Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O=[CH:3][C:4]([OH:6])=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:14]([O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:14]([O:21][C:22]1[N:27]=[CH:26][C:25]([CH:3]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:6])=[O:5])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=CC(=O)O
Reactant: OB(O)c1ccc(OCc2ccccc2)nc1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(O)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Yield: 31.5 %

Procedure:
To a suspension of 2-oxoacetic acid hydrate (0.40 g, 4.37 mmol) and aniline (0.40 ml, 4.37 mmol) in acetonitrile (25 ml), was added 6-(benzyloxy)pyridin-3-ylboronic acid (1.00 g, 4.37 mmol), and the reaction mixture was refluxed for 2 hours. The solvent was evaporated, and the resulting dark brown oil was purified by flash chromatography (DCM/MeOH=97/3) to obtain 2-(6-(benzyloxy)pyridin-3-yl)-2-(phenylamino)acetic acid (460 mg, 31.5% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:11]([C:8]2[C:7](=[O:16])[C:6]3[CH:17]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=3[O:10][N:9]=2)=[O:13])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1noc2ccc(I)cc2c1=O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Temperature: 100 °C
Yield: 979 %

Procedure:
A mixture of ethyl 6-iodo-4-oxo4H-1,2-benzoxazine-3-carboxylate (Preparation 17, 48 mg) and 4-chlorobenzylamine (41 mg) and toluene (1 mL) is heated to 100° C. for 2 minutes. The mixture is cooled and concentrated in vacuo, and the residue is crystallized from ethanol-ether mixture to give 0.60 g (48%) of the title compound. Physical characteristics: mp 188-190° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.49, 7.41, 7.59, 8.25, 8.32, 9.2; IR (drift) 3284, 1680, 1656, 1599, 1571, 1490, 1453, 1433, 1199, 1158, 928, 921, 819, 782, 619 cm−1; MS (FAB) m/z 441 (MH+, 65); HRMS (FAB) m/z 440.9507 (C16H10ClIN2O3+H). Anal. Found: C, 43.56; H, 2.43; N, 6.32; Cl, 8.04.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-:6].[K+].[K+].[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>>[CH3:2][O:3][N:4]([C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=1)[OH:6]
Reactant: CON
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CON(O)C(=O)c1ccc(C#N)cc1

Procedure:
A mixture of 29.4 g (0.350 mole) methoxyaminehydrochloride and 50 g (0.36 mole) potassium carbonate in about 200 mls was stirred, maintaining the temperature below -5° C. until the reactants were dissolved. To that solution, 50 g (0.302 mole) 4-cyano-benzoylchloride were dropped in slowly, maintaining the temperature of the reaction mixture below 0° C. during the addition. The reaction mixture was stirred overnight. The reaction mixture was suction-filtered. The residue, containing the crude product was dried in a heated vacuum oven and then washed with hexane (about 100 mls) and ether (about 2-3 mls) to give the product an off-white solid.
Reaction SMILES: O([Si](C)(C)C)[Na].[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10](F)[C:9]=1[N+:20]([O-:22])=[O:21].[O:23]1CCC[CH2:24]1>O1CCOCC1.CO>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10]([O:23][CH3:24])[C:9]=1[N+:20]([O-:22])=[O:21]
Reactant: C1CCOC1
Reactant: CC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Agent: C[Si](C)(C)O[Na]
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(NC(C)=O)c(F)cc(Cl)c1[N+](=O)[O-]
Yield: 63 %

Procedure:
A solution of 72.5 g (647 mmol) of NaOSi(CH3)3 in 25 ml of tetrahydrofuran was added dropwise at approximately 20° C. to a solution of 81 g (323 mmol) of N-(4-chloro-2,6-difluoro-3-nitro-phenyl)acetamide in 490 ml of dioxane and 50 ml of methanol. The mixture was subsequently heated for two hours at reflux temperature. After cooling and concentrating, the crude product (black oil) was stirred into ice-cold 10% strength hydrochloric acid. The resulting product of value was then extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred once with water. The insoluble components were removed and washed three times with water. After drying, 52.1 g (63%) of the product of value were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:2].[CH:33](=O)[CH3:34]>>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:33][CH3:34])[CH3:32]
Reactant: CCN(CC)CCCNCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC=O
Product: CCN(CC)CCCN(CC)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 125 was coupled with acetaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 462. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1), 8.1 (m, 1), 8.0 (m, 2H), 7.5 (m, 2H), 71 (m, 3H), 6.7 (m, 2H), 4.9 (s, 1H), 3.8 (s, 1H), 3.6 (m, 3H), 3.0 (m, 6H), 2.8 (m, 3H), 2.6 (m, 4H), 1.8 (m, 2H), 1.2 (m, 9H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([CH2:12][CH2:13][N:14]=[N+]=[N-])[CH2:7][CH2:8][N:9]=[N+]=[N-])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH:6]([CH2:12][CH2:13][NH2:14])[CH2:7][CH2:8][NH2:9]
Reactant: [N-]=[N+]=NCCC(CCN=[N+]=[N-])CCN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCC(CCN)CCN
Yield: 100 %

