Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH2:7]([O:9][C:10]1[C:11]([B:19]2[O:23][C:22](C)(C)C(C)(C)[O:20]2)=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])C=O)[CH3:8].Cl>O.C1COCC1>[CH2:7]([O:9][C:10]1[C:11]2[B:19]([OH:20])[O:23][CH:22]([CH2:6][N+:3]([O-:5])=[O:4])[C:12]=2[CH:15]=[CH:16][C:17]=1[F:18])[CH3:8]
Reactant: C[N+](=O)[O-]
Reactant: CCOc1c(F)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(F)ccc2c1B(O)OC2C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a cooled solution of sodium hydroxide (80 mg, 2.0 mmol) in water (3.0 mL), nitromethane (244.0 mg, 4.0 mmol) was added at 0° C. and stirred for 10 min. Then 3-ethoxy-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (588.0 mg, 2.0 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at for 1 h at 0° C. and for 2 h at room temperature. The reaction mixture was acidified with 2.5 M HCl (1.0 mL) and the product was extracted with ethyl acetate (2×20 mL). The organic extracts were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and product was chromatographed on a column of silica gel(CH2Cl2:MeOH=95:5) to give the title compound as a solid (350 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (dd, J=11.3, 8.2 Hz, 1H), 7.16 (dd, J=8.0, 3.3 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.30 (dd, J=13.5, 2.2 Hz, 1H), 4.62 (dd, J=13.5, 9.2 Hz, 1H), 4.35 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS (ESI) m/z=254 (M−1, negative).
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[CH:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].ClC1C=CC=CC=1.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21](Cl)[CH:20]=1>[Cl-].[Zn+2].[Cl-].O>[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21]([C:8]2[C:6](=[O:7])[N:5]([CH3:11])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[CH3:10])[CH:20]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: Cc1cccc(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cccc(-c2c(C)n(C)c(=O)n(C)c2=O)c1
Reaction time: 3 h
Yield: 14 %

Procedure:
In a 100 mL round bottom flask equipped with a condenser and an air lock was placed compound 2 (see FIG. 3) (5.00 g, 32.4 mmol), anhydrous zinc chloride 3 (4.45 g, 32.6 mmol), dry chlorobenzene (20 mL) and m-tolyl chloride (4.6 mL, 5.38 g, 34.8 mmol). The reaction was brought to reflux in an oil bath and vigorously stirred for 3 h. After cooling, water (40 mL) was added through the condenser, dropwise at first and then with increasing speed. The condenser was then rearranged for distillation and the chlorobenzene was removed by azeotropic distillation. The solution was then cooled in an ice bath, and diethyl ether (30 mL) was added while stirring to give a precipitate. The precipitate was filtered and recrystallized from 2-propanol to yield 3d (1.11 g, 26.3%); m.p. 136.8-139° C. 1H NMR (600 MHz, CD2Cl2) δ 7.68-7.66 (m, 1H), 7.65-7.62 (m, 1H), 7.44-7.40 (m, 1H), 7.35 (t, J=7.6, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H). 13C NMR (151 MHz, CD2Cl2) δ 194.00, 161.07, 152.22, 151.98, 139.22, 138.16, 134.94, 130.03, 129.01, 126.93, 113.36, 32.36, 28.32, 21.54, 17.99. MS (ES+) (m/z): [M+1]+ calculated for C15H17N2O3, 273.12. found 237.10.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][N:17]=1>ClCCl>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:21])=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (100 mmol) and N,N′-diisopropylethyl amine (130 mmol) in dichloromethane (500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) was added dropwise under nitrogen. The solution was stirred for one hour as it returned to room temperature. The reaction mixture was filtered through a sica gel pad, washed with 0.5 N sodium hydroxide and water, dried over anhydrous magnesium sulfate. The solution was again filtered through a silica gel pad and evaporated to dryness in vacuo. The residual oil crystallized from diethyl ether to provide the title compound as a colorless crystalline solid, m.p. 165-167° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30]C(C)([O-])C.[K+].[O:36]=[C:37]1[NH:41][C:40](=[O:42])[CH:39]([CH2:43][C:44]2[CH:58]=[CH:57][C:47]([O:48][C:49]3[CH:56]=[CH:55][C:52](C=O)=[CH:51][CH:50]=3)=[CH:46][CH:45]=2)[S:38]1.C(O)(=O)C>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][C:52]2[CH:55]=[CH:56][C:49]([O:48][C:47]3[CH:57]=[CH:58][C:44]([CH2:43][CH:39]4[S:38][C:37](=[O:36])[NH:41][C:40]4=[O:42])=[CH:45][CH:46]=3)=[CH:50][CH:51]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C=Cc2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
To a suspension of 4-methoxybenzyltriphenylphosphonium chloride (419 mg, 1.0 mmol) in THF (10 mL) at 0° C. was added solid potassium tert-butoxide (224 mg, 2.0 mmol). The resultant orange-red solution was stirred for 15 min at 0° C. then cooled to −45° C. Solid compound 53 (327 mg, 1.0 mmol) was added and the reaction mixture stirred for 30 min at this temperature. To this pale yellow solution glacial acetic acid (60 μL, 1 mmol) was added and the solvent was removed in vacuo. The crude product was suspended in dichloromethane, adsorbed onto silica gel and purified by flash chromatography using hexanes-ethyl acetate (7:3) to yield a white solid (143 mg, 33%) after drying under high vacuum. 1H NMR: (400 MHz, DMSO-d6): δ 12.04 (bs, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.53 (d, J=12.4 Hz, 2H), 6.48 (d, J=12.0 Hz, 2H), 4.90 (dd, J=9.2 and 4.4 Hz, 1H), 3.36 (dd, J=14.0 and 4.4 Hz, 1H), 3.11 (dd, J=14.0 and 8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.[CH3:15][N:16]([CH3:35])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:28]=[C:29]([CH2:33]O)[CH:30]=[CH:31][CH:32]=2)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:35][N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=2)[CH2:33][N:8]2[C:7]3[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=3[S:10][C:9]2=[O:11])=[N:23][CH:22]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Reactant: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1cnc(-c2cccc(Cn3c(=O)sc4ccc(C(F)(F)F)cc43)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 114 mg (0.52 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one, 150 mg (0.52 mmol) of {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol and 261 mg (0.78 mmol) of polymer-bound triphenylphosphine (3mmol/g) is shaken at room temperature for 30 min. 178 mg (0.78 mmol) of di-tert-butyl azodicarboxylate are added to the suspension, and, after the mixture has been stirred at room temperature for 24 h, 50 mg (0.15 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 35 mg (0.15 mmol) of di-tert-butyl azodicarboxylate are again present and shaken at room temperature for 2 h. The reaction mixture is filtered, the filtrate is evaporated to dryness, and the residue is purified by means of preparative HPLC. The product is in the form of the trifluoroacetate; ESI: 489 (M+H); Rt.=2.81 min (method A);
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33].C(=O)([O-])O.[Na+].[ClH:42]>C(#N)C.CO>[ClH:42].[CH2:30]([NH:34][C:35](=[O:36])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: CCCCNC(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 38 %

