Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[C:24]([O:26]C(C)(C)C)=[O:25])[CH2:15][CH2:14][S:13][C:12]=2[CH:31]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[ClH:48].O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:48].[ClH:48].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[C:24]([OH:26])=[O:25])[CH2:15][CH2:14][S:13][C:12]=2[CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: COc1ccccc1
Product: N=C(Nc1ccc2c(c1)SCCN2CCN1CCC[C@H]1C(=O)O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of (S)-tert-butyl 1-(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)pyrrolidine-2-carboxylate (200 mg, 0.423 mmol) in CH2Cl2 (5 mL) was treated with anisole (0.092 mL, 0.846 mmol). The reaction was cooled to 0° C., and trifluoroacetic acid (2.76 mL, 25.4 mmol) was then added. The mixture was stirred at 0° C. for 2 hours then concentrated to dryness. To this residue was added 4M HCl in dioxane (3.17 mL, 12.69 mmol), and the resulting suspension was stirred for 20 minutes. This mixture was diluted with Et2O (10 mL) and stirred for 1 hour. The solid was filtered, washed with Et2O (10 mL), and then dried under reduced pressure. The solid was dissolved in 3N HCl (4.0 mL, 12.00 mmol) and heated at 50° C. for 1 hour. The yellow solution was concentrated and dried under reduced pressure to give compound 18 as yellow solid (200 mg, 97%). 1H-NMR (CD3OD) δ 7.98-7.94 (m, 2H), 7.28 (dd, J=4.2, 4.8 Hz, 1H), 7.05-7.01 (m, 2H), 6.92 (d, J=8.7 Hz, 1H), 4.42 (dd, J=7.8, 9.0 Hz, 1H), 3.85-3.56 (m, 6H), 3.48-3.29 (m, 2H), 3.13-3.03 (m, 2H), 2.62-2.47 (m, 1H), 2.26-2.10 (m, 2H), 2.08-1.92 (m, 1H); ESI-MS (m/z, %): 417 (MH+, free base, 100); ESI-HRMS calculated for C20H25N4O2S2 (MH+, free base): 417.1419, observed: 417.1399; HPLC purity: 99.5% a/a; Optical Rotation: 25[α]589=−27.0°, c=0.52 in MeOH.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[CH3:22])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[C:2]([NH:1][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:14]=1
Reactant: O=C1CCOCC1
Reactant: CN1CCC[C@H]1COc1ccc(C(=O)OC(C)(C)C)c(N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1ccc(C(=O)OC(C)(C)C)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Tert-butyl 2-amino-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}benzoate (400 mg, 1.3 mmol) was dissolved in 20 ml of DCM under argon atmosphere. Tetrahydro-4H-pyran-4-one (0.19 ml, 2.05 mmol), TFA (0.29 ml, 3.69 mmol) and Me4BH(OAc)3, (540 mg, 2.05 mmol) were added. The resulting slurry was stirred overnight at room temperature then quenched with 15 ml of NaHCO3 10% and extracted twice with 20 ml of DCM. The organic layers were then dried over Na2SO4, filtered off and concentrated to yield a yellow oil (448 mg, 1.15 mmol, 88%) which was used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[NH-:12].ClC1C2C(=CC=CC=2)[N:17]=[CH:16]C=1[NH-].NO>>[NH:17]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:16]1
Reactant: [NH-]c1cnc2cccnc2c1Cl
Reactant: [NH-]c1cnc2ccccc2c1Cl
Agent: NO
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (1) of Reaction Scheme VII, an N-(4-chloro[1,5]naphthyridin-3-yl)amide or N-(4-chloroquinolin-3-yl)amide of Formula XXXII is reacted with a hydroxylamine of the Formula Boc-CH2—X—CH2—ONH2 and cyclized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine or a 1H-imidazo[4,5-c]quinoline of Formula LX. The reaction can be carried out using the method described in step (3) of Reaction Scheme I. Hydroxylamines of the Formula Boc-CH2—X—CH2—ONH2 can be prepared by conventional methods.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](=[O:11])[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>CO.CCOC(C)=O.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH:4]1[CH2:5][CH:6]2[N:7]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:8](=[O:11])[O:9][CH:10]2[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a degassed solution of (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in MeOH and EtOAc (1:1, 0.1M) was added Pd/C (0.1 equiv.). The reaction was stirred under a hydrogen balloon overnight. Upon completion, the solution was filtered through a pad of Celite and the pad was washed with ethyl acetate. The filtrate was concentrated under vacuo to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate as the desired product as a yellow foam in 93% yield. LC/MS=348.1 (M+H), Rt=055 min.
