Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[CH3:27][NH2:28].C(O)(C(F)(F)F)=O>>[CH3:26][C:24]1[CH:23]=[CH:22][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:25]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:28][CH3:27])=[CH:16][CH:15]=1)=[CH:7]3
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3)cc12
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
8-Methyl-2-(4-((methylamino)methyl)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzaldehyde (from Example 172/Step 1) and methylamine following the procedures described for Example 172, step 2. 1H NMR (Acetone-d6) TFA Salt: δ 8.95 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H), 7.58 (s, 1H), 7.54 (d, 2H), 7.42 (d, 1H), 7.37 (d, 2H), 4.30 (s, 2H), 3.32-3.37 (m, 4H), 2.75 (s, 3H), 2.55 (s, 3H). LRMS [M+H]=357.2
Reaction SMILES: [O:1]=[C:2]1[C:18]2[C:17]([N+]([O-])=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[C:3]1=[O:22].O.NN.N([O-])=O.[Na+].[ClH:30]>C(O)C.ClCCl.[Pd].O>[Cl:30][C:17]1[C:18]2[C:2](=[O:1])[C:3](=[O:22])[C:4]3[N:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]4=[N:6][C:5]=3[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cl
Reactant: O=C1C(=O)c2c(nc3ccccn23)-c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: NN
Agent: O=N[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C1C(=O)c2c(nc3ccccn23)-c2cccc(Cl)c21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A catalytic quantity of palladium on 10% carbon is added to an orange suspension of 80 mg (0.27 mmol, 1 eq) of 5,6-dihydro-5,6-dioxo-4-nitro-naphtho[1',2':4,5]imidazo-[1,2-a]pyridine in ethanol under argon, and the mixture is brought to reflux. 26.4 μL of hydrazine monohydrate (0.27 mmol, 1 eq) are then added. The reaction mixture immediately becomes violet. After 30 min, 26.4 μL of hydrazine monohydrate (0.27 mmol, 1 eq) are added. After 1 h of reaction, the reaction mixture is allowed to return to ambient temperature and the brown-violet precipitate is filtered through dried cotton and solubilized in 5 mL of conc. hydrochloric acid. This solution is cooled to -10° C., then a solution consisting of 34 mg (0.49 mmol, 1.8 eq) of sodium nitrite and 5 mL of distilled water is added dropwise. The medium is left under agitation at this temperature for 0.5 h. The reaction medium is added dropwise to a solution cooled to -5° C., consisting of 18 mg (0.18 mmol, 0.7 eq) of copper chloride(I) and 5 mL of conc. hydrochloric acid. The agitation is continued for 2.5 h. The reaction mixture is then diluted in dichloromethane, washed successively with a saturated solution of sodium carbonate, then with distilled water. The organic phase is extracted, then dried on sodium sulfate and evaporated to dryness. The raw product is purified on preparation plates (support: silica, eluent: dichloromethane/methanol, 90/10) to produce 10 mg of 4-chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:6](O)=[O:7])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:57][N:58]1[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59]1>CN(C=O)C>[CH:1]1([CH2:4][C@H:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:6](=[O:7])[NH:57][N:58]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59]2)[CH2:2][CH2:3]1
Reactant: O=C(N[C@@H](CC1CC1)C(=O)O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NN1CCC(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CC1CC1)C(=O)NN1CCC(O)C1)c1ccc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid (100 mg, 0.29 mmol) in DMF (3 mL), was added TBTU (103 mg, 0.319 mmol), DIEA (249 μL, 1.45 mmol) and finally 1-amino-3-pyrrolidinol (CAN 887591-10-8, 30 mg, 0.29 mmol). The reaction mixture was stirred for 16 h at room temperature, concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 20% methanol in dichloromethane) to give the title compound, an epimeric mixture of products, (90 mg, 72%) as white foam; LC-MS (UV peak area/ESI) 96%, 429.2493 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:13][C:14](=[O:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[CH3:17][S-:18].[Na+]>CN1CCCC1=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:13][C:14](=[O:16])[CH3:15])[CH2:2][S:18][CH3:17])=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: COc1ccc(C[C@@H](CCl)NC(C)=O)cc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C[C@@H](CSC)NC(C)=O)cc1
Reaction time: 2 h