Procedure:
A suspension of 2.00 g (0.0067 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 100 ml of acetonitrile was treated with 1.9 ml (0.013 mol) of triethylamine and 3.0 ml (0.027 mol) of butyl isocyanate. The mixture was boiled under reflux for 20 hours and then poured into aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. After drying the organic phase with sodium sulphate and distillation of the solvent the residue was chromatographed over silica gel with methylene chloride/methanol 20:1. The oil obtained was dissolved in methanol and treated with an equimolar amount of ethanolic HCl. After drying with sodium sulphate, concentration to a volume of about 30 ml and filtration there were obtained 1.11 g (38%) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl butylcarbamate hydrochloride with m.p. 192°-194°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1COCC1>[C:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11][C@@H:10]3[C:21](=[O:30])[N:22]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][C:24](=[O:25])[N:9]23)=[CH:4][CH:3]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(NC(C)=O)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 98 (0.2 g) in THF (15 mL) was added triethylamine (76 μL) and acetyl chloride (39 μL) and the resulting solution was stirred at room temperature for 2 hours. After evaporation of THF, the resulting residue was taken up in CH2Cl2 (100 mL), washed with water (2×50 mL) and dried over Na2SO4. After evaporation of CH2Cl2, the resulting solid was recrystallised from MeOH/H2O to give the title compound as a cream powder (120 mg) m.p.: 246° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:27]=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1)C2=O
Temperature: 150 °C
Yield: 67.8 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (762 mg, 4.01 mmol), cuprous iodide (153 mg, 0.802 mmol) and potassium carbonate (554 mg, 4.01 mmol) were deposited in a sealed type vessel. 6 mL DMSO and 1,3-dibromobenzene (1.89 g, 8.01 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (153 mg, 0.802 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 100% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (939 mg, 2.72 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:16]=[C:15]2[N:10]([C:11]([NH2:20])=[N:12][C:13]3[NH:19][CH:18]=[CH:17][C:14]=32)[N:9]=1.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[CH2:26][CH2:25]1.O>CN(C=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:16]=[C:15]2[N:10]([C:11]([NH2:20])=[N:12][C:13]3[N:19]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])[CH2:28][CH2:29]4)[CH:18]=[CH:17][C:14]=32)[N:9]=1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Nc1nc2[nH]ccc2c2nc(-c3ccco3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCn2ccc3c2nc(N)n2nc(-c4ccco4)nc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (13 mg, 0.32 mmol) in anhydrous DMF (2 mL) at 0° C. is added slowly a solution of the title B compound, 2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (60 mg, 0.25 mmol) in 2 mL of anhydrous DMF. After stirring at 0° C. under N2 for 15 min, 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.275 mmol) is added at 0° C. The mixture is warmed to RT and stirred overnight. The reaction mixture is then poured into water and extracted with DCM (3×). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography using DCM/MeOH/NH4OH (98/2/0 2) as eluent to give 2-(furan-2-yl)-7-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[N:11][N:10]=[C:9]1[CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[C:12]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]2)=[N:11][N:10]=[C:9]1[CH2:25][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCNCc1nnc(C2CCN(c3ccccn3)CC2)n1Cc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN(C)Cc1nnc(C2CCN(c3ccccn3)CC2)n1Cc1ccccc1

