Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][CH:27]=1
Reactant: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(Br)ccc3ncc21
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(-c4cncc(N)c4)ccc3ncc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 245.1.1) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom) to give the title compound as a white solid. (HPLC: tR 2.02 min (Method A); M+H=400 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.02 (s, 1H), 8.15 (s, 1H), 8.12-8.07 (m, 1H), 7.94-7.91 (m, 1H), 7.81-7.76 (m, 2H), 7.54-7.51 (m, 1H), 7.03-7.00 (m, 1H), 5.44 (s, 2H), 4.11 (q, 2H), 3.91 (s, 3H), 1.94 (s, 3H), 1.35 (t, 3H))
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH2:23])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH3:17])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19].[Br:24][CH2:25][C:26](Br)=[O:27]>CC(N(C)C)=O>[Br:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][NH:23][C:26](=[O:27])[CH2:25][Br:24])[C:5](=[O:20])[C:6]1[C:14]([I:15])=[C:13]([NH:16][CH2:17][C:26](=[O:27])[CH2:25][Br:24])[C:12]([I:18])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[I:19])=[O:27]
Reactant: O=C(Br)CBr
Reactant: CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCN)CCN)c1I
Solvent: CC(=O)N(C)C
Product: O=C(CBr)CNc1c(I)c(C(=O)O)c(I)c(C(=O)N(CCNC(=O)CBr)CCNC(=O)CBr)c1I
Temperature: 40 °C
Reaction time: 20 h

Procedure:
50 g (76.1 mmol) of N,N-bis-(2-aminoethyl)-5-(methylamino)-2,4,6-triiodoisophthalic acid amide (title compound 1a) is dissolved in 500 ml of dimethylacetamide, and at 0° C., 70.6 g (350 mmol) of bromoacetyl bromide (Aldrich) is added in drops over 15 minutes. Then, it is stirred for 20 hours at 40° C. The reaction mixture is poured into 4000 ml of ice water, the accumulating solid is filtered off, dissolved in 800 ml of ethyl acetate and extracted three times with 250 ml each of water. The organic phase is dried on sodium sulfate, and the solvent is evaporated to the dry state. The crude product is recrystallized from methyl-tert-butyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]([NH2:14])=[NH:13].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:13][C:12](=[NH:14])[N:11]=[CH:1][C:2]2[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C=NC(=N)N=Cc2ccc(C)cc2)cc1

Procedure:
4-Methylbenzaldehyde (MBA) (0.50 mols-60 grams) is admixed with guanidine hydrochloride (0.25 mols, 25 grams) in molar ratio of 2:1. They are then heated under reflux in 150 ml of toluene under a Dean Stark water collector trap for approximately 17 hours to collect the theoretical amount of H2O evolved. The hot solution is rapidly decanted to ensure the removal of insoluble residues. The solution is then evaporated to dryness on a rotary evaporator. The crude immine is then recrystalized twice from absolute ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]Cl)=[N:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:7][C:6]=2[CH:12]=1
Reactant: ClCc1nc2cc(Br)ccc2o1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2oc(CN3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2 g (8.11 mmol) 5-bromo-2-chloromethyl-benzoxazole in 30 mL DMF is combined with 2.24 g (16.22 mmol) K2CO3 and 0.9 mL (10.78 mmol) pyrrolidine and stirred for 24 hours at RT. The reaction mixture is diluted with water and extracted with EtOAc. The organic phase is dried over Na2SO4, the desiccant is filtered off and the filtrate is evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[N+:18]([O-])=O>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:6][C:5]=1[NH2:18]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1N
Yield: 100.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)-2-nitro-benzoic acid methyl ester (7.0 g, 23.6 mmoles) in 400 mL ethyl acetate was added 1.0 g 10% Pd/C. The reaction mixture was subjected to hydrogenation using a balloon for 24–36 hrs or until the reaction was complete as monitored by HPLC. The mixture was filtered through a celite bed, and the solid cake was thoroughly washed by ethyl acetate. The filtrate was concentrated in vacuo to dryness to afford the title compound (6.3 g, 99%). ES+ MS showed 267 m/z, the correct mass for the product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[C:31]([NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[C:32]5[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]5=[N:34][C:35]=4[CH2:36][CH3:37])=[O:27])[CH:21]=3)=[O:19])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:50][CH:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH3:52]>C1COCC1>[CH2:41]([N:38]1[C:33]2=[N:34][C:35]([CH2:36][CH3:37])=[C:30]([CH2:29][NH:28][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([NH:17][CH2:16][C:11]4[CH:10]=[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:56]6[CH2:57][CH2:58][N:53]([CH:51]([CH3:52])[CH3:50])[CH2:54][CH2:55]6)[CH:4]=5)[C:14]([F:15])=[CH:13][CH:12]=4)=[O:19])[CH:21]=3)=[O:27])[C:31]([NH:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[C:32]2[CH:40]=[N:39]1)[CH3:42]
Reactant: CC(C)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CCl)c3)c2)c1
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(C)C)CC4)c3)c2)c1

