Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(O)CCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 825 mg, 2.50 mmol) was suspended in methylene chloride (12.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.25 mL, 2.5 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (582 μL, 5.00 mmol) was added. The reaction continued to stir at 0° C. for 10 min. 4-(3-Amino-pyrazol-1-yl)-2-methyl-butan-2-ol (424 mg, 2.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to the reaction. The reaction continued to stir at 0° C. for 10 min. The reaction was diluted with methylene chloride (50 mL), washed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyl)-1H-pyrazol-3-yl]-propionamide (653 mg, 54%) as a white foamy solid: ESI-LRMS m/e calcd for C23H32ClN3O4S [M+] 481.18, found 482.35 [M+H+], 464.22 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.23 (m, 2H, CH2), 1.29 (s, 6H, 2×CH3), 1.46-1.94 (m, 8H, 4×CH2), 1.94-2.04 (m, 2 H, CH2), 2.18-2.29 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 3.00-4.25 (m, 2H, NCH2), 6.65 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.61 (d, Jm=1.7 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:19][CH2:18]2)[N:13]=1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[CH:17]1([C:14]2[N:13]=[C:12]([CH2:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:25]3[CH:24]=[CH:23][C:22]([C:36]4[CH:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=4)=[C:21]([F:20])[CH:26]=3)(=[O:10])=[O:9])[O:16][N:15]=2)[CH2:19][CH2:18]1
Reactant: O=S(=O)(Cc1nc(C2CC2)no1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)Cc3nc(C4CC4)no3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-(((2-bromophenyl)sulfonyl)methyl)-3-cyclopropyl-1,2,4-oxadiazole and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18FN5O3S, 451.11; m/z found, 452.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.77 (dd, J=8.2, 6.9, 1H), 7.67-7.61 (m, 1H), 7.61-7.57 (m, 1H), 7.52-7.46 (d, J=7.6, 1H), 7.39-7.35 (dd, J=7.9, 1.6, 1H), 7.35-7.31 (m, 1H), 2.05-1.94 (m, 1H), 1.04-0.94 (m, 1H), 0.79-0.72 (m, 1H).
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17](=[O:30])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S-:31][CH2:32][CH3:33].[Na+]>C(O)C>[CH2:32]([S:31][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17](=[O:30])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:33]
Reactant: CC[S-]
Reactant: CCOC(=O)C(Br)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)SCC
Yield: 353.2 %

Procedure:
Ethyl 2-bromo-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate (1.00 g, 2.05 mmol; Example 37) and 56 ml of ethanol were mixed and, after sodium thioethoxide (268 mg, 2.55 mmol) was added under stirring, the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated, water was added, and the solution was extracted with ethyl acetate. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=2:1 v/v) to obtain 3.4 g (43%) of the title compound as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([O:42]C4CCCCO4)[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1>O1CCOCC1.C(Cl)Cl.O>[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:23])=[O:24])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)-pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (450 mg, 0.66 mmol) in 1,4-dioxane:DCM:water (2:2:1, 5 mL) at room temperature. After 1 h, the reaction was concentrated under reduced pressure. The crude residue was triturated in ethanol (10 mL) overnight. The solid was collected via filtration, washed with ethanol (5 mL), and dried under reduced pressure to afford the title compound as a white solid (110 mg, 33%). MS (LCMS) m/z 511.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.19 (m, 4H) 1.54 (s, 3H) 1.58-1.72 (m, 1H) 1.72-1.89 (m, 4H) 2.04-2.23 (m, 1H) 2.41 (m, 1H) 3.08 (s, 3H) 3.18-3.40 (m, 1H) 3.65-3.84 (m, 3H) 4.01 (td, J=11.61, 4.88 Hz, 1H) 4.49 (br. s., 1H) 6.45 (d, J=7.81 Hz, 1H) 6.94-7.06 (m, 2H) 7.36-7.54 (m, 2H) 7.96 (d, J=6.83 Hz, 1H) 9.21 (s, 1H) 11.07 (s, 1H) 11.12 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:43])=[O:2])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (49 mg, 0.078 mmol) in THF (3 mL) was added LiOH monohydrate (14 mg, 0.326 mmol) in water (2 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenyl)-propionic acid as a white solid (35 mg, 73%). MS (ES+) m/z [(M+H)+]: 612
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11](Cl)=[O:12])[CH:2]=[CH2:3].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][C:11]([CH:5]1[CH2:6][CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)=[O:12]
Reactant: CN
Reactant: C=CCC12C=CC(CC1C(=O)Cl)C2
Solvent: CCOCC
Product: C=CCC12C=CC(CC1C(=O)NC)C2
Reaction time: 1 h

