Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1

Procedure:
Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (Ig, 7 mmol) and 1-Boc-piperazine (1.9 g, 10 mmol) 1H NMR (400 MHz, CDCl3) δ (ppm): 7.03 (t, J=8.0 Hz, 1H), 6.34 (d, J=8.2 Hz, 1H), 6.23 (m, 2H), 3.62 (br, 2H), 3.53 (m, 4H), 3.07 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[S:21][C:20]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1.BrB(Br)Br>>[NH2:23][CH2:22][C:20]1[S:21][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[OH:2])=[CH:18][CH:19]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)s1
Agent: BrB(Br)Br
Product: NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)s1
Yield: 113.6 %

Procedure:
Following General Procedure F, tert-butyl [5-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)thiophen-2-yl]methylcarbamate (30 mg, 0.067 mmol) was reacted with tribromoborane (0.50 mL) to afford the desired product (25 mg, 91%) as a off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=5.4 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.16-7.14 (m, 2H), 6.86 (d, J=3.5 Hz, 1H), 6.35 (d, J=5.4 Hz, 1H), 4.12 (s, 2H); ESI MS m/z 329 [C16H12N2O2S2+H]+; HPLC 95.6% (AUC), tR=9.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(CCN3CCOCC3)c2cc1OC
Temperature: 20 °C
Yield: 60.2 %

Procedure:
A solution of 0.54 g of 4-chloro-2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1.8 g of potassium hydroxide in 18 ml of methanol is brought to around 60° C. for approximately 2 hours. After cooling to approximately 20° C., the precipitate is filter-dried, washed with two times 3 ml of methanol and three times 5 ml of water, and then dried in an oven under reduced pressure (13 kPa) at a temperature in the region of 40° C. for approximately 8 hours. 0.241 g of 4-chloro-2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[N:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:4][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[CH:19]=2)[CH:7]=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(-c3cnn(C(C)(C)C)c3)cc3ncccc23)C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylate (2.24 g, 4.64 mmol) in DCM (14 ml) was added TFA (8.22 ml, 107 mmol) and this was stirred at ambient temperature for 2 h. After this time the reaction had gone to completion and so was concentrated in vacuo to yield the crude product. This was dissolved in methanol and loaded onto an SCX cartridge (50 g). It was eluted with methanol (3 CVs) and product eluted as the free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow foam (1.55 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[H][H]>C(O)C.[C].[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)O)CCCCC2)CC1
Yield: 94.8 %

Procedure:
Further, 4.3 g (9.65 mmol) of the above phenylmethyl 1-[N-[4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylate was dissolved in 200 ml of ethanol and 400 mg of 10% palladium carbon was suspended thereinto and under air current of hydrogen stirred for 15 hours. The insoluble components were removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, whereby 3.25 g of the captioned 1-[N-[4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonyl]amino]cyclohexanecarboxylic acid was obtained in a yield of 45%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:38][C:39]([CH3:52])([O:41][CH2:42][CH2:43][NH:44]C(=O)OC(C)(C)C)[CH3:40])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:17]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[N:37]=1)[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[NH2:44][CH2:43][CH2:42][O:41][C:39]([CH3:40])([CH3:52])[CH2:38][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:37]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
tert-Butyl 2-(1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylcarbamate (1.45 g, 2.07 mmol) was combined with dichloromethane (DCM, 12 mL) to give a colorless solution. TFA (6.0 mL, 77.9 mmol) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture was cooled to 0° C., 2N sodium hydroxide solution (40 mL) was added, and the basic solution was extracted with dichloromethane. Organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0 to 10% methanol in DCM) to give the title compound (0.62 g, 83%) as white solid; LC-MS (UV peak area, ESI) 97.5%, 358.2238 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.ClCCl>Br.C(O)(=O)C>[C:1]1([C:7]2([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: c1ccsc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(C2(c3cccs3)CCCCC2)cc1
Temperature: 25 °C

Procedure:
Phenyl cyclohexene (50 mg) and thiophene (100 mg) were dissolved in 33% HBr in acetic acid (0.5 mL). The mixture was stirred at room temperature over night. Tlc indicated full conversion of the starting material. Dichloromethane (10 mL) was added. The organic phase was washed with saturated NaHCO3 (3×10 mL), dried Na2SO4 and concentrated in vacuo. The desired product was afforded after flash chromatography (eluent: dichloromethane). Yield: 39 mg. LC/MS purity (UV/MS): 100/90%, Rt 6.22 min. M+1: 243
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:12])[C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(c1ccc(Br)s1)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of the alcohol (C1) in DCM at RT was added Dess-Martin reagent (1.0 eq) and the reaction mixture was stirred 3 hr and then quenched by pouring into saturated aqueous NaHCO3 solution containing 7 fold excess of Na2S2O3. The mixture is stirred for 30 min and then the layers were separated and the organic layer was washed with water, brine and dried (Na2SO4). Evaporation of the solvent gave the crude product which was purified flash column chromatography using 1-10% EtOAc/Petroleum ether to yield the desired compound as an oil. 1H NMR (300 MHz, CDCl3, 300K) δ 7.70 (1H, m), 7.21 (1H, d, J=4.2 Hz).
Reaction SMILES: [Li+].[BH4-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12](OCC)=[O:13])=[CH:7][C:6]=1[O:18][CH3:19])#[N:4].O>C1COCC1>[OH:13][CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[C:6]([O:18][CH3:19])[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)C(C)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(C)CO)ccc1C#N
Reaction time: 12 h