Procedure:
N-{[3′-(Chloromethyl)-6-fluoro-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol) and 1-(1-methylethyl)piperazine (0.0325 g, 0.25 mmol) were combined in THF (1 mL) and microwaved at 150° C. for 1 h. The mixture was purified using a Gilson HPLC with a TFA system followed by passing product though a quaternary ammonium hydroxide cartridge to give the free base, the title compound, as a white solid. LC-MS m/z 774.8 (M+H)+, 1.46 min (ret time); mp 165-169° C. Analytical HPLC shows 100% purity, (ret time 10.233 min).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][C:29]6=[O:41])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][NH:31][CH2:30][C:29]6=[O:41])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)=[O:45])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5=O)cn4)sc23)c(F)c1)NC1CC1
Yield: 69.5 %

Procedure:
A solution of 71 (60 mg, 0.095 mmol) and TFA (5 mL) in DCM (20 mL) was stirred at RT for 5 h. The TFA was removed by co-evaporation with DCM and MeOH, diluted with water, and the pH was adjusted to around 12 with 1N NaOH. The resultant gel was extracted with DCM with traces of MeOH. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 10 g column; 2% of ammonium hydroxide in MeOH/DCM; 0/100 to 10/90 over 20 CV, 10/90 to 20/80 over 10 CV then 20/80 over 5 CV), to afford the title compound 72 (35 mg, 0.066 mmol, 69% yield, traces of TFA) as a white sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.72 (s, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 8.35 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.83 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (dd, J=8.9, 1.5 Hz, 1H), 6.65 (dd, J=5.3, 0.6 Hz, 1H), 6.58 (bd, J=2.7 Hz, 1H), 4.59 (s, 2H), 3.37 (s, 2H), 3.28 (t, J=5.5 Hz, 2H), 2.95 (t, J=5.4 Hz, 2H), 2.59-2.51 (m, 1H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H), one NH is missing. MS (m/z): 533.4 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Reactant: CC1(C)CO1
Agent: Cl
Product: CC(C)(O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 177, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2,2-dimethyl-oxirane to give 183 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.45 (s, 1H); 8.31 (s, 1H); 8.17 (s, 1H); 7.84 (td, J=8.75, 5.92 Hz, 1H); 7.66 (ddd, J=10.33, 9.02, 2.79 Hz, 1H); 7.40-7.34 (m, 1H); 7.31 (d, J=8.17 Hz, 1H); 7.00 (d, J=1.69 Hz, 1H); 6.93 (dd, J=8.25, 1.78 Hz, 1H); 4.26 (t, J=5.06 Hz, 2H); 3.79 (t, J=7.52 Hz, 2H); 3.64 (t, J=7.75 Hz, 1H); 3.35 (t, 2H); 3.08 (t, J=5.05 Hz, 2H); 2.35 (t, 2H); 1.10 (s, 6H). LCMS: RT=7.45 min, M+H+=493
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:13]([OH:24])[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:24][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1)[C@@H:14]([NH:16][C:17]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:23])[CH3:15])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl ((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-yl)carbamate (2.0 g, 5.16 mmol) and triethylamine (1.15 ml, 8.26 mmol) at 0° C. in DCM (20 ml) was added methanesulfonyl chloride (0.48 ml, 6.2 mmol). The reaction was stirred at 0° C. for 1 hour and then was quenched with a saturated solution of NH4Cl. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The product was purified by column chromatography to yield (2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate. The crude material was judged to have a 9:1 diastereomeric ratio by 1H NMR analysis. 1H NMR (500 MHz, CDCl3): δ 7.91 (s, 1H); δ 7.87 (s, 0.1H); δ 7.84 (s, 2H); 5.73 (d, J=4.3 Hz, 1H); δ 5.21 (d, J=7.0 Hz, 0.1H); δ 4.58 (s, 1H); 4.18 (br s, 1H); 3.02 (s, 3H); 1.39 (s, 9H); 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:21](COCC[Si](C)(C)C)[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:31]([N:18]1[C:19](=[O:30])[C:20]2[NH:21][C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)=[N:14][C:15]=2[N:16]=[CH:17]1)[CH2:32][CH3:33]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCn1cnc2nc(-c3cn[nH]c3)[nH]c2c1=O
Yield: 36.7 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.201 mmol), Pd(OH)2 (20%) (0.2 g), in ethanol (4 ml) and cyclohexene were stirred under nitrogen balloon for 25 hrs. Reaction mixture was filtered through celite bed washed with methanol (20 ml). The filtrate was concentrated under vacuum and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 5 to 6% methanol in DCM as an eluent to obtain 1-propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one (0.018 g, 24%) as white solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1OCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 45 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 45%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:30])[C@@H:21]([NH:22][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-phenylalanine methyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.41 (t, J=6.0 Hz, 4H), 3.05-3.20 (m, 2H), 3.71 (t, J=6.0 Hz, 4H), 4.55-4.65 (m, 1H), 6.97 (d, J=8.9 Hz, 2H), 7.10-7.45 (m, 5H), 7.73 (d, J=8.9 Hz, 2H), 8.52 (d, J=7.8 Hz, 1H); MS (ES) m/z: 381.3 (MH+); HRMS Calcd. for C22H25N2O4 (MH+): 381.1809. Found: 380.1807.