Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[NH:17][C:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=3[CH:10]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:64]=1[N:63]=[C:62]([NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])[N:61]=[CH:60]2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:66]([NH:65][C:62]1[N:61]=[CH:60][C:59]2[C:64](=[C:55]([C:9]3[NH:17][C:16]4[CH2:15][CH2:14][NH:13][C:12](=[O:18])[C:11]=4[CH:10]=3)[CH:56]=[CH:57][CH:58]=2)[N:63]=1)([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)Nc1ncc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[C:1]1([S:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[N:19]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:38])[CH:44]=4)[C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)c5ccccc5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)c4ccccc4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-benzenesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 13) and 3-chlorophenylboronic acid to afford the desired product as a light brown foam (47%). MS (ISP): 634.3 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[C:73]2[C:78]=1[CH:77]=[N:76][C:75]([NH:79]C(=O)OC(C)(C)C)=[CH:74]2>C1COCC1>[NH2:79][C:75]1[N:76]=[CH:77][C:78]2[C:73]([CH:74]=1)=[CH:72][CH:71]=[CH:70][C:69]=2[CH2:68][N:14]1[C:13]2[CH:18]=[C:19]([F:20])[C:10]([S:7]([NH:6][C:21]3[S:25][N:24]=[CH:23][N:22]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[O:16][C:15]1=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1cc2cccc(CO)c2cn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3, 50 mg, 0.107 mmol), (E)-di-tert-butyl diazene-1,2-dicarboxylate (49.4 mg, 0.214 mmol) and triphenylphosphine (56.2 mg, 0.214 mmol) were added to a 5 mL RB flask. Then THF was added and r×n mixture was stirred at 0° C. for 10 min before addition of tert-butyl (8-(hydroxymethyl)isoquinolin-3-yl)carbamate (29.4 mg, 0.107 mmol) in THF. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 27-5. 1H NMR δ (ppm)(DMSO-d6): 9.08 (1H, s), 7.65 (1H, d, J=5.39 Hz), 7.47 (1H, d, J=8.47 Hz), 7.34-7.26 (2H, m), 6.92 (1H, d, J=7.03 Hz), 6.65 (1H, s), 5.50 (2H, s). HRMS [M+H]C19H13FN6O4S2 calc'd 473.0496. Found 473.0499.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O:30][CH:31]([CH2:36][O:37][N+:38]([O-:40])=[O:39])[CH2:32][CH2:33][CH2:34]O)([O-:29])=[O:28].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:34][CH2:33][CH2:32][CH:31]([O:30][N+:27]([O-:29])=[O:28])[CH2:36][O:37][N+:38]([O-:40])=[O:39])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])OCC(CCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution of 1.72 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of CH2Cl2 at 0° C. was added 1.06 g of 4,5-bis(nitrooxy)pentyl alcohol, 225 mg of DMAP and 970 mg of EDCI. The mixture was stirred at RT for 2 h then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with NaHCO3 sat., brine and dried over sodium sulfate. Purification by flash chromatography afforded 1 g of the titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.43 (d, 2H), 7.18-7.16 (m, 3H), 7.08 (dd, 2H), 5.53-5.50 (m, 1H), 5.20 (s, 1H), 4.97 (dd, 1H), 4.69 (dd, 1H), 4.31 (m, 2H), 3.05 (s, 2H), 1.89 (m, 7H).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH2:16])=[O:15])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=1.[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26]([NH:1][C@H:2]([C:14]([NH2:16])=[O:15])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:11])[CH3:12])[CH:5]=1)=[O:27])[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CC(C)(C)c1cccc(C[C@H](N)C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@@H](Cc1cccc(C(C)(C)C)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 205 mg (0.932 mmol) of Phe(3-tBu)-NH2, 351 mg (1.21 mmol) of Boc-Cha-OH, 164 mg (1.21 mmol) of HOBT and 148 mg (1.21 mmol) of DMAP in 4 ml of DMF, 232 mg (1.21 mmol) of WSCI.HCl was added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=2:1) to give Boc-Cha-Phe(3-tBu)-NH2 in the amount of 326 mg (74%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[NH:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[NH:7][C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[Cl:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14](=[NH:15])[C:13]2[C:8](=[C:9]([Cl:21])[CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[NH:7][C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=N
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)[nH]c2c(Cl)cc(OC)c(OC)c2c1=N

