Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl indole-4-carboxylate (402 mg, 2.30 mmol) in DMF (5 mL) was cooled with an ice/water bath and treated with NaH (100 mg, 2.5 mmol, 60% in mineral oil). The resulting yellow solution was allowed to stir at 0° C. for 30 min., then a solution of MeI (482 mg, 212 μL, 3.4 mmol) in DMF (3.5 mL) was added dropwise. The solution was allowed to warm to ambient temperature. The reaction was quenched at 0° C. with saturated aqueous NH4Cl and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl (N-methyl)-indole-4-carboxylate as a yellow oil, 430 mg (99%). The N-methyl carboxy indole was converted into the N-methyl-[5,6,7]-tricyclic indole in a manner similar to that described for Compound (10) to give 1-N-methyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a shiny white solid, 256 mg (54%, after recrystallization (CH2Cl2/MeOH/hexanes)). mp 194-195° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.96 (m, 2H), 3.43 (m, 2H), 3.82 (s, 3H), 7.29 (m, 2H), 7.64 (d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=7.7 Hz), 8.09 (br t, 1H); HRMS (FAB, MH+) Calcd for C12H13N2O: 201.1028, Found: 201.1020; Anal. (C12H12N2O.0.2H2O) C, H, N.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:18][CH:17]=1>C(#N)C.S(Cl)(Cl)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
A mixture of diethyl malonate (3 g, 16 mmol) in 50 mL ACN was stirred at 0° C., was treated with MgCl2 (2 g, 18 mmol) in one portion, and was treated dropwise with TEA (3 g, 33 mmol). The mixture was stirred at room temperature for 2.5 hours. A mixture of 2-(4-fluorophenyl)-2-methylpropanoic acid (3 g, 16 mmol) in thionyl chloride (20 mL) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN, and was added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours. The resulting mixture was then cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5 g of the product as pale yellow oil. MS m/e=325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:22]([C@H:21]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:15][CH:14]=1)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CO)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(COS(C)(=O)=O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R)-2-[N-(4-chloro-benzenesulfonyl)-N-(4-hydroxymethyl-benzyl)amino]-4-methyl-pentanoic acid amide (1.5 g, 3.5 mmol) in CH2Cl2 (15 mL) cooled to 0° C. was added Et3N (0.74 mL, 5.3 mmol). A solution of methanesulfonyl chloride (0.29 mL, 3.5 mmol) in 5 mL CH2Cl2 was added dropwise and the reaction was allowed to stir at 0° C. for 1 h. The reaction mixture was diluted with 25 mL CH2Cl2, quickly washed with 1 N HCl, brine, and dried by passing the organic phase through a cotton plug. The solvent was removed in vacuo affording the title compound in quantitative yield. The resulting foam was used as is in subsequent reactions. MS (EST), (M-95)+, 409.15 1H NMR (CDCl3) δ 7.70 (d, 2H, J=8.0), 7.48 (d, 2H, J=8.0), 7.41 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 6.27 (br s, 1H), 5.32 (br s, 1H), 5.24 (s, 2H), 4.64 (d, 1H, Jab=16), 4.43 (d, 1H, Jab=16), 4.33 (t, 1H, J=6), 2.90 (s, 3H), 1.90 (m, 1H), 1.60 (m, 2H), 0.96 (d, 3H, J=7.0), 0.91 (d, 3H, J=7.0)
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:55]=[CH:54][C:51]([CH:52]=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:52]([C:51]2[CH:50]=[CH:49][C:48]([O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])=[CH:55][CH:54]=2)[OH:53])=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)cc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithium in hexane (1.59M, 2.83 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde (977 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)-ethyl]amino]ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]-oxy]phenyl]methanol (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:70]=[CH:69][C:68]([CH2:71][NH:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:67][CH:66]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C(N(CC)CC)C>CN(C=O)C>[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[CH:67][C:68]([CH2:71][N:72]([CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:19](=[O:20])[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)nc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared using General Procedure 6: To a stirred solution of 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinic acid INT-15 (20 mg, 0.05 mmol) in DMF (1 mL) was added HATU (22.5 mg, 0.06 mmol). After stirring for 1 h at room temperature, 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)phenyl 4-(heptyloxy)benzoate INT-13 (30.8 mg, 0.06 mmol) was added followed by triethylamine (11.4 mg, 0.11 mmol). The reaction mixture was allowed to stir at room temperature overnight. The final product was isolated by HPLC purification to give 4-((N-(2-(tert-butoxy)-2-oxoethyl)-5-(2-(4-methoxy-2(trifluoromethyl)phenyl)acetamido)picolinamido)methyl)phenyl 4-(heptyloxy)benzoate INT-16. LCMS-ESI (m/z) calculated for C43H48F3N3O8: 792; no m/z observed, tR=4.11 min (Method 7).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=[C:6]2[O:5][N:4]=1)[CH3:2].C(C1OC2C(=C(O)C=CC=2)N=1)C.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[C:7]2[C:8]([O:12][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=3)=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCc1noc2cccc(O)c12
Agent: CCc1nc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Temperature: 110 °C

