Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:48][O:49][CH2:50][CH3:51])[N:24]([CH2:25][C:26]([O:29][C:30](=[O:47])[CH2:31][N:32](CC3C=CC=CC=3)CC3C=CC=CC=3)([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:15][C:14]=2[N:13]=1)=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:48][O:49][CH2:50][CH3:51])[N:24]([CH2:25][C:26]([O:29][C:30](=[O:47])[CH2:31][NH2:32])([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:15][C:14]=2[N:13]=1
Reactant: CCOCc1nc2c(NC(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 5.5 %

Procedure:
Ethyl 3-(4-(benzyloxycarbonylamino)-1-(2-(2-(dibenzylamino)acetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate (182 mg, 232 μmol) was combined with ethyl acetate (20 mL) to give a light yellow solution. Palladium on carbon 10% (600 mg, 232 μmol) was added and the mixture was stirred for 20 h at room temperature under H2. Afterwards the mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 30% methanol in THF) to 27 mg of an impure sample that was further purified by preparative HPLC to give the title compound (6 mg, 5%) as light yellow oil; LC-MS (UV peak area, ESI) 79%, 516.5 (MHCOO−).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[C@@H:17]([CH3:19])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:19][C@H:17]1[NH:18][C:24](=[O:26])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:21][CH3:22])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:20]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 157 %

Procedure:
To a solution of N1-(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 22, 215 mg) in dry dichloromethane (15 mL) triethylamine (0.499 mL, 3.58 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (96 mg, 0.322 mmol) in dry dichloromethane (5 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system, SNAP column) on silica gel using as eluent a gradient cyclohexane/ethyl acetate from 80/20 to 40/60 to afford the title compound as a white solid (165 mg).
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>O>[CH2:33]([O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCCCCCCCCBr
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(N=Nc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
4-(phenyldiazenyl)phenol (2.100 g; 10.60 mmol) and potassium tert-butoxide (1.247 g; 11.13 mmol) were placed in a dry, two-neck, round-bottom flask equipped with a magnetic stirring bar, a reflux condenser, and a rubber septum. The flask was evacuated and purged with dry argon, then 25 mL of anhydrous N,N-dimethylformamide was added while stirring. As soon as the solids disappeared, 11-bromo-1-undecene (2.44 mL; 2.595 g; 11.13 mmol) was added and the solution was quickly heated, and allowed to reflux for 10 min. Formation of white precipitate was observed, and the color of the solution changed from deep red to bright orange. After 10 min, the heating was discontinued, and the flask was allowed to cool down. The reaction mixture was poured into a separatory funnel containing 100 mL of water, and extracted with four 50 mL portions of hexane. Hexane fractions were combined and dried over magnesium sulfate. Hexane was removed on a rotary evaporator, and the residue was purified by column chromatography (ethyl acetate:hexane 1:20) to give 2.95 g (79.5%) of analytically pure product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22](C1C=CC(C(O)(C)C)=CC=1)(=[O:24])=[O:23].CC1(C)C(C)(C)OB(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)O1.BrC1C=C(NS([N:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)(=O)=O)C(Cl)=NC=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([N:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(C)(C)O)cc4)c3)ccc2n1
Agent: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)N4CCOCC4)c3)ccc2n1
Yield: 26 %

Procedure:
Following the procedure described for compound N-(6-(6-chloro-5-(4-(2-hydroxypropan-2-yl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 35), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (122 mg, 404 μmol) (Example 35, Step 3) was reacted with N-(5-bromo-2-chloropyridin-3-yl)morpholine-4-sulfonamide from Step 1 (120 mg, 336 μmol) to afford the title compound as a light green solid (40 mg, 26% yield). MS (ESI positive ion) m/z: 452 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.12 (s, 3H), 3.12-3.18 (m, 4H), 3.60-3.68 (m, 4H), 7.86 (d, J=9.39 Hz, 1H), 8.14 (d, J=9.39 Hz, 1H), 8.33 (s, 1H), 8.54 (d, J=2.15 Hz, 1H), 8.90 (s, 1H), 10.14 (s, 1H), 10.97 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:21]([O:23]C)=O)[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:21]([NH2:25])=[O:23])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 75 °C
Yield: 82 %

Procedure:
Methyl 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxylate (3.0 g, 7.69 mmol) was mixed with 7 N NH3 in MeOH (80 mL) in a pressure bottle. This was sealed and heated at 75° C. for 47 hrs. It was cooled to RT and the solid was collected by filtration, washed with MeOH, and air dried to afford 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (2.64 g, 6.33 mmol, 82% yield) as a yellow solid. MS (ESI) m/z 375.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δppm 11.41 (1H, s), 8.42 (1H, br. s.), 7.96 (1H, d, J=8.85 Hz), 7.85-7.91 (2H, m), 7.19 (1H, d, J=1.83 Hz), 7.03 (1H, dd, J=8.70, 1.98 Hz), 3.72-3.85 (4H, m), 3.16-3.25 (4H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.[CH:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([CH:28]([OH:37])[CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[OH:20])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: COc1cccc(C=O)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(O)C(O)c2ccncc2)c1
Temperature: -20 °C