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Mg+2:12].[OH-]>O>[C:1]1([P:7](=[O:8])([O-:10])[O-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2:12]
Reactant: O=P(O)(O)c1ccccc1
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
1.58 g (10.0 mmol) of phenylphosphonic acid (manufactured by Nissan Chemical industries, Ltd.), 0.583 g (10.0 mmol) of magnesium hydroxide and 41 g of water were mixed, stirred at 80° C. for 3 hours, then water was distilled off under reduced pressure and dried at 200° C. to obtain 1.78 g (yield 99%) of the aimed product as white crystal. Decomposition temperature: 524° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]1[C:9](P(OC(C)C)(=O)OC(C)C)=[N:8][C:7]([P:20]([O:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])=[N:6][C:5]=1[P:30]([O:36][CH:37]([CH3:39])[CH3:38])(=[O:35])[O:31][CH:32]([CH3:34])[CH3:33]>>[CH3:1][N:2]([CH3:3])[C:9]1[N:8]=[C:7]([P:20]([O:26][CH:27]([CH3:28])[CH3:29])(=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])[N:6]=[C:5]([P:30]([O:31][CH:32]([CH3:34])[CH3:33])(=[O:35])[O:36][CH:37]([CH3:39])[CH3:38])[N:4]=1
Reactant: CNC
Reactant: CC(C)OP(=O)(OC(C)C)c1nc(P(=O)(OC(C)C)OC(C)C)nc(P(=O)(OC(C)C)OC(C)C)n1
Product: CC(C)OP(=O)(OC(C)C)c1nc(N(C)C)nc(P(=O)(OC(C)C)OC(C)C)n1

Procedure:
Following the procedure of Example 20, aqueous dimethylamine (40% w/w, 50.63 g, 20.25 g (CH3)2NH, 0.450 mol) was reacted with hexaisopropyl 1,3,5-triazine-2,4,6-triphosphonate (42.98 g) to produce tetraisopropyl 2-dimethylamino-1,3,5-triazine-4,6-diphosphonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9][C:10](=N)N)[CH:5]=[CH:6][C:7]=1[OH:8].C[O-].[Na+].[Na].S(C1C=CC(C)=CC=1)(O[CH2:21][CH:22](C)[CH2:23][CH3:24])(=O)=O>CO>[CH3:21][CH:22]([CH2:23][CH3:24])[CH2:10][S:9][C:4]1[CH:3]=[C:2]([OH:1])[C:7](=[CH:6][CH:5]=1)[OH:8]
Reactant: N=C(N)Sc1ccc(O)c(O)c1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCC(C)CSc1ccc(O)c(O)c1

Procedure:
22 g (0.1 mole) of S-(3,4-dihydroxyphenyl)-isothiourea were dissolved in 50 ml of anhydrous methanol in a 1 litre flask equipped with a magnetic stirrer and under a nitrogen flow. The solution was heated and a solution of sodium methoxide containing 9.2 g of sodium (4 equivalents) in 150 ml of anhydrous methanol was added. 24.2 g (0.1 mole) of 2-methylbutyl tosylate in solution in 50 ml of methanol were poured into the reaction mixture at the boiling point of methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:16]=[O:17])[CH:3]=1.O1CCC[CH2:19]1.C[Mg]I>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[C:4]([CH:16]([OH:17])[CH3:19])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C=O
Reactant: C1CCOC1
Agent: C[Mg]I
Solvent: CCOCC
Product: CC(O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To an ice-cooled solution of tert-butyl 6-chloro-4-formylpyridin-3-ylcarbamate (1.0091 g, 3.9313 mmol) in tetrahydrofuran (20 mL, 200 mmol) in an oven-dried flask was added 3.0 M of methylmagnesium iodide in ether (3.4 mL). The reaction mixture was stirred at 0° C. for one hour and then quenched with 10 mL saturated aqueous NH4Cl. The resulting mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, and the organic layer was dried with brine and MgSO4 and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-40% ethyl acetate in heptane) to yield 0.870 g (81%) of tert-butyl 6-chloro-4-(1-hydroxyethyl)pyridin-3-ylcarbamate. LCMS (ESI): M+H=273.2; 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.43 (s, 1H), 7.45 (s, 1H), 5.76 (s, 1H), 4.95 (d, J=6.4 Hz, 1H), 1.46 (s, 9H), 1.28 (d, J=6.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[Br:20][C:21]1[N:22]=[CH:23][N:24]([C:2]2[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH3:18])[CH:9]=3)[N:7]=2)[CH:25]=1
Reactant: Brc1c[nH]cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example A.40) (0.40 g, 1.4 mmol) and commercially available 4-bromo-imidazole (0.31 g, 2.1 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.54 g, 97%). MS (ISP) 399.0 [(M+H)+]; mp 157.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>N1C=CC=CC=1>[CH3:29][S:30]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (107 mg, 0.29 mmol, prepared in Example 43) in pyridine (2 ml) was added methanesulfonyl chloride (47 mg, 0.41 mmol, 1.4 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried and purified by flash column chromatography to afford 3-(4-methanesulfonylaminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (84 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[CH:15]=[CH:14][N:13]3[C:21]=2[CH3:22])=[CH:4][C:3]=1[OH:23].[N:24]#[C:25]Br>C(O)C>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][N:13]2[C:21]([CH3:22])=[C:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:25]([NH2:24])[O:23][C:3]=4[CH:4]=3)[N:11]=[C:12]2[CH:17]=1)[CH3:20]