Procedure:
LiBH4 (0.55 mL, 1.1 mmol, 2 M in THF) was added to a stirred solution of ethyl 2-(4-cyano-3-methoxyphenyl)propanoate (0.17 g, 0.73 mmol) in THF (25 mL) at 0° C. The resulting solution was stirred for 12 h. Water (15 mL) was added, and the resulting solution was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give 4-(1-hydroxypropan-2-yl)-2-methoxybenzonitrile.
Reaction SMILES: [NH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([N:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCC2(CC1)CCCCN2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCCC12CCCCC2

Procedure:
The 1-azaspiro[5.5]undecane starting material can be prepared by the method described by H. Hodjat, et al., in J. Heterocyclic Chem., 9, 1081 (1972). This starting material is treated with benzoyl chloride in pyridine to form the N-benzoyl-1-azaspiro-[5.5]undecane, shown at the beginning of step 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH2:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][C:26](Cl)=[O:27].O>N1C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH:11]([CH3:12])[CH3:13])[N:5]=[C:4]([NH:14][C:26](=[O:27])[CH2:25][C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH:3]=1
Reactant: CC(C)Oc1nc(N)cc(N)c1C#N
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OC(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
To a solution of 100 mg (0.520 mmol) of 4,6-diamino-2-isopropoxy-nicotinonitrile in 1 mL of pyridine was added 3 mL of CH2Cl2 followed by a solution of 150 mg (0.699 mmol) of 2,5-dimethoxyphenylacetyl chloride (prepared from (2,5-dimethoxyphenyl)acetic acid and oxalyl chloride in CH2Cl2) in 1 mL of CH2Cl2. The mixture was stirred at ambient temperature for 10 minutes then 1 mL of water was added, and the mixture was concentrated under reduced pressure. The residue was taken up in 20 mL of warm ethyl acetate and extracted with water (1×5 mL), 1M HCl(aq.) (2×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a solid. Recrystallization from methanol or 2-propanol provided 90 mg (47%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.06 (s, 1H), 7.10 (s, 1H), 6.90 (m, 1H), 6.84 (s, 2H), 6.79 (m, 2H), 5.28 (septet, 1H, J=6.1 Hz), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 2H), 1.29 (d, 6H, J=6.1 Hz); MS (ESI) m/e=329 (M−Pr+H)+, 371 (M+H)+, 369 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[N:29][CH:28]=5)[CH:20]=4)=[O:18])[NH:14][C:13]=3[CH:37]=2)[CH2:5][CH2:4]1.B(Br)(Br)Br>ClCCl.[Cl-].[NH4+]>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[N:29][CH:28]=5)[CH:20]=4)=[O:18])[NH:14][C:13]=3[CH:37]=2)[CH2:7][CH2:8]1
Reactant: COc1ccc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)cc3[nH]2)cc1-c1cncc2ccccc12
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CN(C)C1CCN(c2ccc3nc(C(=O)c4ccc(O)c(-c5cncc6ccccc56)c4)[nH]c3c2)CC1
Yield: 17 %

Procedure:
To a cooled (−78° C.) solution of [6-(4-Dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-(3-isoquinolin-4-yl-4-methoxy-phenyl)-methanone (6 mg, 0.012 mmol) in dichloromethane (6 mL) was added boron tribromide (0.118 mL, 10 eq) dropwise resulting in bright yellow solution. The reaction mixture was allowed to warm, diluted with saturated ammonium chloride solution, and extracted with dichloromethane. The organics were dried over Na2SO4, filtered, concentrated and purified by HPLC (Deltapak C18, acetonitrile: 0.1% trifluoroacetic acid), then neutralized using PL-HCO3 SPE to obtain 1 mg [6-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-(4-hydroxy-3-isoquinolin-4-yl-phenyl)-methanone in 20% yield. MS m/z 492.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[O:16][C:15]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][N:13]=1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[O:16][C:15]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
0.14 ml (1.1 mmol) of benzyl isocyanate was added to 20 ml of pyridine solution containing 278 mg (1.0 mmol) of the compound of Example 43, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under a reduced pressure, and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (50:1) to give 406 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C:28](=[O:34])[NH:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:22])[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:15]=1)=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:30]1([NH:29][C:28]([C@@H:24]2[CH2:25][CH2:26][CH2:27][N:23]2[C:21](=[O:22])[CH2:20][O:19][C:17]2[N:16]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:15]=[C:14]([C:12]([NH:11][C@@H:4]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:3]([OH:41])=[O:2])=[O:13])[CH:18]=2)=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H](C(=O)O)C1CCCCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
To a solution of 428 mg (S)-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-cyclohexyl-acetic acid methyl ester in 20 ml THF and 5 ml water were added 30 mg lithium hydroxide at 0° C. After stirring for 4 h it was acidified with 1 N HCl and concentrated in vacuo to give the crude product as colorless oil. Yield: 380 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:22][NH2:23]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(F)c2)c(C(=O)O)c1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(-c3cccc(F)c3)n[nH]c(=O)c2c1
Yield: 34.8 %

