Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: CCOC(=O)Nc1c(F)cc(F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(F)cc(F)cc1C#C[Si](C)(C)C
Yield: 67.3 %

Procedure:
In a 2 L flask, 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150 mmol) in CH3CN (500 mL) is degassed with vacuum and purged with N2. Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol %), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41 mL) are added and rinsed in with 100 mL of CH3CN. Trimethylsilyl acetylene (31.8 ml, 225 mmol) is added and reaction is refluxed under N2. Approximately 2 hours later, the starting material is consumed, indicated by TLC (20% ethyl acetate/hexane, UV). The reaction is cooled, filtered, concentrated, and the residue is dissolved in ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 30 g of 2-(trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (71%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:11][C@H:12]([CH2:30][O:31][CH3:32])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C:23]2=[O:28])=[C:18]([CH3:29])[CH:17]=1)=[O:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C@@H:12]([C:13](=[O:14])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C:23]3=[O:28])=[C:18]([CH3:29])[CH:17]=2)[CH2:30][O:31][CH3:32])=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)O)s1
Reactant: COC[C@@H](N)C(=O)Nc1ccc(N2CCOCC2=O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C#Cc1ccc(C(=O)N[C@H](COC)C(=O)Nc2ccc(N3CCOCC3=O)c(C)c2)s1

Procedure:
Prepared analogously to Example 1a from 5-ethynylthiophene-2-carboxylic acid and 2-(R)-amino-3-methoxy-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide with TBTU and NMM in DMF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a round bottom flask was added 5-bromopyridin-3-amine (0.80 g, 4.6 mmol, Matrix Scientific, Columbia S.C.), ethanol (15 mL) and 4-fluorobenzenesulfonyl chloride (2.2 g, 12 mmol, Fluka, St. Louis, Mo.). The mixture was allowed to stir at ambient temperature overnight. The mixture was diluted with CH2Cl2 and sat. NaHCO3, then the solution was extracted with CH2Cl2 (3×25 ml). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% EtOAc/CH2Cl2) afforded the title compound as an off-white crystalline solid (0.35 g, 23% yield). MS (ESI pos. ion) m/z: 333 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.35 (s, 1H), 8.22 (s, 1H), 7.83-7.89 (m, 2H), 7.76-7.81 (m, 1H), 7.25-7.32 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[NH:4][N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6](=[O:25])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([S:16](O)(=[O:18])=[O:17])[C:13]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][CH:11]=1)#[N:2].CC(C)=O.P(Cl)(Cl)([Cl:38])=O>CN(C)C(=O)C>[C:1]([C:3]1[NH:4][N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6](=[O:25])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([S:16]([Cl:38])(=[O:18])=[O:17])[C:13]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][CH:11]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 51.0 g of the 3-cyano-4-[4-(2-methoxyethoxy)-5-sulfophenylazo]-1-phenyl-5-pyrazolone, 250 ml of acetone and 50 ml of phosphorus oxychloride was dropwise added 50 ml of N,N-dimethylacetamide at 50° C. or below. After the addition, the reaction mixture was stirred for about 1 hour and gradually poured into 1.0 l of ice water. The crystals precipitated were collected by filtration, washed with 100 ml of acetonitrile and dried by air. Thus, 46.7 g of 3-cyano-4-[4-(2-methoxyethoxy)-5-chlorosulfonylphenylazo]-1-phenyl-5-pyrazolone was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][NH:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Cc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 4-benzyl aniline (200 mg, 1.1 mmol) in dichloroethane (1.5 mL) was added a solution of N-(t-butoxycarbonyl)-D-prolinal (239 mg, 1.2 mmol) in dichloroethane (1.5 mL) at 0-5° C. Sodium triacetoxyborohydride (393 mg, 1.85 mmol) was added to the above solution. Acetic acid (65 mg, 1.1 mmol) in dichloroethane (1 mL) was added dropwise, over a period of 5 min at 0-5° C. The reaction mixture was stirred at 0-10° C. for 3 h. The mixture was diluted with saturated aq NaHCO3 and extracted with dichloromethane. Organic layer was dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (340 mg, 85%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:19][C:15]=1[C:16](Cl)=[O:17])#[N:13].O>CN(C)C=O>[C:12]([C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:19][C:15]=1[C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17])#[N:13]
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-cyano-5-(2,4-dichlorophenoxy)benzoyl]phthalimide.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[C:36]([O:35][C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:6]2[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:22][CH:23]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 65.3 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 0.92 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 8) and 1.28 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 1.23 g of the title compound were obtained as crystals, melting at 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([CH:22]=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[CH2:24]([Mg]Br)[CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:23])[CH2:24][CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (3.00 g, 8.67 mmol) in tetrahydrofuran (25 mL) was added dropwise ethylmagnesium bromide (3.0 M solution in diethyl ether, 3.4 mL, 10.4 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by methanol, and the mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (2.95 g, 7.84 mmol, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)Cc1ccccc1
Reactant: Cc1cccc(B(O)O)c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NN(Cc2ccccc2)C(=O)OC(C)(C)C)c1C
Temperature: 50 °C
Yield: 39.6 %