Procedure:
Tris(2-azidoethyl)methane (15.06 g, 0.0676 mol), (assuming 100% yield from previous reaction) in ethanol (200 ml) was treated with 10% palladium on charcoal (2 g, 50% water) and hydrogenated for 12 h. The reaction vessel was evacuated every 2 hours to remove nitrogen evolved from the reaction and refilled with hydrogen. A sample was taken for NMR analysis to confirm complete conversion of the triazide to the triamine. Caution: unreduced azide could explode on distillation. The reaction was filtered through a celite pad to remove the catalyst and concentrated in vacuo to give tris(2-aminoethyl)methane as an oil. This was further purified by Kugelrohr distillation bp. 180-200° C. at 0.4 mm/Hg to give a colourless oil (8.1 g, 82.7% overall yield from the triol).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[CH:38]=[C:37]([NH:39][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:36]=[N:35]2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cn2)CC1

Procedure:
4-{4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-pyrazol-1-yl}-piperidin-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.150 g, 0.48 mmol) and 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.168 g, 0.63 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as a tan solid (0.134 g, 51%). MP=Softened at 161-166° C. then melted at 207-209° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.78 (d, J=6.52 Hz, 1H), 8.42 (d, J=8.00 Hz, 2H), 8.06 (d, J=7.89 Hz, 2H), 7.94 (d, J=7.45 Hz, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 7.12 (t, J=6.89 Hz, 1H), 4.32 (s, 1H), 4.04 (d, J=11.40 Hz, 2H), 3.28 (s, 3H), 2.91 (s, 2H), 2.005 (d, J=11.77 Hz, 2H), 1.76 (q, J=12.21 Hz, 2H), 1.42 (s, 9H). MS=538 (MH)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: COc1cc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc(OC)c1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc(OC)c1
Yield: 90.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 23) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (179 mg, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[C:7]([N+:20]([O-])=O)=[C:8]([CH:10]=[C:11]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)[NH2:9].[H][H]>[OH-].[Pd+2].[OH-].[C].CO>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:8]([NH2:9])[C:7]=1[NH2:20]
Reactant: [H][H]
Reactant: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1N

