Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[C:12]([C:29]#[N:30])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Temperature: 120 °C
Yield: 25 %

Procedure:
{2-[3-bromo-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.734 mmol, 1 eq), zinc cyanide (1.734 mmol, 1 eq), bis(tri-tbutylphosphine)palladium(0) (1.561 mmol, 0.9 eq) and zinc (0.173 mmol, 0.1 eq) were dissolved in N,N-dimethylformamide (48 ml) and heated in microwave Biotage Initiator at 120° C. for 3 min. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (7×15 ml). Crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-30% for 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product {2-[3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.442 mmol, yield=25%, purity=91%). [M+H]+=408.35 1H NMR (300 MHz, CDCl3) δ/ppm 1.38 (s, 9H), 2.84 (s, 2H), 3.31-3.46 (m, 2H), 4.53-4.70 (m, 1H), 7.22 (s, 2H), 7.43-7.54 (m, 2H), 7.91-8.00 (m, 1H), 8.34-8.41 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([NH:43][C:44]3([C:49](O)=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[CH:26]1[C:38]2[CH:37]([CH2:39][O:40][C:41]([NH:43][C:44]3([C:49]([NH:20][C@H:19]([C:18]([N:17]([CH3:25])[C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:50])[CH2:45][CH2:46][CH2:47][CH2:48]3)=[O:42])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCC1c2ccccc2-c2ccccc21
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To #6 (287 mg, 0.801 mmol, 1 eq.) in dichloromethane (4 mL, 0.2 M) were added 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}cyclopentanecarboxylic acid (309 mg, 0.879 mmol, 1.1 eq.), diisopropylethylamine (281 μL, 1.60 mmol, 2 eq.) and HATU (376 mg, 0.960 mmol, 1.2 eq.). The mixture was stirred for 18 hours and diluted with ethyl acetate (15 mL). The reaction mixture was washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine (5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) to provide #27 (502 mg, 91%) as a white foam. LC-MS: m/z 692.3 [M+H+], 714.3 [M+Na+], 636.3 [(M−2-methylprop-1-ene)+H+], retention time=1.13 minutes; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 7.89 (br d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.60 (br s, 1H), 7.38-7.44 (m, 2H), 7.30-7.36 (m, 2H), 7.21 (br d, J=8.8 Hz, 1H), 4.44-4.59 (m, 2H), 4.17-4.27 (m, 3H), 3.68-3.78 (br m, 1H), 3.21 (s, 3H), 2.88 (br s, 3H), 2.09-2.20 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.O[CH2:14][C:15]([C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:15]2[N:3]3[NH:4][C:5](=[O:12])[C:6]4[C:11]([C:2]3=[N:1][CH:14]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:21]=1
Reactant: Nc1n[nH]c(=O)c2ccccc12
Reactant: Cc1cc(C(=O)CO)no1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnc3c4ccccc4c(=O)[nH]n23)no1
Yield: 42.8 %

Procedure:
4-Amino-1-phthalazinone (2.28 g, 14.2 mmol) [Angew. (1967) 6(2) 173-4] and 2-hydroxy-1-(5-methylisoxazol-3-yl)ethanone (2.0 g, 14.2 mmol) were suspended in toluene (100 ml) and trifluoroacetic acid (5 ml) was added. The suspension was heated at reflux under Dean & Stark conditions, for 24 hours. The solvent was then removed in vacuo and the residue was purified by chromatography on silica gel eluting with 10% methanol:dichloromethane, to provide the title product (1.62 g, 43%), 1H NMR (360 MHz, d6-DMSO) 2.50 (3H, s), 5.96 (2H, br s), 7.79-8.22 (4H, m) 11.48 (1H, s).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:48]=[C:49]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C.O>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:69]1[CH2:68][CH2:67][N:66]([C:49](=[O:48])[CH2:50][NH:51][C:52]([C:54]2[CH:59]=[CH:58][C:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:56][CH:55]=2)=[O:53])[CH2:71][CH2:70]1)=[O:22])([CH3:11])([CH3:12])[CH3:13]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.3 %

Procedure:
DIPEA (194.78 mg, 0.26 mL, 0.15 mmol) was added to a stirred solution of 2-tert-butoxycarbonylamino-benzoic acid (79.47 mg, 0.33 mmol) in DMF (3 mL). HOBT (49.7 mg, 0.36 mmol) and EDCI (160.5 mg, 0.83 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (130 mg, 0.4 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silicagel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 90 mg (49.5% yield) [2-(4-{2-[(Biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-phenyl]-carbamic acid tert-butyl ester
Reaction SMILES: C1(C=O)CCC=CCC1.[CH:10]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[C:18]12([O:28][CH2:29][C:30]3[NH:34][C:33]([CH:35]4[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]4)=[N:32][C:31]=3[C:42]([OH:44])=[O:43])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.[CH2:45]([O:52][C:53](=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([NH2:61])[CH:56]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:16]([O:17][C:42]([C:31]1[N:32]=[C:33]([CH:35]2[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]2)[NH:34][C:30]=1[CH2:29][O:28][C:18]12[CH2:25][CH:24]3[CH2:26][CH:20]([CH2:21][CH:22]([CH2:23]3)[CH2:27]1)[CH2:19]2)=[O:43])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:45]([O:52][C:53](=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][C:42]([C:31]2[N:32]=[C:33]([CH:35]3[CH2:41][CH2:40][CH:39]=[CH:38][CH2:37][CH2:36]3)[NH:34][C:30]=2[CH2:29][O:28][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[O:44])[CH:56]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Nc1cccc(CC(=O)OCc2ccccc2)c1
Reactant: O=CC1CCCCC1
Reactant: O=C(O)c1nc(C2CCC=CCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2
Agent: O=CC1CCC=CCC1
Product: O=C(Cc1cccc(NC(=O)c2nc(C3CCC=CCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1)OCc1ccccc1
Product: O=C(OCc1ccccc1)c1nc(C2CCC=CCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2

