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless liquid, MS: 359 (M, 1Br).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=O.[CH3:10][O:11][C:12](=[O:15])[CH2:13][SH:14].C(N(CC)CC)C.C[O-].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:11][C:12]([C:13]1[S:14][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=1)=[O:15]
Reactant: O=CC1=C(Cl)CCCC1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 2-chlorocyclohex-1-enecarbaldehyde (50 g, 346 mmol) and methyl-2-mercaptoacetate (40 g, 380 mmol) in Pyridine (100 mL) was added triethylamine (105 g, 1037 mmol) at room temperature. The mixture was stirred for 2 h, and partitioned between ethyl acetate (200 mL) and 1N aqueous HCl (50 mL). The separated organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness, which was dissolved in Methanol (100 mL). To the above solution was added sodium methoxide (1.9 g, 34.6 mmol), then, the mixture was heated at reflux for 3 hrs, which was poured into ice water and partitioned between ethyl acetate (200 mL) and 1N aqueous NaHCO3 (50 mL). The separated organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness, which was purified by silica gel chromatography eluted with PE:ethyl acetate 10:1 to give title product (25 g, 36% yield) as yellow solid. LCMS (m/z) ES+=197 (M+1)
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2)=[CH:3][CH:2]=1.B(O)(O)[C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:42][CH:43]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:41]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:43][C:38]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][C:1]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:2][CH:3]=4)[C:9]([O:20][CH:21]4[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:39][CH:40]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 120 °C

Procedure:
A solution of ethyl 3-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (0.290 g, 0.481 mmol), biphenylboronic acid (0.105 g, 0.530 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol) in 4.8 mL of DMF was treated with a 1 M solution of K2CO3 (0.960 mL). The resulting yellow solution was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (0-25% EtOac/hexanes) afforded the desired compound as a white solid. LCMS: calculated for C40H34F2N2O3 628.71, observed m/e 629.1 (M+H)+ (Rt 2.82/4 min).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:37]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:22]=1[Br:37])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(N[C@H]1CCCC[C@@H]1OCc1ccccc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCCC[C@@H]1OCc1ccccc1)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Yield: 86.1 %

Procedure:
A solution of N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide (Table entry 276) (198 mg, 0.380 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75° C. for 3 days. The solution was purified by preparative HPLC to give N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide as a white solid (196 mg, 86%). LC-MS m/z 598.1 (MH+), retention time 3.72 min (method 2).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH2:27]([C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:28].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>CCCCCC>[CH2:27]([C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[CH3:28]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1ccc(C(=O)c2ccccc2)cc1CC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CCc1ccc(C(=CC#N)c2ccccc2)cc1CC

Procedure:
3-(3,4-Diethylphenyl)-3-phenylacrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-diethylbenzophenone (0.95 g, 4 mmol), diethylcyanomethylphosphonate (0.73 mL, 4.4 mmol) and lithium hexamethyldisilazide (3.4 mL, 4.4 mmol, 1.3M) with a reaction time of 2 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate/methylene chloride) to afford an oil which was stirred in hexane until it solidified. The resulting slurry was filtered, the solid washed with hexane, air dried and then dried in vacuo to afford 0.6 g (57%) of a mixture of the E and Z isomers as a white solid: mp 63-64° C.; 1H NMR (CDCl3) δ 7.51-6.99 (m, 16H), 5.72 (s, 2H), 2.76-2.55 (m, 8H), 1.32-1.14 (m, 12H); 13C NMR (CDCl3) δ 163.3, 144.7, 142.2, 137.3, 136.5, 130.2, 129.8, 129.6, 128.6, 128.5, 128.4, 128.3, 127.2, 126.2, 118.2, 93.9, 93.7, 25.5, 25.3, 15.2, 15.0.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[C:10]3[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:10]3[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(C3=CCCCC3)cnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C3=CCCCC3)cnc21