Procedure:
1 g of 20% palladium hydroxide-carbon catalyst was added to a methanol (20 ml) solution of 1.33 g of 3-(2-methoxyphenoxy)-2-nitro-5-(pyridin-3-yloxy)-aniline, and the reaction liquid was stirred for 4 hours in a hydrogen atmosphere. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2 to ethyl acetate) to obtain the entitled compound as a pale orange oily substance.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][C:29]([S:33]([N:36]([CH2:43][CH2:44][CH2:45][N+:46]45[CH2:53][CH2:52][N:49]([CH2:50][CH2:51]4)[CH2:48][CH2:47]5)[C@H:37]([CH3:42])[C:38]([O:40]C)=[O:39])(=[O:35])=[O:34])=[CH:28][C:27]=3[F:54])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:55][CH3:56].[Li+].[OH-]>CC#N>[Cl-:2].[C:38]([C@H:37]([N:36]([CH2:43][CH2:44][CH2:45][N+:46]12[CH2:47][CH2:48][N:49]([CH2:50][CH2:51]1)[CH2:52][CH2:53]2)[S:33]([C:29]1[CH:28]=[C:27]([F:54])[C:26]([CH2:25][S:24][C:15]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:12]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:55][CH3:56])[CH:5]=3)([CH3:10])[CH3:11])=[CH:13][N:14]=2)=[C:31]([F:32])[CH:30]=1)(=[O:34])=[O:35])[CH3:42])([OH:40])=[O:39]
Reactant: COC(=O)[C@@H](C)N(CCC[N+]12CCN(CC1)CC2)S(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Agent: [Br-]
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)N(CCC[N+]45CCN(CC4)CC5)[C@H](C)C(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Product: [Cl-]
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
To a solution of (R)-1-(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluoro-N-(1-methoxy-1-oxopropan-2-yl)phenylsulfonamido)propyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide (118 mg, 0.14 mol) in MeCN (2 mL) was added 1N LiOH (0.3 mL). After stirring 1.5 h, the volatiles were removed under educed pressure. The resulting aqueous layer was acidified to pH 0 with 1N HCl and washed with EtOAc (2×10 mL). After extractions, the aqueous layer was neutralized to pH 7 with 1N NaOH and satd NaHCO3, and extracted with DCM/IPA (2:1, v/v, 3×10 mL). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated in DCM, slurried with Celite and filtered over a pad of Celite to remove any inorganic salts. The DCM layer was concentrated and the residue recrystallized from DCM/Et2O (1:3) to give the title compound (83 mg, 71%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.O1CCCC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:1]([NH:4][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
First, 10 g of propylamine, 26 g of triethylamine, and 200 mL of tetrahydrofuran (THF) were put in a 500 mL three-neck flask, and stirred. This mixed solution was cooled in ice, and a mixed solution of 24 g of benzoyl chloride and 50 mL of THF was dripped, and then, the temperature was increased to room temperature and the mixture was stirred for 2 hours. After the stirring, chloroform was added to this mixture, the mixture was washed with water and then a saturated aqueous solution of sodium hydrogen carbonate, and anhydrate magnesium sulfate was added for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with hexane, so that 25 g of N-propylbenzamide was prepared as a white solid with a yield of 92%. The synthetic scheme of Step 1 is shown by (a-15).
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Li].CC[O:28][CH2:29][CH3:30].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:29]([OH:28])([CH3:30])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[F:15]
Reactant: [Li]C
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (0.500 g, 1.32 mmol) in THF (9.0 mL) at −78° C. was treated dropwise over 10 min with 1.6 M methyllithium in ether (2.47 mL, 3.96 mmol). The mixture was stirred at −78° C. for 30 min, then was treated with additional methyllithium solution (1.65 mL, 2.64 mmol) and the mixture was stirred at −78° C. for 45 min more. The mixture was treated with saturated aqueous NH4Cl and allowed to warm to room temperature. The mixture was diluted with EtOAc and washed sequentially with water and brine. The aqueous layers were extracted with EtOAc and the combined organic layers were dried and concentrated to provide a pale yellow solid which was purified by reverse phase preparative HPLC. The appropriate fractions were neutralized with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated to provide 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a pale yellow solid (0.240 g, 50% yield). Mass spectrum m/z 347, 349 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 8.22 (br. s., 1H), 7.96 (d, J=10.3 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.65 (br. s., 1H), 7.39 (dd, J=8.5, 1.5 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])CC=CC[CH2:2]1.Cl([O-])(=O)=[O:15].[K+].[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O.[Os](=O)(=O)(=O)=O>[OH:19][CH:23]1[CH:22]([OH:15])[CH2:21][CH2:20][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)C(O)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 21 g (115 mmol) of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate from Step A in 5 mL of tetrahydrofuran was added 300 mL of water, followed by 18 g (149 mmol) of potassium chlorate. Then a solution of 200 mg of osmium tetroxide in 30 mL of water was added slowly in portions. The mixture was stirred at 80° C. for 16 h. At this time, additional portions of potassium chlorate (11.2 g, 92 mmol) and osmium tetroxide (138 mg) were added, and stirring was continued at 80° C. for another 3.5 h. The reaction mixture was partitioned between diethyl ether and water. The aqueous phase was extracted with dichloromethane and then concentrated in vacuo. The resultant residue from the aqueous phase was extracted with tetrahydrofuran. The combined organic fractions were concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.93 (br s, 2H), 3.92 (m, 1H)-3.83 (m, 1H), 3.63 (m, 2H), 3.39 (m, 1H), 3.25 (m, 1H), 1.84 (m, 1H), 1.72 (m, 1H), 1.47 (s, 9H). LC/MS: 240 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
74.4 g (0.147 mol) methyl (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate dissolved in 600 mL THF was combined with 5.4 g (0.221 mol) lithium hydroxide hydrate in 300 mL water while cooling with an ice bath and stirred overnight at RT. The reaction mixture was evaporated down under reduced pressure, 300 mL water was added and the mixture was extracted three times with 200 mL EtOAc. The aqueous phase was freed from the organic solvent under reduced pressure and combined with 500 mL 2 M HCl with stirring and cooling with the ice bath. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([CH2:4][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=3)[CH:5]=1)[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11])=[CH:5][N:6]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(F)cc1Cl
Product: Fc1ccc(C(c2cn(Cc3ccccc3)c3cccc(Cl)c23)c2cn(Cc3ccccc3)c3cccc(Cl)c23)c(Cl)c1

Procedure:
The compound Bis(4-chloro-1-benzylindol-3-yl)-(2-chloro-4-fluorophenyl)methane was prepared following procedure A, starting from 4-chloro indole and 2-chloro 4-fluorobenzaldehyde, resulted compound was reacted with benzyl bromide following procedure B. LC: Tr 2.94 min, MS: 623 (M+H)+
Reaction SMILES: C(OC([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)/C(=C/c1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1
Yield: 94.5 %

Procedure:
5 g of methyl (Z)-2-[(benzyloxy)carbonyl]amino-3-(3-[(tert-butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-propenoate was dissolved in methanol. 0.7 g of 10% palladium-carbon was added thereto, followed by stirring for 16 hours in a hydrogen atmosphere. The reaction solution was filtered and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), to give 3.4 g of methyl 2-amino-3-(3-[(tert-butoxycarbonyl)amino]methyl-4-methoxyphenyl)propanoate was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]>CCOCC>[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(15-carbomethoxypentadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH2:11][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:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)OCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-carbamic acid benzyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.