Procedure:
The amine from example 43 (50 mg, 0.12 mmol), formaldehyde (37% aq, 40 μl, 0.49 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) in dichloromethane (1 ml) was stirred vigorously at room temperature for 21 hours. The reaction mixture was partitioned between dichloromethane and aqueous sodium carbonate solution, and the layers separated. The organic phase was dried (MgSO4), evaporated under reduced pressure, and the product triturated from ether to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][N:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:33]2[CH:32]=[CH:31][C:30]([NH2:34])=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][N:12]([CH3:17])[CH2:13][C:14]([NH:34][C:30]2[CH:31]=[CH:32][C:33]3[N:21]([CH2:19][CH3:20])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)CN(C)CC(=O)Nc3ccc(C#N)cc3)ccc21

Procedure:
Using the compound obtained in Step 1 and 9-ethyl-9H-carbazol-3-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=O)=[CH:31][C:29]=2[N:30]=1.[Si:38]([O:45][CH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH2:53][N:54]2[CH2:64][CH2:63][C:57]3([O:62][CH2:61][CH2:60][NH:59][CH2:58]3)[CH2:56][CH2:55]2)[S:51][CH:52]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(N(CC)CC)C>CN(C=O)C>[CH3:28][CH2:29][CH2:31][CH:32]([CH3:35])[CH3:33].[Si:38]([O:45][CH2:46][CH2:47][C:48]1[CH:49]=[C:50]([CH2:53][N:54]2[CH2:64][CH2:63][C:57]3([O:62][CH2:61][CH2:60][N:59]([C:35]([C:32]4[CH:33]=[CH:34][C:28]5[S:27][C:26]([CH3:25])=[N:30][C:29]=5[CH:31]=4)=[O:37])[CH2:58]3)[CH2:56][CH2:55]2)[S:51][CH:52]=1)([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CNCCO3)c1
Reactant: Cc1nc2cc(C(=O)O)ccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(C)C
Product: Cc1nc2cc(C(=O)N3CCOC4(CCN(Cc5cc(CCO[Si](C)(C)C(C)(C)C)cs5)CC4)C3)ccc2s1
Reaction time: 1 h

Procedure:
HATU (0.333 g) was added to stirred solution of 2-methylbenzo[d]thiazole-5-carboxylic acid (0.17 g), 9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 43, step b) (0.3 g) and triethylamine (0.407 mL) in DMF (3 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, once with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate:isohexane:triethylamine, 2:8:1 gave the subtitled compound as a gum. Yield 0.36 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:31][CH3:32])CC)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCCC1>[C:37]1([O:36][C:34](=[O:35])[N:24]([C:20]2[CH:19]=[C:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:25])=[CH:12][CH:13]=3)[CH:23]=[CH:22][N:21]=2)[C:9]([O:25][C:32]2[CH:31]=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:8])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2)ccn1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1)OCc1ccccc1

Procedure:
To a solution of [4-(2-aminopyridin-4-yloxy)phenyl]carbamic acid benzyl ester (500 mg) in tetrahydrofuran (15 ml) were added triethylamine (0.519 ml) and phenyl chloroformate (0.467 ml) while stirring in an ice water bath. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to provide a crude product of the titled compound as brown foam (935.6 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)/[N:22]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37][CH2:36]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.S(Cl)(Cl)=O.[CH:49]([NH2:52])([CH3:51])[CH3:50].Cl>C1COCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)/[N:22]([C@H:35]4[CH2:36][CH2:37][C@@H:38]([C:41](=[O:42])[NH:52][CH:49]([CH3:51])[CH3:50])[CH2:39][CH2:40]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(CN)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A suspension of cis-4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.57 g, 0.94 mmol) in thionyl chloride (6.85 mL, 94 mmol) under nitrogen atmosphere was stirred for 30 minutes at RT and then concentrated to dryness. The residue was suspended in THF (9.4 mL) and cooled in an ice bath under nitrogen atmosphere. To the resulting mixture was added isopropylamine (0.804 mL, 9.38 mmol) as a solution in THF (1 mL). The ice bath was removed and the mixture was stirred for 1 hour at RT. The resulting mixture was diluted with water (10 mL) and the aqueous layer extracted with DCM (30 mL). The organic layer was dried over sodium sulfate and concentrated to dryness under high vacuum to afford a tan solid. The solid was suspended in HCl (4.0M in dioxanes) (23.45 mL, 94 mmol) and stirred for 16 hours. The mixture was concentrated, suspended in DCM and washed with aqueous NaHCO3 solution. The organic portion was collected, dried over sodium sulfate, and concentrated to dryness under high vacuum to afford a tan solid. The solid was purified by silica gel chromatography (1-10% MeOH/DCM (1% NH4OH)) to afford (E)-N-(6-((4-(aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (0.3 g, 58.3% yield). MS m/z=549.2 [M+H]. Calc'd for C31H41FN6O2: 548.3.