Procedure:
With cooling, 9.8 g of allylbicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise to 50 ml of a 40% aqueous methylamine solution. After 1 hour at 20° C., 100 ml of ether are added. The organic phase is separated, and working up is effected as described in Example 4, affording 8.0 g (84% of theory) of a yellow liquid. For the purpose of characterisation, a sample is distilled in a bulb tube; nD20 =1.5160; η25 =420 mPas.
Reaction SMILES: C([O:8][C:9]1[CH:56]=[CH:55][CH:54]=[CH:53][C:10]=1[CH2:11][S:12]([NH:15][CH2:16][CH2:17][C:18]1[N:19]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)=[CH:24][C:23]([Cl:39])=[CH:22][CH:21]=2)(=[O:14])=[O:13])C1C=CC=CC=1.[CH2:57]1COCC1>[Pd].CO>[CH3:57][O:36][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH2:28][CH2:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:39])[CH:24]=3)[N:19]([CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:18]=2[CH2:17][CH2:16][NH:15][S:12]([CH2:11][C:10]2[CH:53]=[CH:54][CH:55]=[CH:56][C:9]=2[OH:8])(=[O:13])=[O:14])=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To 4-{2-[2-[2-({[2-(benzyloxy)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid (Step 9, Example 1, 109 mg, 0.14 mmol) was added THF and MeOH. 10% of Pd/C (11 mg) was added. The mixture was stirred at room temperature under H2 (1 atm) overnight and filtered through celite, concentrated, and column chromatographed (35% EtOAc/hex) to give 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-hydroxy-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid methyl ester (74 mg, 76%), an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[S:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:8][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[CH3:10]
Reactant: Cc1nsc(C)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(C)c1CO

Procedure:
3,5-Dimethyl-4-isothiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 4-hydroxymethyl-3,5-dimethylisothiazole. Treating this hydroxymethyl compound with thionyl bromide gives 4-bromomethyl-3,5-dimethylisothiazole which is used as the starting material in the procedure of Example 121 to give N-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-isothiazolyl)methylthio)ethyl]guanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:15][C@H:16]1[CH2:19][CH2:18][N:17]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:16]1[CH2:15][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1cncc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF was added KOH (0.2 g, 3.8 mmol) at room temperature. 1-t-Butoxycarbonyl-2-(R)-azetidinylmethyl tosylate (0.8 g, 2.4 mmol, from example 10d) was then added, and the reaction mixture was stirred at 80° C. for 16 hours. The DMF was removed by washing with H2O/brine (1:1) in EtOAc. The organic layer was dried, concentrated and chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (0.6 g, 87%): 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.21-2.40 (m, 2H), 3.89 (t, 2H, J=8 Hz), 4.12 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 7.29 (m, 1H), 8.20 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=3 Hz); MS (CI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH:5]=[C:6]1[C:15]2[C:10](=[C:11]([F:16])[CH:12]=[CH:13][CH:14]=2)[N:9]([C:17](=[O:43])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH2:32][N:31]4[CH:39]=[CH:40][CH:41]=[C:30]4[CH2:29]3)=[O:27])=[CH:22][C:21]=2[CH3:42])[CH2:8][CH2:7]1)[CH3:2].C(OC(=O)CC1C2C(=C(F)C=CC=2)N(C(=O)NCC2C=CC(C(N3C4C=CC=CC=4CN4C=CC=C4C3)=O)=CC=2C)CC=1)C>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([F:16])[CH:12]=[CH:13][CH:14]=2)[N:9]([C:17](=[O:43])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH2:32][N:31]4[CH:39]=[CH:40][CH:41]=[C:30]4[CH2:29]3)=[O:27])=[CH:22][C:21]=2[CH3:42])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)NCc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)c2c(F)cccc21
Agent: [Pd]
Agent: CCOC(=O)CC1=CCN(C(=O)NCc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)c2c(F)cccc21
Solvent: CO
Product: CCOC(=O)CC1CCN(C(=O)NCc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)c2c(F)cccc21
Reaction time: 6 h