Procedure:
5-(Adamantan-1-yloxymethyl)-2-cyclohept-4-enyl-1H-imidazole-4-carboxylic acid benzyl ester was prepared according to the procedure of Example 216, steps a, b, c, d with the modification that cyclohept-4-enecarboxaldehyde (D. F. Murray et al. J. Org. Chem. 1986, 51, 1) was used in step d instead of cyclohexanecarboxaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the resulting 5-(adamantan-1-yloxymethyl)-2-cyclohept4-enyl-1H-imidazole4-carboxylic acid was reacted with (3-amino-phenyl)-acetic acid benzyl ester according to the procedure of Example 20, step d to afford (3-{[5-(adamantan-1-yloxymethyl)-2-cyclohept-4-enyl-1H-imidazole-4-carbonyl]-amino}-phenyl)-acetic acid benzyl ester. The benzyl ester was hydrolysed according to the procedure of Example 211, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.25 (2H, br m), 9.45 (1H, br s), 7.62 (2H, m), 7.24 (1H, t), 6.94 (1H, d), 5.82 (2H, br s), 4.78 (2H, s), 3.53 (2H, s), 3.03 (1H, m), 2.30 (2H, m), 2.13 (5H, m), 1.94 (2H, m), 1.76-1.58 (14H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.40; H, 8.07; N, 7.72%. C37H54N4O9.2.1 mols H2O requires: C, 60.38; H, 7.96; N, 7.61%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[O:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[CH:17]1>O1CCOCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]4[O:16][CH:17]=[N:18][CH:19]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3cnco3)c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution containing 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (20 mg, 0.071 mmol) and 3-(1,3-oxazol-5-yl)-aniline (17 mg, 0.11 mmol) in aqueous dioxane (1 mL, 95:5 dioxane/water) was stirred at room temperature for 4 weeks. The reaction mixture was diluted with MeOH/water and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 63% yield (18 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 7.09-7.16 (m, 1 H) 7.35 (t, J=7.93 Hz, 1 H) 7.45 (d, J=8.06 Hz, 1 H) 7.52 (t, J=1.83 Hz, 1 H) 7.56 (dd, J=8.79, 2.20 Hz, 1 H) 7.61 (s, 1 H) 8.00 (d, J=1.71 Hz, 1 H) 8.06 (d, J=8.30 Hz, 1 H) 8.43 (s, 1 H) 10.96 (s, 1 H). MS (ESI+) m/z 405 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][C:11]([C:19]#[N:20])=[C:10]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1.N1CCOCC1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:7]([N:6]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:19]#[N:20])[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NCCCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N1CCCC1
Temperature: 750 °C
Reaction time: 7 h

Procedure:
A mixture of 2.5 g of 6-(4-chlorobutylamino)-4-(3-chloro-4-fluorophenyamino)-7-methoxy-3-quinolinecarbonitrile, 7.54 g of morpholine, and 0.17 g of sodium iodide in 30 ml of dimethylformamide was stirred at 750° C. for 7 hrs. The mixture was poured into dilute sodium bicarbonate and solid was collected. This material was dissolved in ethylacetate. The solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel using ethyl acetate-methanol-triethylamine mixtures. A more polar component (0.54 g) was 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-(4-morpholin-4-yl-butylamino)-quinoline-3-carbonitrile; a less polar component (0.28 g) is the compound of this invention, 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-6-pyrrolidin-1-yl-quinoline-3-carbonitrile, obtained as a yellow solid: mass spectrum electrospray, m/e): M+H 397.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13].[H][H]>O1CCCC1.[O-2].[O-2].[Ti+4]>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: [H][H]
Reactant: N
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Agent: [Ti+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC1(C)CC(N)CC(C)(CN)C1
Yield: 95.2 %