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:28]1[C:32]2([CH2:37][CH2:36][C:35](B(O)O)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:35]2[CH2:36][CH2:37][C:32]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:33][CH:34]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.312 g, 2.86 mmol) and 1,4-dioxaspiro[4,5]dec-7-en-8-boronic acid (1.066 g, 4.01 mmol) in DMF (12 mL) was added 2M solution of Na2CO3 (6 mL), and the mixture was deoxygenated by bubbling nitrogen through solution for 10 min. Then Pd(PPh3)4 was added to the mixture, and it was heated at 100° C. for 40 min. The mixture was brought to room temperature, diluted with CH2Cl2, acidified with 3N HCl till pH 2-3, and extracted with EtOAc. Organic fraction was washed with NaHCO3 and brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexanes-EtOAc gradient to afford 1.368 g (92%) of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:3]=1.[CH2:17]([NH2:19])[CH3:18].O>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:19][CH2:17][CH3:18])[N:3]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:5]=1
Reactant: CCN
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Solvent: O
Solvent: CC(C)=O
Product: CCNc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 5.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile in 50 ml of acetone was cooled to 0° to -5°, and 2.8 grams of an aqueous solution of 70% ethylamine in 40 ml of acetone was added dropwise. The temperature of the reaction mixture was maintained at 0° to -5° throughout the addition, then during 2 hours following complete addition. The reaction mixture was warmed to room temperature where it was stirred for 1 hour. Water was added to the reaction mixture, which caused precipitation of a solid. The solid was collected by filtration and recrystallized from a mixture of benzene and methylcyclohexane to give 3.3 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-ethylamino-5-pyrimidinecarbonitrile; mp, 157°-160°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](O)(=O)[C:12]1C(=CC=C[CH:20]=1)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>O.CC(C)=O>[CH:12]([NH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:20])[CH3:11]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Cc1ccc(C#N)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C#N)c(NC(C)C)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 264 g. of 2-amino-4methylbenzonitrile, 504 g. of phthalic acid and 2.32 liters of reagent grade acetone is added 80 g. of sodium borohydride portionwise over 40 minutes at a temperature of 18°-30° C. The resulting solution is stirred for 30 minutes during which the temperature rises from 29°-30° C. to 35° C. and then dropped to 34° C. The resulting solution is then heated from 34° C. to 53° C. over a period of 30 minutes and their maintained at 55° C. for one hour. The mixture is cooled to 37° C., 500 ml. of water added followed by addition of 417 g. of 50% aqueous sodium hydroxide, after which the temperature is allowed to rise to 56° C. to maintain the solution. An additional 92 ml. of water is added and the acetone and aqueous salt layers separated at 45°-50° C. The acetone layer is concentrated in vacuo to obtain a brown oil and salt solution which is diluted with 800 ml. of heptane and the aqueous and heptane layers separated. The heptane layer is dried, filtered and cooled to 10° C. to obtain the major portion of the desired 2-isopropylamino-4-methylbenzonitrile, m.p. 55°-57° C. Additional product is also recovered from the mother liquor and phthalic acid is recovered to a high degree from aqueous salt layer above referred after dilution with a total of 4.5 liters of water, filtering and acidifying with sulfuric acid (other aqueous alkaline solutions obtained in the work up being combined with said aqueous salt layer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(Cl)cc4)ccc31)C1CCC(C2)N1
Yield: 40 %

Procedure:
Intermediate 18 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-chlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (100 mg, 40%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.16 (s, 1H), 7.86-7.90 (m, 2H), 7.62-7.66 (m, 1H), 7.43-7.45 (m, 1H), 7.32-7.42 (m, 1H), 7.29-7.32 (m, 1H), 5.25 (br s, 1H), 4.68 (br s, 1H), 4.70 (s, 1H), 3.60 (s, 3H), 2.50 (d, J=16.3 Hz, 1H), 2.17-2.33 (m, 2H), 1.89-1.97 (m, 1H), 1.55-1.65 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=S)=[CH:7][CH:6]=1)=[O:4].[C:14]([O:18][C:19](=[O:45])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[C:29]([C:31]([N:33]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH:28]=[CH:27][C:26]=1[NH2:44])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[CH3:42][CH:41]([CH3:43])[CH2:40][CH2:39][N:33]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([C:29]1[CH:28]=[CH:27][C:26]2[N:44]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[N:24]([CH2:23][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:45])[C:25]=2[CH:30]=1)=[O:32]
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
4-methoxycarbonylphenyl isothiocyanate (327 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are added successively to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 17 hours then cooled down to ambient temperature and aminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 1:1) produces the expected compound in the form of a white solid (409 mg; 60% yield).