Procedure:
The N-[(1S)-2-chloro-1-(4-methoxybenzyl)ethyl]acetamide in solution in N-methylpyrrolidone prepared in the preceding stage is added to a suspension of sodium thiomethoxide (1.8 g) in 3.8 ml of N-methylpyrrolidone at 20° C. The reaction medium is brought to 40° C. for 2 hours. The product formed is precipitated by addition of 5.7 ml of water. After filtration and drying, 3.7 g of N-[(1S)-1-(4-methoxybenzyl)-2-(methylthio)ethyl]acetamide are isolated.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:39]([NH2:41])=[S:40])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:39]([NH:41][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:40])([CH3:30])[CH3:29]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Product: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropyl-5-methylphenyl)thiourea isolated as an off-white solid (0.019 g, 6%): 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.12 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.62 (ddd, J=7.8, 1.9, 0.9 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.24-7.17 (m, 2H), 7.12-7.05 (m, 1H), 7.02 (t, J=5.8 Hz, 1H), 3.52-3.42 (m, 2H), 2.91 (dt, J=14.1, 6.9 Hz, 3H), 2.25 (s, 3H), 1.13 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])=O)C.[NH3:31].[Cl-].[NH4+]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])(=[O:3])[NH2:31]
Reactant: N
Reactant: CCOC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Reaction time: 10 h

Procedure:
1-[1-(3-Ethoxycarbonylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g), aqueous ammonia (10 ml) and ammonium chloride (the effective amount as a catalyst) are dissolved in ethanol (10 ml) and the mixture is stirred at 110°-130° C. for 10 hours in an autoclave. Ethanol is distilled off under reduced pressure and the residue is extracted with methylene chloride. The organic layer is washed with water and saturated saline solution, dried with sodium sulfate and concentrated. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=10:1) to give 1-[1-(3-carbamoylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.15 g).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:25][C:20]1[CH:21]=[CH:22][C:23]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[Cl:25])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:24][CH:19]=1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4-c4ccccc4Cl)nc2-3)cc1
Temperature: 130 °C
Yield: 41.2 %

Procedure:
9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.88 mmol) 4-chlorophenylboronic acid (188 mg, 1.20 mmol), Cs2CO3 (314 mg, 0.96 mmol) and dioxane/water (3:1, 5 ml) were combined in a tube. Pd(dppf)Cl2 (65 mg, 0.08 mmol) was added and N2 was bubbled through the solution. The mixture was heated in the microwave reactor at 130° C. for 30 min. The reaction mixture was filtered. The filtrate was concentrated, and purified by HPLC to give 568 (86 mg, 20%). 1H NMR (DMSO, 400 MHz) δ 8.17 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=8.4 Hz, 3H), 7.64-7.60 (m, 3H), 7.54 (d, J=6.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.25-7.20 (m, 2H), 4.44 (s, 4H). LCMS (ESI): m/z 470.0 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:33](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:44][CH3:45].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:33][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:44][CH3:45]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCCNC(=O)OC(C)(C)C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCNC(=O)OC(C)(C)C)ccnc3[nH]1)cn2C
Yield: 83.4 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.19 g of tert-butyl (2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}ethyl)carbamate instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 1.2 cm3 of 5N potassium hydroxide. 0.120 g of tert-butyl (2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}ethyl)carbamate is obtained with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)=[O:14])OCC[O:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[C:18]1[NH:19][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:3])[CH3:1])=[N:16][CH:17]=1
Reactant: CC1(CCCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCCCC(=O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ketone E3 was dissolved in TFA/DCM (1:1) and stirred for 4 hr at RT. After evaporation of the solvent under reduced pressure, the crude product was purified by preparative RP-HPLC (column: C18), using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford E4 as a white solid. 1H NMR (300 MHz, DMSO) δ: 8.17 (1H, s), 7.92-7.79 (3H, m), 7.76-7.64 (2H, m), 7.55-7.45 (2H, m), 3.15 (2H, t, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz), 2.15 (3H, s), 1.74 (2H, m), 1.58 (2H, m), 1.37 (4H, m). MS (ES) C22H24N2O2 requires: 348, found: 349 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:61])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44]([CH:59]=O)[CH2:45][C:46]2[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)[CH3:35].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:34]([O:36][C:37](=[O:61])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44](/[CH:59]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][C:46]2[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)[CH3:35]
Reactant: CCOC(=O)CC1(CCC(C=O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.75 h