Procedure:
A solution of 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21 g, 76.5 mmol) in hydrazine hydrate (4.09 mL, 84.0 mmol) and EtOH (300 mL) was heated overnight at 80° C. The reaction mixture was concentrated, diluted with water (300 mL), and the precipitate was filtered and dried to yield 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.2 g). (270.85 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.36-7.43 (m, 3H), 7.46-7.49 (m, 1H), 7.57-7.64 (m, 2H), 7.73-7.73 (d, J=2.8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].[K]>C(O)CCC>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: NCCCO
Agent: [K]
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO

Procedure:
A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodic and 200 parts of butanol is stirred and refluxed overnight. The butanol is removed be evaporated in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichoromethane and 5% of methanol as elluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 31.7 parts of 3-[(4,5-dichloro-2-nitrophenyl)amino]-1-propanol; mp. 97° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:21]=[CH:22][N:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.CCCCC.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[C:48](Cl)=[O:49]>C1COCC1>[C:27]1([S:24]([N:20]2[CH:21]=[C:22]([C:48]([C:47]3[CH:51]=[C:52]([O:56][CH3:57])[C:53]([O:54][CH3:55])=[C:45]([O:44][CH3:43])[CH:46]=3)=[O:49])[N:23]=[C:19]2[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of 1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole (10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 M tert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10 min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0 mmol) in THF was added at −78° C. and stirred overnight. The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (300 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) to give a white solid. Yield: 30%. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=10 Hz, 1H), 8.04 (d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz, 1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C33H27N3O8 657.0. found 680.1 [M+Na].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([NH:20][NH2:21])([C:15]([O:17]CC)=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO[C:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)=[C:25]([C:28]#[N:29])[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([N:20]3[N:21]=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)[C:25]([C:26]#[N:27])=[C:28]3[NH:29][C:15]2=[O:17])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1(NN)CCN(Cc2ccccc2)CC1
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Yield: 58.9 %

Procedure:
A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylate hydrochloride (350 mg, 1.0 mmol), 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (276 mg, 1.0 mmol) and K2CO3 (414 mg, 3.0 mmol) in MeOH (20 mL) was heated to reflux for 16 hr. The mixture was filtered and the filtrate was concentrated to give the crude product (280 mg, 58.9%) as a yellow solid. MS (ESI, m/e) [M+1]+ 475.9.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.CN(C)[CH:31]=[O:32]>O1CCCC1.O>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cnccc1Cl
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
Form a solution of lithium diisopropylamide by the adding n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.40 mL, 0.06 mol) in tetrahydrofuran (200 mL) at −10 to −20° C. under a nitrogen atmosphere. Stir for 30 min., and cool to −60° C. Add 4-chloropyridine hydrochloride (3.75 g, 0.025 mol) in small portions and stir for 1.5 hours at this temperature. Add dimethylformamide (4.0 mL, 0.052 mol) dropwise via syringe and stir for 1 hour near −60° C. Add water (200 mL) when the mixture has warmed near 0° C. Extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica with methanol/dichloromethane, allowing for isolation of the desired aldehyde (2.80 g, 79%) as a light yellowish solid. MS(BI): (M)+ 141.0, 142.0, 143.0 m/z.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[CH:7]=[CH:8][C:9]([N+:16]([O-])=O)=[CH:10][C:11]=32)[CH2:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:16])=[CH:10][C:11]=32)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Product: CCN1CC2CCC(C1)c1cc(N)ccc12
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
10-Ethyl-4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-triene (68 mg, 0.276 mmol) was placed in methanol (4 mL) and 10% palladium on carbon (6.8 mg) was added. The reaction was hydrogenated at 15 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2(7),3,5-trien-4-ylamine as a yellow oil (59.6 mg, 100%). LCMS (m/e) 217 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.85 (d, 1H, J=7.4 Hz), 6.50-6.45 (m, 2H), 3.52 (bs, 2H), 2.94-2.85 (m, 4H), 2.42 (q, 2H, J=7.1 Hz), 2.20-2.12 (m, 4H), 1.60-1.56 (m, 2H), 0.99 (t, 3H, J=7.1 Hz).