Procedure:
A solution of 0.5 g (1.77 mmol) of 3-butyl-5,6-dimethoxy-4-imino-2(1H)quinazolinone and N-chlorosuccinimide (0.45 g, 3.35 mmol) in 100 ml of CHCl3 was heated at reflux for 18 hours. The reaction mixture was cooled, washed with 10% aqueous sodium thiosulfate (3×35 ml), dried with anhydrous MgSO4 and evaporated to give the crude product as an orange-brown solid. Recrystallization from 2-propanol afforded the desired product in analytical purity; yield 0.30 g (54.5%) mp 155°-157°.
Reaction SMILES: C([O:3][C:4](=[O:28])[C@H:5]([CH2:24][CH2:25][S:26][CH3:27])[NH:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])C.OCC1C=CC(C(O)=O)=C(C2C=CC=CC=2)C=1.Cl.[NH2:47][C@@H:48]([CH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH2:49]O.C(N(C(C)C)CC)(C)C.C([BH3-])#N.[Na+].BrC1(C)C(O)=CC=CC1.Cl.C(O)C>C1(C)C=CC=CC=1.C(O)C>[OH:15][CH:14]([NH:47][CH:48]([CH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH3:49])[C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:28])[CH2:24][CH2:25][S:26][CH3:27])=[O:23])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:10]=1
Reactant: CCOC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: N[C@H](CO)CC1CCCCC1
Agent: CC1(Br)CC=CC=C1O
Agent: Cl
Agent: O=C(O)c1ccc(CO)cc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSCC[C@H](NC(=O)c1ccc(C(O)NC(C)CC2CCCCC2)cc1-c1ccccc1C)C(=O)O
Temperature: 25 °C
Yield: 106.4 %

Procedure:
A mixture of [4-formyl-2-(2-methylphenyl)benzoyl]methionine ethyl ester (614 mg, 1.54 mmol), prepared according to Example 158F except substituting [4-hydroxmethyl-2-(2-methylphenyl)benzoic acid for 4-hydroxymethyl-2-phenylbenzoic acid in Example 158E, (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (357 mg, 1.84 mmol) and diisopropylethylamine (0.135 mL, 0.77 mmol) in toluene was refluxed for 5 hours using a Dean-Stark apparatus. The reaction mixture was cooled to ambient temperature and diluted with ethanol. Sodium cyanoborohydride (145 mg) and o-bromocresol green was added. The reaction mixture was stirred while acidity was maintained using HCl-ethanol. The reaction was quenched with saturated aqueous potassium carbonate and the mixture was extracted with dichloromethane (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (5% methanol-chloroform) gave the desired compound (840 mg).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)([CH3:3])[CH3:2].CC1C=CC(C(O[C@H](C(O)=O)[C@H](OC(C2C=CC(C)=CC=2)=O)C(O)=O)=O)=CC=1.C(O)C.CC(C)=O>CCOCC.[OH-].[K+]>[CH:1]([NH:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: COc1cccc2c1CC(NC(C)C)CO2
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cccc2c1C[C@@H](NC(C)C)CO2
Temperature: 20 °C
Yield: 32 %