Procedure:
A mixture (75 mg, 0.13 mmol) of {1-[4-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methylbenzylcarbamoyl]-8-fluoro-2,3-dihydro-1H-quinolin-4-ylidene}acetic acid ethyl ester from Example 4 and {1-[4-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methyl-benzylcarbamoyl]-8-fluoro-1,2-dihydroquinolin-4-yl]acetic acid ethyl ester from Example 5 was dissolved in methanol (50 ml). To the solution was added a catalytic amount of 10% palladium on carbon and the mixture was stirred under a hydrogen atmosphere for 6 h. The mixture was filtered through Celite® and evaporated. The mixture was redissolved in methanol (50 ml), a further catalytic amount of 10% palladium on carbon was added and the mixture stirred under a hydrogen atmosphere for 3 h. The mixture was filtered and evaporated to give a white solid, yield 74 mg (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27]([O-])([O-])=O.[Cs+].[Cs+].Cl>O.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:27])[C:12]2[C:13](=[O:23])[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2ccccc2oc2cc(OCc3ccccc3)cc(O)c12
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)cc2oc3ccccc3c(=O)c12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
The compound (0.40 g, 1.26 mmol) prepared in Step 1 of Example 9, methyl iodide (535.68 mg, 3.77 mmol), and DMF (10 mL) were charged to a dry round-bottom flask, and Cs2CO3 (0.82 g, 2.52 mmol) was added thereto with stirring. The reaction mixture was stirred at 50° C. for 3 hours. After the reaction was completed, the reaction liquid was transferred to an Erlenmeyer flask, and the reaction container was washed with methylene chloride. The reaction contents were combined and acidified with 2M-HCl on ice water. After being warmed to room temperature, CH2Cl2 (20 mL) and water (10 mL) were added and the reaction liquid was repeatedly extracted with methylene chloride. The organic layer was combined, washed with water and brine, and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Ethanol was added to the resulting sludge-like material, followed by trituration, and the resulting solid was filtered to give a white solid compound (0.41 g, 97.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH2:16][C:17]#[N:18])=[CH:5][CH:4]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C(OCC)(=O)C>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][C:16]([C:17]#[N:18])([C:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CC#N)c2c1oc1ccccc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2oc3ccccc3c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of (4-methoxy-dibenzofuran-1-yl)-acetonitrile (7 g, 0.029 mol) in acetonitrile (200 ml), Triton B (2.7 ml, 0.0147 mol) was added under N2 at RT. The reaction mass was heated to reflux and at reflux temperature methyl acrylate (28.25 ml, 0.295 mol) was added drop wise. The reaction mass was stirred for 4 hrs at 90° C. Once the product is formed, the reaction mass was diluted with ethyl acetate and concentrated under vacuum. 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-heptane dioic acid dimethyl ester was isolated by column chromatography. Yield 8 g (65%)
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[O:33])[CH2:26][CH2:25]3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]([C:22]([CH:24]3[CH2:25][CH2:26][CH:27]([CH2:30][NH:31][C:32]([CH:34]4[CH2:35][CH2:36][N:37]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:38][CH2:39]4)=[O:33])[CH2:28][CH2:29]3)=[O:23])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)C1CCC(CNC(=O)C3CCNCC3)CC1)C2
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN1CCC(C(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of piperidine-4-carboxylic acid [4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-amide hydrochloride (Compound number 238) (2.43 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=507.4
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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]>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:9])=[CH:11]1
Reactant: Cc1ccccc1Br
Reactant: Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1cc(C)c2ccccc21
Reaction time: 12 h
Yield: 88.1 %

Procedure:
The above general procedure was followed using 2-bromotoluene (205 mg, 1.20 mmol), 3-methylindole (131 mg, 1.00 mmol), 3 mo % Pd(dba)2, 2.4 mol % tri-t-butylphosphine, and cesium carbonate (1.70 mmol) in 1.0 mL of toluene. After 12 hours at 100° C., the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 195 mg (88%) of N-(2-methylphenyl)-3-methylindole. 1H NMR (300 MHz, CDCl3) δ 7.76 (m, 1H), 7.46 (m, 2H), 7.40 (m, 2H), 7.28 (m, 2H), 7.15 (m, 1H), 7.06 (s, 1H), 2.53 (S, 3H), 2.21 (s, 3H). 13C NMR (76 MHz, CDCl3) δ 138.4, 137.1, 135.7, 131.1, 128.6, 128.1, 127.8, 126.6, 126.2, 121.9, 119.3, 118.9, 111.6, 110.4, 17.7, 9.6.
Reaction SMILES: C[Li].[CH3:3]C1(C)CCCC(C)(C)N1.[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([C:21]([CH3:3])=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCOc1ccc(C#N)c(F)c1OCC
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1cc(C)c(C#N)c(F)c1OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Under a stream of nitrogen gas, methyl lithium (1.03 M diethyl ether solution, 18.2 mL, 18.8 mmol) was added to an ice-cooled solution of 2,2,6,6-tetramethylpiperidine (3.16 mL, 18.7 mmol) in tetrahydrofuran (30 mL), followed by 30 minutes of stirring. After cooling the reaction system to −78° C., a solution of 3,4-diethoxy-2-fluorobenzonitrile (3.90 g, 18.6 mmol) in tetrahydrofuran (20 mL) was added dropwise, and 30 minutes later, methyl iodide (1.4 mL, 22.4 mmol) was added dropwise, followed by 2 hours of stirring. The reaction system was gradually warmed to room temperature, and 1N hydrochloric acid was added to the reaction solution, after which ethyl acetate extraction was performed. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 3.40 g of the subject compound (yield: 81.7%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH2:21][CH3:22]>C(OCC)(=O)C>[CH2:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCNc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A mixture of ethyl anthranilate (4.96 g, 30 mmol), potassium carbonate (13.8 g, 100 mmol), and n-butyl iodide (25 mL) was stirred at ambient temperature for 48 hours and refluxed for 8 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue obtained chromatographed eluting with ethyl acetate/hexane mixtures to afford the title comound as a light yellow liquid (2.2 g, 33%).