Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(C2C=C3C(C(C)=CC(=O)N3CC3OCCO3)=CC=2)CCCCC=1>[C].[Pd].C(O)C>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([CH3:24])=[CH:12][C:13](=[O:23])[N:14]3[CH2:17][CH:18]3[O:19][CH2:20][CH2:21][O:22]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(C3C=CCCC3)ccc12
Agent: [Pd]
Agent: Cc1cc(=O)n(CC2OCCO2)c2cc(C3=CCCCC3)ccc12
Solvent: CCO
Product: Cc1cc(=O)n(CC2OCCO2)c2cc(C3CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5 mL of an ethanol solution containing 0.39 g of the mixture of 7-(2-cyclohexen-1-yl)-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one and 7-(1-cyclohexen-1-yl)-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 0.12 g of 5% palladium carbon was added, the mixture was stirred at room temperature for 1 hour and 30 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtain 0.31 g of a colorless oily substance, 7-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[F:8].Br>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.9 %

Procedure:
Trans-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (242 mg, 0.72 mmol) was dissolved in hydrobromic acid (33% in AcOH, 4 mL, 24.31 mmol) and stirred at room temperature for 20 h. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC (Instrument: Agilent, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,4-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (137 mg, 68%). 1H NMR (600 MHz, dmso) δ 1.74-1.81 (m, 2H), 1.84-1.89 (m, 1H), 1.98-2.03 (m, 1H), 2.65-2.71 (m, 1H), 2.81 (dt, 1H), 3.09-3.13 (m, 1H), 3.70 (dd, 1H), 5.96 (s, 1H), 7.18-7.22 (m, 1H), 7.30-7.36 (m, 1H), 7.39-7.44 (m, 1H). HRMS Calcd for [C14H14F2N2O2+H]+: 281.1101. Found: 281.1114.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22](=[O:23])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(F)c1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine (8g, 45.4 mmol), 3-fluorophenyl acetic acid (7.7 g, 50 mmol), triethylamine (7 ml, 50.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol) were stirred together in dry dichloromethane (150 ml) for 24 hours. The volatiles were evaporated then the residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried then evaporated. The residue was purified by column chromatography on silica using 2% methanol in dichloromethane→10% methanol in dichloromethane. The title compound was obtained as a yellow oil (11.1 g, 77%). δ (250 MHz, CDCl3) 2.28 (2H, t, J=5 Hz), 2.42 (2H, t, J=5 Hz), 3.43 (2H, t, J=5 Hz), 3.44 (2H, s), 3.65 (2H, t, J=5 Hz), 3.71 (2H, s), 6.90-7.37 (9H, m).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1.B(Br)(Br)Br.C(Cl)Cl>>[CH3:1][CH2:2][C@H:3]1[CH:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@H:7]2[CH2:6][CH:5]([CH2:10]3)[CH2:4]1
Reactant: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC[C@@H]1CC2C[C@@H]3c4[nH]c5ccc(O)cc5c4CCN(C2)C13

Procedure:
Noribogaine is synthesized by the O-demethylation of ibogaine. This may be accomplished, for example, by reacting ibogaine with boron tribromide/methylene chloride at room temperature and then purifying the product using known procedures. At present, noribogaine may also be obtained from the National Institute on Drug Abuse (Rockville, Md.). The compound has the following structure:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7]2.[CH:28](=O)[CH3:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:28][CH3:29])[CH2:7][CH:8]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:9]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2N(Cc2ccccc2)C1=O
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cccc2c1N(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 8-amino-1-benzyl-1,2,3,4-tetrahydro-2-oxoquinolin-3-ylcarbamate (1.0 g) was dissolved in methanol (10 mL), and acetaldehyde (599 mg), acetic acid (10 mg), and sodium cyanoborohydride (171 mg) were sequentially added to the solution under cooling on ice. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure. The thus-recovered residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, and solvent was evaporated under reduced pressure. The recovered residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:3), whereby the title compound (600 mg) was yielded.
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:35][C@H:36]([C:41]([CH3:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].Br.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(C)=O)CC(C)C)=O)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:35][C@H:36]([C:41]([CH3:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: CC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Product: CC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Z-Phe-Gly-Leu-LeuCH3 was prepared by coupling Z-Phe-Gly-Leu-OH (2.23 g, 4.76 mmol) to H-LeuCH3.HBr by a procedure substantially similar to that described for preparation of Z-Phe-Gly-Ala-LeuCH3 in Example 1, above. Product was recrystallized from ethyl acetate to yield 2.34 g of Z-Phe-Gly-Leu-LeuCH3 (m.p. 165.5°-166.5°).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Reactant: Fc1ccc(CCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(F)cc4)CC3)cccc2s1
Yield: 11 %