Procedure:
A mixture of N-benzyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 27; 790 mg, 3.55 mmol), 2,3-dimethylphenylboronic acid (Aldrich; 522 mg, 3.48 mmol), copper(II) acetate (646 mg, 3.55 mmol) and triethylamine (500 μL, 3.55 mmol) in 1,2-dichloroethane (5.5 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N-benzyl-N′-(2,3-dimethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (450 mg, 39%) as a yellow oil.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39](=[O:47])[N:40]3[CH2:43][C:44]([OH:46])=O)=[N:35][CH:34]=2)=[CH:28][CH:27]=1.[OH-].[NH4+]>CN(C=O)C.O>[NH2:2][C:44](=[O:46])[CH2:43][N:40]1[C:41]2[C:36](=[N:35][CH:34]=[C:33]([CH2:32][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:42]=2)[C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39]1=[O:47]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(N)=O)c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of HATU (1.14 g, 3 mmol) in DMF (4 mL) was added in portions to a stirred suspension of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid (1 g, 2.3 mmol) in 29% ammonium hydroxide (0.4 mL, 2.9 mmol), TEA (0.4 mL, 2.9 mmol) and DMF (4 mL) at 60° C. The mixture was stirred 40 min at rt and additional HATU (350 mg, 0.92 mmol), 29% ammonium hydroxide (0.15 mL, 1 mmol) and DMF (3 mL) were added. Stirring was continued 20 min and the suspension was diluted with water and filtered. The filter cake was washed with water and EtOH; then dried in a vacuum oven to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.25 (1H, t, J=5 Hz), 8.52 (1H, d, J=1 Hz), 7.83 (1H, s), 7.64 (1H, br s), 7.33 (2H, dd, J=8.6, 5.7 Hz), 7.27 (1H, br s), 7.11 (2H, t, J=8.6 Hz), 4.83 (2H, s), 4.11 (2H, s), 3.50 (4H, m), 3.28 (3H, s); HRMS calcd for C21H21FN4O5+H+: 429.1574. Found: 429.1575.
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]2[N:6]([C@H:9]3[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:30][C:7]1[N:6]([C@H:9]2[O:21][C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 80 °C