Procedure:
A mixture of 3-ethyl-1,2-benzisoxazol-4-ol and 2-ethyl-1,3-benzoxazol-4-ol (Intermediate 31, 38 mg), was dissolved in DMF (3.0 mL) and 2-chloro-5-nitropyridine (36.9 mg, 0.23 mmol) was added, followed by potassium carbonate (97 mg, 0.70 mmol). The reaction mixture was heated under microwave irradiation at 110° C. for 1 hour. After removal of the volatiles, the crude was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 1/0 to 1/1) to afford the title compound (9.5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(O)(=O)C(C)C>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:25]3[N:21]([CH3:20])[N:22]=[CH:23][C:24]=3[CH3:26])[CH:3]=1)[CH2:17][CH2:16]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(Br)c1
Reactant: Cc1cnn(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(C)C(=O)O
Product: Cc1cnn(C)c1-c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 100 °C
Yield: 9.9 %

Procedure:
To a stirred solution of 2-(5-bromo-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (example 7) (80 mg, 0.25 mmol) and 1,4-dimethyl-1H-pyrazole (23 mg, 0.25 mmol) in NMP (2.0 mL) were added Pd(OAc)2 (2.0 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (DavePhos) (6.3 mg, 0.016 mmol), Bu4NOAc (153 mg, 0.5 mmol) and isobutyric acid (0.085 mL, 0.08 mmol). The resulting reaction mixture was heated to 100° C. for 6 hours before it was poured into H2O (25 mL) and extracted with EtOAc (2×90 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (8.7 mg, 9.9%) as a yellow solid. MS: 353.1 (M+H+).
Reaction SMILES: [CH3:1][I:2].[CH3:3][N:4]([CH3:19])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[C:15]([NH2:16])=[N:14][C:13]([NH2:17])=[C:12]([Cl:18])[N:11]=1)=[O:9]>C(Cl)Cl>[I-:2].[NH2:16][C:15]1[C:10]([C:8]([NH:7][CH2:6][CH2:5][N+:4]([CH3:1])([CH3:19])[CH3:3])=[O:9])=[N:11][C:12]([Cl:18])=[C:13]([NH2:17])[N:14]=1
Reactant: CI
Reactant: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: ClCCl
Product: C[N+](C)(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Product: [I-]