Reactant: CCOc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: N#CBr
Solvent: CCO
Product: CCOc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
A mixture of 2-[2-(4amino-3-hydroxyphenyl)ethyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (1.6 g) and cyanogen bromide (0.7 g) in ethanol (24 ml) was stirred for 1.5 hours at ambient temperature. The solvent was evaporated in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with a solution of diethyl ether and ethyl acetate and precipitate was collected by filtration to give 6-[2-(7-ethoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzoxazole (1.12 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:14]([N:17](CC)C(C)C)(C)C.CN.O1CCCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:17][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (0.5 g, 2.7 mmol) in dichloromethane (10 mL) was cooled with an ice water bath before the addition of N,N-diisopropylethylamine (1.13 g, 8.1 mmol). To this solution 2M methylamine in tetrahydrofuran (1.6 g, 3.24 mmol) was added dropwise over 5 minutes. 1-Propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.56 mL, 4.05 mmol) was added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on a 2 g ABW column to afford 5-fluoro-N-methyl-2-nitrobenzamide (0.26 g, 1.31 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1>CO.[Pd]>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1
Reactant: N#Cc1ccc2[nH]cc(C=C3CCCC3=O)c2c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CC3CCCC3=O)c2c1
Yield: 17.3 %

Procedure:
A solution of 3-(2-oxo-cyclopentylidenemethyl)-1H-indole-5-carbonitrile (800 mg, 3.39 mMol) in methanol (120 mL) was hydrogentated at atmospheric pressure for 16 h over 10% Pd/C catalyst (300 mg). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (5% ethyl acetate/hexanes-80% ethyl acetate/hexanes) to give 3-(2-oxo-cyclopentylmethyl)-1H-indole-5-carbonitrile (140 mg, 18%). LCMS (4.6×50 mm XTERRA C-18 S5 column, 5 mL/min, 0–100% MeOH/H2O/0.1% TFA, 2 min gradient): Tr=1.51 min, m/e 261 (M+H+Na)+.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:18]2[C:1](=[O:13])[CH2:2][C:3]3[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]2=[O:7])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Product: O=C1Cc2ccccc2C(=O)N1c1cccc(Cl)c1
Yield: 58 %

Procedure:
A mixture of homophthalic acid (45.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) was heated by an oil bath to 175°-180° C. for two hours. When removed from the oil bath, the reaction mixture solidified and was recrystallized twice from ethanol/ethyl acetate, giving 2-(m-chlorophenyl)-isoquinoline-1,3 (2H, 4H)-dione, 36.0 g. (58% yield), m.p. 160°-161° C.
Reaction SMILES: N[C:2]1[C:12](/C=C/C(OC)=O)=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:8]1(=[O:9])[NH:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:2]=[C:3]12
Reactant: COC(=O)/C=C/c1cc(Br)c2c(c1N)C(=O)NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccccc21
Yield: 225.1 %

Procedure:
In a similar manner to Step 2 of Example 1, (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-bromophthalimide (100 mg, 0.308 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with Compound BB (292 mg, 0.616 mmol), palladium acetate (5.5 mg, 0.025 mmol), tri(o-tolyl)phosphine (15 mg, 0.049 mmol) and triethylamine (0.429 mL, 3.08 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=6/1) to obtain (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-(tert-butoxycarbonyl)-5-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indol-2-yl)phthalimide (102 mg, yield 49%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([OH:44])=O)[N:38]=[N:37]1.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][N:50]=[N:49][CH:48]=1>CN(C=O)C>[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([N:46]([CH3:45])[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[O:44])[N:38]=[N:37]1
Reactant: COCCn1nnc(C(=O)O)c1C