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed up-stream of the hydrogenation reactor and packed with 63.5 g (100 ml) of titanium dioxide (anatase) in the form of 1.5 mm extrudates there were passed upwardly, per hour, 80.4 g of a 50% solution of isophoronenitrile (purity 99.0%) in tetrahydrofuran and 303.0 g of liquid ammonia at a pressure of 250 bar and a temperature of 80° C. Hydrogen was then added to the stream at a rate of 60 standard liters (2.7 moles) per hour, and the effluent from the in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure or 250 bar and a temperature of 120° C. Gas-chromatographic analysis of the hydrogenation product gave 95.2% of isophoronediamine in addition to 0.8% of 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, corresponding to a diamine yield of 96.2% of theory.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N([CH2:23][CH3:24])CC)C.ClCC(Cl)=[O:28].[H-].[Na+]>C1COCC1.CN(C=O)C>[O:28]=[C:3]1[CH2:2][O:1][CH2:24][CH2:23][N:4]1[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCOCC2=O)CC1
Temperature: 0 °C
Yield: 18 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)amino-1-piperidinecarboxylate (2.4 g) obtained in Example 91a) and triethylamine (1.0 g) were dissolved in THF (70 ml). While the mixture was cooled to 0° C., chloroacetyl chloride (0.72 ml) was added dropwise thereto, and mixed at 0° C. for 2 hours. Sodium hydride (60%; 1.0 g) and DMF (30 ml) were added to the reaction mixture, and mixed at 80° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added thereto, and then extracted with ethyl acetate. The extract was washed with water, a 5% aqueous citric acid solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to obtain the title compound as a colorless oil (0.51 g, 18%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC)=O.[NH2:28][CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[NH2:33][C:30]([CH3:32])([CH3:31])[CH2:29][NH:28][C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(N)CN
Reactant: O=C(O)CNC(=O)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(N)CNC(=O)CNC(=O)Cc1ccccc1
Temperature: -23 °C
Reaction time: 0.08 h

Procedure:
A mixture of phenylacetylglycine (10.0 g.), N-methyl morpholine (5.78 ml.) and chloroform (60 ml.) was stirred for 5 minutes. After cooling to -23° C., ethyl chloroformate (4.7 ml.) was added rapidly to the mixture during 1 minute, whereupon the temperture of the mixture rose to -15° C. After stirring for 1 minute, 1,2-diamino-2-methyl-propane (5.4 ml.) was added rapidly to the reaction mixture and the temperature was allowed to rise to room-temperature. After 1 hour at room temperature, the reaction mixture was poured into water (50 ml.) and the organic layer discarded. The aqueous layer was basified with excess potassium carbonate, and extracted with chloroform (4×100 ml.). The combined extracts were dried (MgSO4) and evaporated. Trituration and filtration of the solid residue with ether gave N1 -(2-amino-2-methylpropyl)-N2 -phenylacetylglycinamide as a solid (8.8 g.), m.p. 150°-155° C.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=[O:26])[C:13]4[CH:24]=[C:23](Br)[C:16]5=[CH:17][CH:18]=[CH:19][C:20]6[C:21](=[O:22])[C:4](=[C:5]([C:14]=4[C:15]=65)[C:6]=23)[CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].[C:45]1(C)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:27]1([C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:12](=[O:26])[C:13]5[CH:24]=[C:23]([C:45]6[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=6)[C:16]6=[CH:17][CH:18]=[CH:19][C:20]7[C:21](=[O:22])[C:4](=[C:5]([C:14]=5[C:15]=76)[C:6]=34)[CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1c2cc(Br)c3cccc4c(=O)c5cc(Br)c6cccc1c6c5-c2c34
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1c2cc(-c3ccccc3)c3cccc4c(=O)c5cc(-c6ccccc6)c6cccc1c6c5-c2c34
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 3 L of three neck flask were charged with 30 0 g (0.065 mol.) of 4,10-Dibromo-dibenzo[def,mno]chrysene-6,12-dione, 17.8 g (0.146 mol.) of phenyl boronic acid, and 0.2 g of 18-c-6 in a mixture of 1200 mL of toluene, 300 mL of ethanol, and 250 mL of 2.0 N potassium carbonate. After mixture was bubbled with house nitrogen for 15 min, 0.3 g of Pd (PPh3)4 was added to the reaction mixture under nitrogen. Then the reaction mixture was heated to reflux with efficient stirring under nitrogen protection. After the reaction proceeded for three hours, 0.2 g of Pd (PPh3)4 was added to the reaction mixture under nitrogen. The reaction mixture was continued to reflux for overnight. The newly formed orange solid was suspended in organic layer. After cool the reaction mixture to room temperature, the water phase was separated. The organic layer (with newly formed orange solid was suspended) was washed with water for three times (3×300 mL). The orange precipitates was filtered and washed with acetone (for easy dry). A 28.8 g of pure 4,10-Diphenyl-dibenzo[def,mno]chrysene-6,12-dione was obtained. Yield is in 96.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.O>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
40 mg (0.094 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine were dissolved in 2 ml of dry dimethylformamide and 12 μL (0.094 mmol) of p-trifluoromethylphenylisocyanate were added. The solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and the product extracted several times with ethylacetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted with dichloromethane-acetone 9/1, affording 40 mg (70% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>ClCCl>[C:37]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:21])[CH3:22])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To the mixture of tert-butyl (2S,4S)-2-(aminomethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (202 mg, 0.5 mmol, step 2 of Example 17) and triethylamine (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added acetyl chloride (43 μL, 0.55 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solution was added to water and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was PTLC eluting with dichloromethane/methanol (30:1 and 20:1 twice) to give 200 mg (90%) of the title compound as a colorless amorphous.