Procedure:
To a stirring solution of diisopropylamine (4.5 g, 5.8 mL, 44 mmol) in tetrahydrofuran (170 mL) at -78° C. was added n-butyllithium (17.7 mL of a 2.5M solution in tetrahydrofuran) dropwise. After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (9.0 g, 40 mmol) in tetrahydrofuran (35 mL) was added dropwise, and the temperature allowed to rise to -15° C. The solution was recooled to -78° C. and to it was added a solution of 3-anisaldehyde (5.5 g, 4.9 mL, 40 mmol) in tetrahydrofuran (35 mL) dropwise. The solution was allowed to warm to -20° C. and poured into saturated aqueous sodium hydrogen carbonate (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran (120 mL) and to this solution was added tetrabutylammonium fluoride (48 mL of a 1.0M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil was chromatographed on silica gel eluting with 97:3 ethyl acetate:methanol to give a mixture of diastereomeric diols as a foam (8.5 g) which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2C=C[CH:49]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:57])[CH3:56])=[O:53])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.CCO[CH2:62][CH3:63].CO.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:56])[CH3:57])=[O:53])[CH:49]=[CH:62][C:63]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCc1nc2c(NC(=O)NN(C)C)cccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc2ccc(NC(=O)NN(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 58b from 4'-[(2-n-butyl-4-dimethylaminoaminocarbonylamino-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in ether/methanol/methylene chloride.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>C(O)C.[OH-].[Na+]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1

Procedure:
A 3.15 g sample of methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoate is refluxed for 8 hours in 100 ml of ethyl alcohol and 2.5 ml of 10N sodium hydroxide. The cooled reaction mixture is acidified with [[? acid]] and the desired product collected and dried to give 2.9 g of the desired product as a solid m.p. 246°-249° C. M+H=318.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[N:28]1[CH:32]=[CH:31][N:30]=[N:29]1>>[C:26]([C:23]1[C:22]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)=[C:21]([NH:20][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: N#Cc1csc(N)c1-n1ccnn1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-n1ccnn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.072 g, 0.27 mmol) and 5-amino-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile (0.025 g, 0.13 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS retention time (min)=5.505, method [7], MS (ESI) 445.1 (M+H). 1H NMR (CDCl3) δ 11.17 (s, 1H), 8.41 (s, 1H), 7.91-7.87 (m, 3H), 7.79 (d, J=9.0 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:23]=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][O:16][C:12]=2[CH:11]=1>CN(C)C=O.O>[CH3:1][O:9][C:10]1[CH:23]=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][O:16][C:12]=2[CH:11]=1
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1noc2cc(OC)ccc12
Temperature: 25 °C
Yield: 19 %

Procedure:
Potassium carbonate (9.42 mmol) and iodomethane (8.45 mmol) were added to a solution of crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate (2.42 mmol) in N,N-dimethylformamide (30 mL) and the reaction mixture was maintained for 48 h at rt in the dark. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (30/1 petroleum ether/ethyl acetate) to provide ethyl 6-methoxybenzo[d]isoxazole-3-carboxylate in 19% yield as a yellow solid.
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[O:7]1[CH2:10][CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:5][C:2]([N:14]1[CH2:15][CH2:16][N:11]([CH:9]2[CH2:10][O:7][CH2:8]2)[CH2:12][CH2:13]1)([CH3:6])[CH:3]=[O:4]
Reactant: CC(C)(Br)C=O
Reactant: C1CN(C2COC2)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-2-methyl-propanal (696.6 mg, 4.61 mmol) in DCM (10 mL) was cooled with an ice bath and 1-(oxetan-3-yl)piperazine (328 mg, 2.31 mmol), diluted with 5-10 mL of DCM, was slowly added via addition funnel over a 15 min period. Next, Hunig's base (0.4 mL, 2.31 mmol) was added and then the cooling bath was removed. The reaction mixture was stirred at room temperature overnight and the DCM layer was washed three times with 0.5N HCl. The combined aqueous layer was neutralized with NaOH to pH 10-11 and extracted with DCM. The combined organic layer was washed with brine and dried over Na2SO4. Filtration and removal of solvent afforded 2-methyl-2-[4-(oxetan-3-yl)piperazin-1-yl]propanal as a light yellow liquid, which was used directly in the next step without further purification.
Reaction SMILES: [OH-].[K+].CS(O[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])(=O)=O.C(Cl)Cl.C(OCC)(=O)C>O.C(OCC)(=O)C>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([N:10]1[CH2:8][CH2:9]1)(=[O:13])=[O:12])([O-:22])=[O:21]
Reactant: CS(=O)(=O)OCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1