Reactant: CNc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCn1nnc(C(=O)N(C)c2ccnnc2)c1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphat (HATU; 1.23 g, 3.24 mmol, 3.00 eq) and N-methylmorpholine (0.71 ml, 0.66 g, 6.5 mmol, 6.0 eq) was added to a solution of 1-(2-methoxyethyl)-5-methyltriazole-4-carboxylic acid (200 mg, 1.08 mmol) and N-methylpyridazin-4-amine (118 mg, 1.08 mmol, 1.00 eq) in DMF (2.5 ml) and the mixture was stirred at room temperature for 4 d. After removal of the solvent, the residue was dissolved in dichloromethane, washed twice with sat. aq. NaHCO3 sol. and once with brine and dried over Na2SO4. Removal of the solvent under vacuum and chromatographic purification (CH:EtOAc) gave the title compound as a brown oil (200 mg, 64%, 95% purity).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:28]([O-])=O)=[C:12]([CH:15]=[C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=[O:35])C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:28][C:11]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[CH:17][C:16]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH3:20])=[CH:15][C:12]=1[C:13]([NH2:14])=[O:35]
Reactant: CC(=O)[O-]
Reactant: C[C@H](Nc1cc(C#N)c([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)c(C(N)=O)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile (Method 97; 4.20 g, 10.0 mmol) and zinc dust (3.40 g, 52 mmol) in MeOH-THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was then added saturated ammonium acetate solution (50 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (200 ml). The organic layer was separated, washed with brine (100 ml), dried over sodium sulfate, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd: 394; Found: [M+H]+ 395.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH2:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[NH:24][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
411 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester were dissolved in 10 ml of anhydrous DMF and cooled to 0° C. 191 mg of 4-toluenesulfonyl chloride and 0.34 ml of diisopropylethylamine were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solvents removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 295 mg. MS (ES+): m/e=506.2 (M+H)+; 450.2.
Reaction SMILES: CC1CCCN(C2OC(C(NC3C=CC(N4CCN(CC5C=C(C=CC=5)C(OC)=O)C(=O)C4)=NC=3)=O)=C(C(F)(F)F)N=2)C1.[N:44]1([C:51]2[N:56]=[CH:55][C:54]([NH:57][C:58]([C:60]3[O:64][C:63]([N:65]4[CH2:70][CH2:69][CH2:68][CH:67]([CH3:71])[CH2:66]4)=[N:62][C:61]=3[C:72]([F:75])([F:74])[F:73])=[O:59])=[CH:53][CH:52]=2)[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[F:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[N:83]=[C:84]=[O:85]>>[CH3:71][CH:67]1[CH2:68][CH2:69][CH2:70][N:65]([C:63]2[O:64][C:60]([C:58]([NH:57][C:54]3[CH:53]=[CH:52][C:51]([N:44]4[CH2:50][CH2:49][CH2:48][N:47]([C:84]([NH:83][C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=5[F:76])=[O:85])[CH2:46][CH2:45]4)=[N:56][CH:55]=3)=[O:59])=[C:61]([C:72]([F:74])([F:75])[F:73])[N:62]=2)[CH2:66]1
Reactant: O=C=Nc1ccccc1F
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCNCC4)nc3)o2)C1
Agent: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCN(C(=O)Nc5ccccc5F)CC4)nc3)o2)C1

Procedure:
Compound 40 was prepared by the general procedure for compound 8, by using compound 39 and 2-fluorophenylisocyanate as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.15 (d, 1H, J=2.5 Hz), 8.10 (t, 1H, J=8 Hz), 7.90 (dd, 1H, J=2.5, 9 Hz), 7.50 (s, 1H), 7.10 (m, 2H), 7.00 (m, 1H), 6.60 (d, 1H, J=4 Hz), 6.55 (d, 1H, J=9 Hz), 4.10 (m, 2H), 3.90 (m, 2H), 3.75 (m, 4H), 3.45 (t, 2H, J=6.5 Hz), 3.05 (t, 1H, J=12 Hz), 2.75 (t, 1H, J=13 Hz), 2.10 (t, 2H, J=6 Hz), 1.90 (d, 1H, J=13 Hz), 1.80 (m, 2H), 1.65 (m, 1H), 1.20 (q, 1H, J=11.5 Hz), 1.00 (d, 3H, J=6.5 Hz). MS (M+1): 590.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.ClCCl>O1CCOCC1.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]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 1,3-dibenzyl-5-bromo-2-methyl-1H-indole (1.842 g, 6.133 mmol) was reacted with aqueous 2M K2CO3 (6.1 ml), 4-methoxyphenylboronic acid (1.118 g, 7.360 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.100 g, 0.123 mmol) in dioxane (61 ml) to give the product (0.702 g, 1.681 mmol, 27%) as a pale-yellow solid, mp 136-139° C. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 3.76 (s, 3H), 4.10 (s, 2H), 5.43 (s, 2H), 6.95-7.00 (m, 4H), 7.09-7.13 (m, 1H), 7.20-7.30 (m, 8H), 7.39 (d, J=8.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.57 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 418 (M+H)+.