Procedure:
Methyl iodide (120 μL, 1.9 mmol) is added to a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (2-dimethylamino-ethyl)-amide (Intermediate H) (100 mg, 0.39 mmol) in DCM (4 mL), and the resultant solution is stirred at RT for 2 h. The white solid which has formed is collected by filtration and washed with DCM (5 mL) to afford the title compound. M+ 273. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (1H, t), 7.09 (2H, br s), 3.61 (2H, m), 3.45 (2H, t), 3.11 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)nc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cnc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a solution 2-chloropyrimidine-5-carboxylic acid (1.63 g, 10.28 mmol) in a mixture of methanol (20 ml) and benzene (50 ml) was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 10 ml) at room temperature. The mixture was stirred for 30 min, and then was concentrated to give the title compound (1.77 g) as a yellow solid. Mass spectrum (ESI) 173.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.18 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[N:24]1[CH:28]=[N:27][N:26]=[N:25]1)=[O:11])=O)(C)(C)C.[ClH:32]>CCOC(C)=O>[Cl:32][C:18]1[CH:17]=[CH:16][C:15]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:14]([CH:19]=1)[CH2:13][NH:12][C:10](=[O:11])[C@@H:9]1[CH2:29][CH2:30][CH2:31][NH:8]1.[N:24]1([C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[CH2:13][NH:12][C:10](=[O:11])[C@@H:9]2[CH2:29][CH2:30][CH2:31][NH:8]2)[CH:28]=[N:27][N:26]=[N:25]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Solvent: CCOC(C)=O
Product: O=C(NCc1cc(C(F)(F)F)ccc1-n1cnnn1)[C@@H]1CCCN1
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, cold (0° C.) solution of 1-(tert-butoxycarbonyl)-N-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)benzyl]-L-prolinamide (92 mg, 0.209 mmol) in EtOAc (1 mL) was added a freshly-prepared, saturated solution of HCl in EtOAc (6 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue azeotroped with diethyl ether to afford the hydrochloride salt of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.66 (s, 1H), 8.83 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1 H), 4.66–4.40 (m, 2H), 4.20 (apparent t, J=8.0 Hz, 1H), 3.40–3.35 (m, 2H), 2.41–2.33 (m, 1H), 2.06–1.88 (m, 3H). LCMS (M+H): 341.1.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:18]=1.O>O1CCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:25]=2)[CH:18]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
In 6 ml of anhydrous tetrahydrofuran was suspended 700 mg of sodium hydride (purity: 50%), and into the suspension was dropped a mixture of 3.65 g of ethyl diethylphosphonoacetate and 3 ml of anhydrous tetrahydrofuran at a temperature of 30° to 35° C., after which the resulting mixture was subjected to reaction at room temperature for one hour. To the reaction mixture was added dropwise a mixture of 3.0 g of 4-(pyridin-3-yloxy)benzaldehyde and 3 ml of anhydrous tetrahydrofuran at room temperature, and the temperature thereof was gradually elevated. The mixture was subjected to reaction at 60° C. for 15 minutes. Subsequently, the reaction mixture was cooled to room temperature, and 20 ml of water was added to the mixture, after which the resulting mixture was subjected to extraction with 20 ml of ethyl acetate. The extract was washed with 10 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-20, eluant: chloroform], to obtain 3.64 g (yield 89.8%) of colorless, oily ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:19][C:20]1([CH3:37])[O:24][C@@H:23]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:25][C@H:23]4[CH2:22][O:21][C:20]([CH3:37])([CH3:19])[O:24]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(O)cc2CCc2cc(Cl)ccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Cl)ccc2C3=O)O1

Procedure:
For the preparation of the title compound, 0.50 g (1.9 mmol) of 2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g (2.6 mmol) of (R)-toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) of K2CO3 in 10 ml of dry DMF are reacted by method M. C21H21ClO4 (Mr=372.85)
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:16])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(NC(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of m-phenylenediamine (2.00 g), cyclohexanecarboxylic acid (2.37 g), HOBt (2.75 g) and EDCI (3.9 g) in DMF (20 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2 v/v) to give N-(3-aminophenyl)cyclohexanecarboxamide (2.2 g) as a white powder.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:41](O)C>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:34][CH2:35][CH3:41])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1

Procedure:
Prepared analogously to Example 7 by reacting methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate with sodium hydroxide in ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N:19]1([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:2]([N:22]1[CH2:21][CH2:20][N:19]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23]1)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Acetone (1.95 g) and NaBH(OAc)3 (7.12 g) were added to a solution of 3-piperazin-1-yl-phenol (2.00 g) in THF (40 ml), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and filtered to give the titled compound (1.48 g, colorless powder).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([Br:10])[C:6](N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:10][C:8]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Dissolve 4-ethyl-2-nitro-6-bromoaniline (6.62g, 27mmol) in ethanol (40mL). Add, by dropwise addition, concentrated sulfuric acid (5mL) and heat at reflux, adding sodium nitrite (4.55g, mmol) in small portions over 25 minutes. Stir at room temperature for several hours, pour onto ice and extract into ethyl acetate. Wash with water (3×) and brine (3×). Dry (MgSO4) and evaporate the solvent in vacuo and purify by silica gel chromatography to give 3-bromo-5-ethylnitrobenzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:45])[CH2:22][C@H:23]([NH:37]C(=O)OC(C)(C)C)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH2:16]1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[NH2:37][C@@H:23]([CH2:22][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:16]1)=[O:45])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])=[CH:27][CH:26]=1.[C:48]([OH:50])([C:47]([F:52])([F:51])[F:46])=[O:49]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(N4CCCC4=O)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(N4CCCC4=O)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(tert-Butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxo-1-(4-(2-oxopyrrolidin-1-yl)phenyl)butan-2-ylcarbamate (104A) was dissolved in 25% trifluoroacetic acid and stirred at room temperature for 3 hrs. Solvent was removed under vacuum and the residue was purified by preparatory LC/MS (15-40% CH3CN in H2O) to give the product 1-(4-((R)-2-amino-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)phenyl)pyrrolidin-2-one (209) as a TFA salt (8 mg, 17% yield). ESI-MS:m/z 518.2 (M+H)+.