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(6-cyclohexenyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 66 (a)) with TFA. MS (ESI, pos. ion) m/z: 357 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.48 (t, J=5.6 Hz, 1 H), 8.93 (d, J=2.3 Hz, 1 H), 8.28 (d, J=1.9 Hz, 1 H), 6.39 (br. s, 1 H), 4.13 (d, J=5.6 Hz, 2 H), 3.69 (s, 3 H), 2.39-2.46 (m, 2 H), 2.17-2.27 (m, 2 H), 1.70-1.84 (m, 2 H), 1.59-1.69 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:28]3[C@H:30]([C:31]([OH:33])=[O:32])[C:29]3([CH3:37])[CH3:36])=[CH:38][CH:39]=2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)cc3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 4-fluorophenyl boronic acid in Step A. MS (ESI): mass calcd. for C36H30FN3O3, 571.23; m/z found, 572.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.6, 1H), 7.85 (d, J=8.0, 1H), 7.79-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.54-7.47 (m, 4H), 7.34-7.32 (m, 1H), 7.28-7.26 (m, 1H), 7.16-7.09 (m, 5H), 5.49-5.34 (m, 4H), 2.31 (d, J=8.1, 1H), 2.12 (d, J=8.2, 1H), 1.21 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[CH:7]([CH3:16])[CH2:6]2>C(O)C.[Fe]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:16])[C:8]2=[O:15])=[CH:4][C:3]=1[Cl:2]
Reactant: CC1Cc2cc(Cl)c([N+](=O)[O-])cc2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1Cc2cc(Cl)c(N)cc2C1=O
Reaction time: 4 h

Procedure:
13.6 Milliliters of concentrated hydrochloric acid are added dropwise to a mixture of 30.7 g (0.136 mole) of 5-chloro-2-methyl-6-nitro-1-indanone and 24.55 g of iron powder in 340 ml of ethanol, and the suspension is boiled for 4 hours. The mixture is filtered off with suction from the precipitate in a hot state, after which process the compound precipitates partially from the filtrate when cooling. After having distilled off the solvent to a large extent, the precipitate is completed by diluting with water.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[CH:25]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47]C)=[O:46])=[CH:41][CH:40]=1)[CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=1.[Cl-].[NH4+]>CN(C=O)C>[C:45]([C:42]1[CH:41]=[CH:40][C:39]([CH2:38][CH:25](/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:44][CH:43]=1)([OH:47])=[O:46]
Reactant: O=C1CCCCN1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 19.0 mg (0.191 mmol) of 2-piperidinone [CAS Reg. No. 675-20-7] is initially charged in 1.0 ml of dry DMF, and 7.9 mg (0.197 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C., and a solution of 30 mg (0.056 mmol) of methyl 4-{(4E)-5-{2-[(5-chloro-pentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 32A) in 1.5 ml of dry DMF is added. The mixture is stirred at room temperature for 1.5 h. The reaction solution is then carefully poured into 15 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 1.9 mg (3.25 μmol, 6.0% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1/[CH:12]=[CH:13]/[C:14]1[C:15]([C:24]([O:26][CH3:27])=[O:25])=[CH:16][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[N:18][CH:19]=1>C1COCC1.CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[C:15]([C:24]([O:26][CH3:27])=[O:25])=[CH:16][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[N:18][CH:19]=1
Reactant: COC(=O)c1cc(OC(C)C)ncc1/C=C/N1C(=O)c2ccccc2C1=O
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(OC(C)C)ncc1CCN1C(=O)c2ccccc2C1=O
Yield: 40.1 %

Procedure:
A solution of methyl 5-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112b, 1.56 g, 4.26 mmol) in THF/EtOH (25 mL/5 mL) was hydrogenated on an H-Cube with Wilkinson's catalyst (10 bar, 75° C., 18 hours). The solvent was removed under vacuum and the resulting gum was purified by column chromatography (0-50% ethyl acetate/heptanes) to give methyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-2-(propan-2-yloxy)pyridine-4-carboxylate (112c, 0.63 g, 40%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C1COCC1.[Pd].ClCCl>[CH2:1]([O:3][C:4]([CH:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Yield: 89.4 %