Procedure:
The racemic 3-(N-isopropylamino)-5-methoxychroman (IV; 54 g, 0.224 mol) was mixed with an equimolar amount of (+)-di-1,4-toluoyl-D-tartaric acid (98.6 g, 0.244 mol). The mixture was dissolved in boiling ethanol (170 mL)/acetone (70 mL). The salt started to crystallize in the hot solvent mixture but was not filtered off until the solvent had cooled down to room temperature (20° C.). The salt was then recrystallized nine times from ethanol/acetone (1:5) to give the pure diastereomeric salt. Yield: 35% (54 g) (99% e.e). Mp: 166°-168° C. The free enantiomer as the base (R)-3-(N-isopropylamino)-5-methoxychroman was obtained by the extraction of the salt in ether/KOH (1M). Yield: 32%, 17.5 g,
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][C:8]=1[NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH3:41])=[CH:35][CH:34]=2)=[O:30])(=O)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH2:21]([O:20][C:18]([NH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][CH2:5][OH:4])=[C:8]([NH:28][C:29]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][CH3:41])=[CH:35][CH:34]=3)=[O:30])[CH:9]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCOC(C)=O)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCO)cc2c1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.5 g, 0.91 mmol) in methanol: tetrahydrofuran=1:1 (10 mL) was added potassium carbonate (0.13 g, 0.91 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with AcOEt (100 mL) and washed with H2O (20 mL), saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a brown foam 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.42 g, 94%): mp 198° C. (decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 10.18 (s, 1H), 8.26 (d, 8.5, 1H), 7.97 (d, 8.5, 1H), 7.51 (t, 7.0, 1H), 7.43 (d, 8.5, 1H), 7.39 (d, 7.5, 2H), 7.33 (s, 1H), 7.31 (s, 1H), 7.28 (t, 7.5, 2H), 7.18 (t, 7.5, 1H), 7.11 (brs, 1H), 7.08 (d, 2.5, 1H), 6.91 (t, 6.0, 1H), 6.86 (dd, 9.0, 2.5, 1H), 6.81 (s, 1H), 5.35 (t, 4.5, 1H), 4.47 (d, 5.5, 2H), 3.76 (s, 3H), 3.69 (m, 2H), 3.11 (t, 6.0, 2H);); FABMS (NBA) m/z 465 (M−CO2+), IR (neat) νmax 3272, 2945, 2874, 1646, 1594, 1528, 1479, 1453, 1422, 1404, 1261, 1213, 1162, 1030, 841, 805, 758, 734, 699 cm−1.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH3:50][SH:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:50][S:51][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 56.1 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), methylmercaptan (15%, 0.51 g) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 6 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1 ml) was added to the solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.22 g, 54%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]2[C:12]([C:13]#[N:14])=[C:11]([F:15])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27](Cl)[C:26]([C:30]#[N:31])=[C:25]([CH3:32])[N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]3[C:12]([C:13]#[N:14])=[C:11]([F:15])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])[C:26]([C:30]#[N:31])=[C:25]([CH3:32])[N:24]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)c(C#N)c3n2-c2ccccn2)c1C#N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-((S)-1-aminoethyl)-5-fluoro-3-pyridin-2-yl-3H-benzoimidazole-4-carbonitrile (0.085 g, 0.240 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.057 g, 0.335 mmol) and DIPEA (0.17 mL, 0.960 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed microwave tube for 16 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to give 368 as an off white solid (0.064 g, 64%). LCMS (Method K): RT 2.87 min [M+H]+ 414.1. 1H NMR (DMSO, 400 MHz): δ 8.76-8.74 (1H, d), 8.02-7.97 (1H, t), 7.96-7.92 (1H, m), 7.58-7.54 (1H, m), 7.47-7.44 (1H, d), 7.15-7.10 (1H, t), 6.06-6.02 (1H, d), 5.42-5.35 (1H, m), 5.15-5.11 (2H, s), 2.32 (3H, s), 1.61-1.59 (3H, d)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][N:22]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
A solution of N-t-butoxycarbonyl-4(R)-t-butyldimethylsilyloxy-2(S)-azidomethylpyrrolidine (9.06 g, 25.39 mmol) in EtOAc (120 ml) was purged with argon and 10% palladium on carbon (1.05 g) added. The flask was evacuated and stirred under an atmosphere of hydrogen (49 psi) for 16 hrs. The hydrogen was replaced by argon, the catalyst removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed (SiO2, 2.5 to 5% saturated NH4OH in acetonitrile, gradient elution), to afford the title compound as an oil.
Reaction SMILES: [CH3:1][Al](C)C.[C:5](=[C:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][C:9]1=[O:15])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:5]([CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][C:9]1=[O:15])([CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)=C1CCC(C)CC1=O
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
28.5 ml (33 mmol) of trimethyl aluminum as 10% solution in toluene is instilled in 4.56 g (30 mmol) of 2-isopropylidene-5-methyl-cyclohexan-1-one (pulegon) and 214.5 mg (1.5 mmol) of CuBr in 30 ml of ethyl acetate. The reaction solution is stirred 1 hour more at 25° C. 2 ml of water is carefully added for hydrolysis and stirred for 15 minutes more. The inorganic solid is suctioned off, washed again with ethyl acetate and the solution is concentrated by evaporation in a vacuum. Distillation of the crude product at 120° C./6 torr yields 3.4 g of 2-tert-butyl-5-methyl-cyclohexanone (70% of theory) as isomer mixture.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([NH:15][O:16][C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]([O:26][C:27](OC3C=CC=CC=3)=[O:28])[N:11]=[C:10]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:9]=2[CH:42]=1.O>CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:13]([NH:15][O:16][C:17](=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]([O:26][C:27](=[O:28])[N:2]([CH3:3])[CH3:1])[N:11]=[C:10]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:9]=2[CH:42]=1
Reactant: O=C(Nc1ccccc1)ONC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1OC(=O)Oc1ccccc1
Reactant: CNC
Solvent: CO
Solvent: O
Product: CN(C)C(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NOC(=O)Nc1ccccc1

Procedure:
5 ml of a solution of dimethylamine in methanol (content 30 g of dimethylamine in 100 ml) are added to 0.5 g of 7-chloro-5-phenyl-2-phenylcarbamoyloxyamino-3-phenyloxycarbonyloxy-3H-1,4-benzodiazepine in 10 ml of methanol, whilst stirring. The mixture is stirred for 5 hours at room temperature and water is added to it; the residue is filtered off and dried.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and 2-chloropyridine-4-boronic acid to afford the desired product as a light-brown solid (32%). MS (ISP): 573.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(Br)cc1
Yield: 100 %

Procedure:
The title compound was prepared in substantially the same way as intermediate (iv) by coupling of tetrahydropyran-4-yl amine with 4-bromobenzoic acid to give 0.65 g (100% yield) as white solid.