Procedure:
In an analogous manner to example 6, the title compound (0.83 g, recrystallized from 27 mL methanol and 15 mL acetonitrile) as a white solid, mp 265°-270° C. dec., is prepared from ethyl-4-(1-piperazinyl)benzo[b]thiophene-2-carboxylate monohydrochloride (5.5 g, 16.8 mmol, prepared in example 5), 4-fluorophenethyl bromide (3.42 g, 16.8 mmol), sodium bicarbonate (2.83 g, 33.7 mmol) and N,N-dimethylformamide (85 mL); 1H NMR (DMSO-d6) δ 11.33 (1H, bs), 8.10 (1H, s), 7.76 (1H, d, J=8.2 Hz), 7.50 (1H, t, J=7.9 Hz), 7.37 (2H, m), 7.20 (2H, m), 7.08 (1H, d, J=7.6 Hz), 4.37 (2H, q, J=7.1 Hz), 3.69 (2H, m), 3.58 (2H, m), 3.37 (6H, bm), 3.15 (2H, m), 1.34 (3H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 162.77, 161.87, 148.21, 142.83, 132.63, 132.00, 130.59, 128.34, 127.83, 118.04, 115.56, 115.27, 113.73, 61.51, 56.16, 51.14, 48.82, 28.46, 14.17; 19F NMR (DMSO-d6) δ-115.65; IR (KBr) 1716, 1512, 1446, 1282, 1246, 754 cm-1 ; CI/MS (CH4) 413(100%). IC50 =7.4 nM (5-HT1ABinding Affinity) IC50 =120 nM (5-HT1DBinding Affinity) pA2 =7.53 (0% ) (blocking of 5-HTl-like-mediated contraction in canine saphenous vein )
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+]>C(O)(=O)C>[CH3:3][NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: CNC=CC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CNCCC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
In brief, exemplary methods include sodium borohydride (800 mg, 21.0 mmol) added in portions to a vigorously stirred solution of 3-methylamino-1-phenyl-2-propen-1-one (600 mg, 3.7 mmol) in glacial acetic acid (15 ml) over a period of 30 minutes at 5 to 10° C. The reaction mixture was stirred for another 30 minutes at the same temperature, and then for 3 hours at room temperature. Work up was done using 4 M aqueous sodium hydroxide (60 ml) that was added dropwise under cooling (water/ice bath). The resulting mixture was extracted with ethyl acetate (3 times 70 ml), washed with water (50 ml), and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave 470 mg (77%) of 3-methylamino-1-phenyl-1-propanol as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCOCC1.O>[CH2:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([CH3:14])[CH2:13][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[CH2:9]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
((3R,5R)-5-Methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (2.9 g, 13.53 mmol) was dissolved in 70 mL of a 1:1 mixture of dioxane and H2O and NaHCO3 (4.55 g, 54.13 mmol) was added. To the resulting suspension benzyl chloroformate (2.2 mL, 14.2 mmol) was added slowly. After 2 hours the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated. The remaining oil was purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0 to 20% EtOAc) to give 3.6 g of (3R,5R)-3-tert-butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester as a colorless oil (76% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:9][NH2:10]>C1(C)C=CC=CC=1>[CH:1](=[CH:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: NC=Cc1cccnc1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Nicotinaldehyde (10.7 g, 0.1 mol) was dissolved in toluene (100 ml) and thereto was added 40% aqueous methylamine solution (23.3 g, 0.3 mol) and the mixture was subjected to azeotropic dehydration for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain N-nicotinylidenemethylamine (11.7 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]1[N:45]([CH3:46])[C:44]([CH3:47])=[N:43][CH:42]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:46][N:45]1[C:41]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:10]4[S:9][C:5]5[C:6](=[O:8])[NH:7][C:2]([CH3:1])([CH3:31])[CH2:3][C:4]=5[N:11]=4)[C:17]=3[CH:18]=2)=[CH:42][N:43]=[C:44]1[CH3:47]
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(B5OC(C)(C)C(C)(C)O5)cc43)sc2C(=O)N1
Reactant: Cc1ncc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(-c2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1C
Temperature: 140 °C
Yield: 28.7 %