Procedure:
50 g of 4-(2-ethoxycarbonyl-4-methyl-3-oxo-pent-1-enyl)benzoic acid are dissolved in 300 ml of THF, 1.00 g of palladium on carbon (10%) is added, and the mixture is hydrogenated under a hydrogen pressure of 4 bar in an autoclave for 24 h. The mixture is diluted with dichloromethane and filtered with suction through Celite, the residue is washed with dichloromethane and concentrated in vacuo. The residue is purified by chromatography on silica gel (ethyl acetate/n-heptane=3/1). 45 g of compound 45 are obtained as an oil. C16H20O5 (292.3) MS (ESI+): 293.1 (M+H)+, tR=1.37 min (Gradient 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:34][C:35]([NH2:37])=[O:36].C1CCN2C(=NCCC2)CC1.O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:34][C:35]([NH2:37])=[O:36])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(O)cc23)cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OCC(N)=O)cc23)cc1
Yield: 36.5 %

Procedure:
A solution of tert-butyl[6-hydroxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 1 mmol), 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 ml, 2 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.18 g, 36.7%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[N:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O.O.C(=O)([O-])O.[Na+]>C(N(CC)C(C)C)(C)C>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)nc[nH]c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ncnc2cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
6-Methoxy-7-methyl-1H-quinazolin-4-one (275 mg) was suspended in N,N-diisopropylethylamine (3.78 ml), phosphorus oxychloride (0.3 ml) was added to the suspension, and the mixture was stirred at 100° C. for 6 hr. The reaction solution was added in small portions to water of 0° C., an aqueous sodium hydrogencarbonate solution was further added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 4-chloro-6-methoxy-7-methyl-quinazoline (199 mg, yield 66%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3][CH:2]=1.[N+:25]([C:28]1[O:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.ClCCl>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:31]3[O:34][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CN2CCN(CC(O)COc3cccc4[nH]c5ccccc5c34)CC2)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 28.8 %

Procedure:
To a mixture of 1-(9H-carbazol-4-yloxy)-3-piperazin-1-yl propan-2-ol (0.5 g 1.54 mmol) in THF (10 mL), was added 2-3 drops of glacial acetic acid, followed by 5-nitrofurfural (0.325 g, 2.3 mmol). To the above solution Na(OAc)3BH (0.98 g, 4.6 mmol) was added carefully at room temperature and the reaction mixture was stirred at room temperature for 6 hours. Subsequently the reaction mixture was diluted with dichloromethane (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography using dichloromethane/MeOH (9:1) to afford the title compound as a yellow colored solid (0.2 g, 29% yield) with m.p.: 54-59° C. 1H NMR (400 MHz, CDCl3): δ 2.40-2.65 (m, 6H), 2.70-2.80 (m, 4H), 3.67 (s, 2H), 4.20-4.25 (m, 1H), 4.27-4.34 (m, 2H) 6.49 (d, 1H, J=3.6 Hz), 6.67 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 7.20-7.50 (m, 5H), 8.27 (s, 1H), and 8.30 (d, 1H, J=8 Hz). MS m/z: 451 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:9][CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cccnc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1ncccc1CO
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Ethyl 2-methylnicotinate 18-1 (257 mg) was mixed with dichloromethane (4 ml) and to the mixture at −78° C. was added dropwise 1 M diisobutyl aluminium hydride (4 ml), followed by siring for 1 hour. The reaction was quenched with methanol and to the mixture was added aqueous Rochel solution (20 ml), followed by stirring for 2 hours. The resulting mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was column-chromatographed (ethyl acetate/hexane=1/1) to yield the compound 18-2 (166 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].F[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Fc1cccnc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 2-methylimidazole (256 mg, 3.13 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 180 mg, 4.50 mmol) and the resultant solution was stirred at room temperature for 30 min under argon. To the solution was added a solution of 3-fluoropyridine (88 μL, 1.01 mmol) in DMF (1 mL), the resultant solution was heated to 100° C. and stirred overnight. The solution was cooled to rt, poured into aqueous saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.12) to afford the title compound 62 (48 mg, 30% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.69 (m, 1H), 8.63 (m, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 2.38 (s, 3H); LRMS (ESI) m/z calcd for C9H10N3 [M+H]+ 160. found 160; HRMS (ESI) m/z calcd for C9H10N3 [M+H]+ 160.0875. found 160.0866; HPLC>99% (tR=7.75 min, 55 (A):45 (B): 0.032 (C); tR=5.45 min, 55 (A):45 (B): 0.01 (C)).