Procedure:
At 0° C., 3.11 ml (7.78 mmol) of a 2.5 M solution of n-butyllithium in hexane are added slowly to a solution of 1.874 g (4.2 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 25 ml of anhydrous THF, and the mixture is stirred for 45 minutes. At this temperature, 1.080 g (2.78 mmol) of tert-butyl 4-{4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-formylbutyl}benzoate are metered in slowly, and the mixture is stirred at 0° C. for four hours. After complete conversion, saturated ammonium chloride solution is added, and the reaction solution is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated to dryness. The crude product obtained is purified by preparative HPLC. This gives 162 mg (8% of theory) of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:33][C:34]([F:66])([F:65])[C:35]1[CH:36]=[C:37]([CH:62]=[CH:63][CH:64]=1)[CH2:38][NH:39][C:40](=[O:61])[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:57][CH2:58][CH3:59])[CH2:54][CH2:55][CH3:56])[CH:50]=[CH:49][C:48]=2[NH2:60])[CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:65][C:34]([F:33])([F:66])[C:35]1[CH:36]=[C:37]([CH:62]=[CH:63][CH:64]=1)[CH2:38][NH:39][C:40]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:54][CH2:55][CH3:56])[CH2:57][CH2:58][CH3:59])[CH:50]=[CH:49][C:48]=2[NH:60][C:14]([C:13]2[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])[CH:42]=1)=[O:61]
Reactant: CCCN(CCC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 10-mL vial, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (355.2 mg, 1.20 mmol, 2.00 equiv) in dichloromethane (5 mL), EDC.HCl (228 mg, 1.19 mmol, 2.00 equiv), 4-dimethylaminopyridine (146.4 mg, 2.00 mmol), and N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(dipropylamino)phenyl)isonicotinamide (300 mg, 0.64 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane and washed with 3×50 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5-1:3). The product was obtained as 320 mg (67%) of a yellow to green oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(OCCOC)C(OCCOC)=CC=1N)C.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
5-Hydroxy-2-nitro-benzoic acid (compound A′) (1.5 g) was dissolved in methanol (15 ml). Thionyl chloride (1.5 ml) was added dropwise to the solution on an ice bath, and the mixture was then stirred at 80° C. for 12 hr. After the completion of the reaction, the reaction solution was neutralized with a saturated aqueous sodium hydrogencarbonate solution, and was then subjected to separatory extraction with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to give crude 5-hydroxy-2-nitro-benzoic acid methyl ester (1.1 g, crude yield 70%).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26]C(=O)[C@@H](N(C2C=CC=CC=2)C(N)=S)CC2C=CC=CC=2)[C:9]1=[O:47])=[O:6])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH2:26])[C:9]1=[O:47])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)N(C(N)=S)c1ccccc1)CN2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
(+)-1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (3.24 g) was dissolved in trifluoroacetic acid (40 ml), the solution was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 1.44 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C.C(OCC)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1.[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH:14]([CH3:25])[CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C

Procedure:
The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (219 mg, 0.5 mmole) was dissolved in ethyl methyl ketone (40 ml). Chlorotrimethylsilane (95 μl, 0.75 mmole) was added dropwise with stirring at RT. After one hour's stirring at RT, no precipitate had formed. The reaction solution was reduced to 5 ml under a vacuum and combined with diethyl ether (15 ml). The mixture was then vigorously stirred at RT for 1 h. An almost colorless precipitate was formed. The solid was filtered out, washed with diethyl ether (3×3 ml) and dried under a vacuum. The hydrochloride of the more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea (219 mg, m.p. 170-174° C., 93%; Example 26) was obtained in this manner as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]([NH2:10])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([NH:10][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:8]=[CH2:9]
Reactant: C=CCN
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Product: C=CCNC(=O)CCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[I:17]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[CH2:1]([C:4]([I:17])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: O=C1CCC(=O)N1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(I)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following the method of Flynn and Zabrowski, J. Org. Chem. 55: 3673-3674 (1990), such reference herein incorporated by reference with regard to such synthetic teaching, diethyl allylmalonate (18.0 g, 90.0 mmol) was dissolved in tetrahydrofuran (THF) (50 mL). Sodium hydride (11.5 g, 288 mmol, 60% dispersion in oil) was added to the reaction. After 30 min of stirring at ambient temperature, a solution of N-iodosuccinimide (21.9 g, 97.2 mmol) in THF (100 mL) was added, and the reaction was stirred in the dark at ambient temperature for 15 min. The reaction was poured onto 100 g of silica gel. The contents were diluted with 400 mL of ether and stirred with a glass rod. The contents were then filtered through a bed of silica gel (100 g) in a sintered funnel. The silica gel was washed with ether (4×400 mL). The combined filtrates were concentrated by rotary evaporation to give diethyl 2-allyl-2-iodomalonate, as a yellowish orange liquid, that was used immediately in the next reaction.