Procedure:
To a solution of Example 292 (75 mg, 0.17 mmol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (107 mg, 0.34 mmol), potassium phosphate (72 mg, 0.34 mmol), 5-bromo-1,2-dimethyl-1H-imidazole (60 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The reaction was heated at 140° C. under microwave irradiation for 25 minutes. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 7) to yield the title compound (20 mg, 28%) as a white solid. δH (CDCl3) 7.99 (1H, d, J 1.9 Hz), 7.06 (1H, dd, J 8.5 and 1.9 Hz), 7.01 (1H, d, J 8.5 Hz), 6.93 (1H, s), 5.34 (1H, s), 4.40-4.35 (2H, m), 4.19-4.13 (2H, m), 3.57 (3H, s), 2.87 (2H, s), 2.46 (3H, s), 1.40 (6H, s). LCMS (ES+) 410.0 (M+H)+, RT 1.95 minutes (Method 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH3:33][N:34]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[N:35]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:37]4[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cnn(C)c4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 290 mg, 0.574 mmol), 1-methylpyrazolboronicacid pinacol ester (190 mg, 0.886 mmol), PdCl2(dppf) (43 mg, 59 μmol) and saturated aqueous Na2CO3 (0.7 ml) in DME (2.1 ml) was sealed in a vial and purged with argon. The reaction mixture was stirred at 120° C. for 20 min in a microwave. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM, followed by another purification eluting with a gradient of MeOH (1-5%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.95 min; ESI-MS 507.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCS(=O)(=O)c1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of 1-(ethylsulfonyl)-4-methylbenzene (5 g, 25.7 mmol) in CCl4 (30 mL) was added N-bromosuccinimide (5.54 g, 30.8 mmol) and azobisisobutyronitrile (0.46 g, 2.57 mmol). The mixture was stirred at 80° C. overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was added to water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×40 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 1-(bromomethyl)-4-(ethylsulfonyl)benzene (6.62 g, 98%) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:27]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:25][CH2:26]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCCCn1cnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: c1ccc(C(c2ccccc2)N2CCN(CCCn3cnc4ccccc43)CC2)cc1
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A mixture of 4.5 g of 1-(3-chloropropyl)-1H-benzimidazole, 5.1 g of 1-(diphenylmethyl)piperazine, 3.7 g of sodium carbonate, 0.1 g of potassium iodide and 100 ml of 4-methyl-2-pentanone was stirred overnight at reflux temperature. After cooling, there was added water and the reaction mixture was separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.5 g (14.5%) of 1-[3-[4-(diphenylmethyl)-1-piperazinyl]propyl]-1H-benzimidazole; mp. 132.3° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.C(OC([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.Cl[Pd]Cl.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:23]2[CH2:24][CH2:25][NH:20][CH2:21][CH:22]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(C2=CCNCC2)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6 g, 25.86 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (7.996 g, 25.86 mmol), Na2CO3 (38.79 mL of 2 M, 77.58 mmol) and dichloropalladium; triphenylphosphane (544.5 mg, 0.7758 mmol) was stirred in DME (120.0 mL) at 100° C. for 5 hours. After this time water and EtOAc were added and the organics separated, dried and concentrated in vacuo. The residue was redissolved in DCM (20 mL) and TFA (20 mL) and the resulting solution stirred at ambient temperature for 2 hours. After this time saturated NaHCO3 was added and the organics separated, dried and concentrated. The solid was then triturated with MeOH, filtered and washed with MeOH to give the desired product as a yellow solid (4.15 g, 69%). 1H NMR (400.0 MHz, DMSO) d 2.43 (3H, s), 3.41 (2H, m), 3.80-4.02 (5H, m), 6.52 (1H, s), 7.33 (2H, s), 8.52 (1H, s) ppm; MS (ES+) 234.97
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)(=O)C>[C:23]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-(3-carboxybenzoyl)-6-chloroindole (Example 131) and acetyl chloride. m.p.: >290° C. (ethyl acetate) 1H-NMR (DMSO-d6) δ: 11.85 (1H, s), 9.90 (1H, s), 8.39 (1H, br s), 8.20 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.7 Hz), 7.65 (1H, d, J=8.8 Hz), 7.54-7.43 (2H, m), 7.09 (1H, dd, J=1.8, 8.4 Hz), 1.67 (3H, s)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:16](=O)[CH2:17][CH3:18])[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[BrH:21].[NH:22]([C:24]1[NH:25][CH2:26][CH2:27][N:28]=1)[NH2:23].C(O)(C)C.C(OCC)C>C(OCC)C>[BrH:21].[C:4]([C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:23]([NH:22][C:24]2[NH:28][CH2:27][CH2:26][N:25]=2)[C:16]=1[CH2:17][CH3:18])([O:3][CH2:1][CH3:2])=[O:20]
Reactant: CCOC(=O)C(C(=O)CC)C(C(=O)CC)C(=O)OCC
Reactant: NNC1=NCCN1
Agent: Br
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)c1c(C(=O)OCC)c(CC)n(NC2=NCCN2)c1CC

Procedure:
The compound is obtained following substantially the method described in Example 3, by reacting 13 g. (0.0455 mole) of diethyl-2,3-dipropionyl-succinate with 8.14 g. (0.0449 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide. Yield 55 g. M.p. 181°-2°C (from isopropanol/diethyl ether). The free base melts at 155°C (from diethyl ether).