Procedure:
A solution of KOH (1.73 g, 31 mmol) in water (50 mL) was added to a solution of compound 55 (10 g, 31 mmol) in ethyl acetate (100 mL). The aqueous layer stained in yellow. The mixture was stirred at room temperature for 1 h (TLC monitoring, eluent: CH2Cl2-ethyl acetate, 1:1). If necessary, additional portions of KOH solution (0.5 eq.) were added. The organic layer was separated, washed thoroughly with water, a solution of citric acid (to pH 7), again with water, dried over Na2SO4, and evaporated. Yield of 56: 6.6 g (93%) as a yellowish fluid oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24]O)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:37]1C=CC=C[CH:38]=1>>[CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24][C:38]#[N:37])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2C[C@H]1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#CC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
11.24 g of (3S)-2-benzyloxycarbonyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline are dissolved in 40 ml of pyridine. 7.01 g of p-toluenesulfonyl chloride are added dropwise to the mixture of 5° C., and the mixture is stirred at the same temperature for 30 minutes. The mixture is evaporated under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with 5% HCl and water, dried and then evaporated to remove the solvent. The residue is dissolved in 50 ml of dimethylformamide, and the solution is added dropwise to a suspension of 2.21 g of sodium cyanide in 40 ml of dimethylformamide. The addition is carried out at 5° C. The mixture is stirred at the same temperature for 2 hours, and then at room temperature for 60 hours. The mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (Solvent; ethyl acetate:n-hexane=1:2). 3.78 g of (3S)-2-benzyloxycarbonyl-3-cyanomethyl-1,2,3,4-tetrahydro-β-carboline are obtained as pale red oil. Yield: 36%
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)[C:12]#[N:13].[CH3:28][O-].[Na+].CI.[Cl-].[NH4+]>CO.COCCOC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)([CH3:28])[C:12]#[N:13]
Reactant: C[O-]
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: COCCOC
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Yield: 70 %

Procedure:
Methanol (3 ml) and 2 ml of DME were added to 802 mg of alpha-(2-benzothiazolylthio)(m-benzoylphenyl)-acetonitrile, and the mixture was stirred in an argon atmosphere under ice cooling. Then, 0.78 ml of a 2.7 M methanol solution of sodium methoxide was added, and then 0.19 ml of methyl iodide was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and after adding an aqueous solution of ammonium chloride (1 g/20 ml), extracted with 40 ml of methylene chloride three times. The extract was washed with 50 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; benzene and methylene chloride) to afford 580 mg (yield 70%) of alpha-(2-benzothiazolylthio)-alpha-(m-benzoylphenyl)propionitrile as an oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Yield: 99.4 %

Procedure:
A solution of 775 mg (2.75 mmol) of nitro compound from Example 215 in 20 mL of methanol with 10% palladium on carbon (150 mg) was introduced hydrogen via balloon at room temperature for 4 h. The catalyst was filtered off through Celite, and the filterate was concentrated under vacuum to give 690 mg of the title compound: 1H NMR (200 MHz, CDCl3) 8 6.69 (d, 2H, J=8Hz), 6.58 (d, 2H, J=8Hz), 4.94 (bs, 1H, N-H), 3.89 (bt, 2H, J=5.0Hz), 3.40 (q, 2H, J=5.0Hz), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH:12]=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].[CH2:18]([OH:20])[CH3:19]>O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][C:12]([O:20][CH2:18][CH3:19])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(C)(C)CC=O)cc1F
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)(C)Cc1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of silver nitrate (5.76 g, 33.9 mmol) in 20 ml H2O was added to a solution of the product of STEP 4 (3.8 g, 16.9 mmol) in 80 ml ethanol. A solution of Sodium hydroxide (2.71 g, 67.7 mmol) in 10 ml H2O was added dropwise at room temperature. After 2 h, the reaction was filtered through a short column of Celite®. The filtrate was diluted with H2O and extracted with ether (3×30 ml). The aqueous layer was acidified with concentrated HCl and extracted with chloroform. Chloroform layer was dried with MgSO4 and concentrated. The residue was dissolved in 50 ml ethanol and 25 ml 4N HCl/dioxane solution. It was stirred at room temperature for 60 h and then concentrated to afford a colorless oil in 4.14 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)OC)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)O)c(Cl)c1

Procedure:
By the method of Example 11, 320 mg of the product of Example 14 was treated with 200 mg of lithium hydroxide monohydrate to give the product of Example 11, the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C1C2CC3(N)CC(C2)CC1C3.Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.O.O1CCOCC1>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[C:2]([CH:9]=1)=[C:13]1[C:12]([CH:17]=[CH:16][CH:15]=[CH:14]1)=[N:11][C:4]=2[NH2:5]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc2ccccc2c2cc(F)ccc12
Yield: 3082.6 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.0 g, 6.42 mmol), 2-aminophenylboronic acid pinacol ester (1.6 g, 7.1 mmol), palladium(II) acetate (0.07 g, 0.32 mmol), amantadine hydrochloride (0.24 g, 1.3 mmol) and cesium carbonate (4.6 g, 14.1 mmol) were added to dioxane previously deaerated with nitrogen and heated to reflux for 17 hours. After cooling, both distilled water and methylene chloride (50 mL) were added to the reaction mixture. The solvent layer was separated and concentrated to give a crude oil that was purified by column chromatography by first using 1:1 ethyl acetate and hexanes ratio followed by 4:1 ethyl acetate/hexanes as the eluants. The pure product was collected to give 9-fluoro-6-phenanthridinamine (42 g, 32% Yield) whose NMR spectrum is consistent with the proposed structure.