Procedure:
5,6-Dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.0 g, 2.25 mmol) was combined with N-bromosuccinimide (0.88 g 4.94 mmol) in anhydrous 1,4-dioxane (50 mL). This solution was heated in an 80° C. oil bath for 15 min. The solution was cooled, diluted with ethyl acetate and extracted with 10% sodium bicarbonate (2×50 mL). The organics were dried with anhydrous Na2SO4, decanted and concentrated. The residue was purified on a silica gel column (5×11 cm, 230-400 mesh) with (1:50) methanol:dichloromethane to give a white solid which was identified as product by comparing it's 1H NMR to that of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][C:37](=[O:40])[CH2:38]Br)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
15.1 g (46.1 mmol) of N-benzyl-tyrosine-tert-butyl ester (Example i) is dissolved in 50 ml of tetrahydrofuran and mixed with 5 ml of water and 9.54 g (69 mmol) of potassium carbonate. After instillation of 9.89 g (51 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for two days at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O.NN>C(O)C>[N:1]1[N:2]=[C:3]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCSc1nnc2ccccn12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCSc1nnc2ccccn12
Yield: 87.5 %

Procedure:
A mixture of N-[6-(s-triazolo[4,3-a]pyridin-3-ylthio)hexyl]phthalimide (16.5 g), hydrazine monohydrate (4.34 g) and ethanol (135 ml) was heated under reflux for 1 hour. The deposited crystals were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 6-(s-triazolo[4,3-a]pyridin-3-ylthio)hexylamine as an oil. Yield: 87.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13](Cl)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:10]([CH3:16])=[C:11]([C:13]([NH:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NN1CCCCC1
Reactant: Cc1c(C(=O)Cl)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
Part C: 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonyl chloride (1.5 gram, 3.75 mmol), 1-aminopiperidine (0.725 gram, 7.25 mmol) and triethylamine (0.549 gram, 5.44 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (heptane/ethyl acetate=1/1 (v/v), silicagel) to give 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (0.220 gram, 13% yield) as a white foam. MS: 463.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32](=[O:45])[N:33]([CH3:44])[N:34]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([C:32](=[O:45])[N:33]([CH3:44])[N:34]4[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
300 mg (796 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) and 231 mg (876 μmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 229 mg (46% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:19])=[O:18]
Reactant: OCCn1cccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cccc1

Procedure:
The 1-(2-hydroxyethyl)pyrrole (TCI-US, 0.138 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)=CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 89%), MS (ISP) m/z=413.5 [(M+H)+], mp 183.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10]([CH3:12])=O)[C:6]([O:8][CH3:9])=[O:7].[NH2:17]/[C:18](/[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21].CO>CC(O)C>[CH3:24][CH2:23][O:22][C:20]([C:19]1[CH:4]([C:3]2[C:2]([Cl:1])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([CH3:12])[NH:17][C:18]=1[CH2:25][O:26][CH2:27][CH2:28][N:29]1[C:30](=[O:39])[C:31]2[C:32](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:34])=[O:21]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Reactant: CCOC(=O)/C=C(\N)COCCN1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 0 °C
Yield: 69.6 %

Procedure:
Methyl 2-(2-chlorobenzyliden)acetoacetate (40.6 g; 169.9 mmol) was condensed with ethyl 3-amino-4-[2-(phthalimido)ethoxy]crotonate (51.5 g; 161.8 mmol) in 2-propanol (160 ml) under reflux for 11 hours. Methanol (103 ml) was added and mixture was cooled to 5/0° C. The solid was filtered off and dried at 40° C. Phthaloyl Amlodipine (60.7 g, purity: 98.6%; 0.86% of impurity HA) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].C(Cl)(Cl)(Cl)[Cl:21].ClN1C(=O)CCC1=O.CN(C)C=O>ClCCl>[C:16]([O:15][CH2:14][C@H:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:21])[C:2]=2[NH2:1])[C:7]1=[O:12])[CH3:19])(=[O:18])[CH3:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetic acid (R)-2-(5-amino-1-oxo-1H-isoquinolin-2-yl)-propyl ester (20 g, 0.07 mol) in carbon tetrachloride (400 mL, 4 mol) at 60° C. was added a solution of N-chlorosuccinimide (11 g, 0.082 mol) in N,N-dimethylformamide (140 mL, 1.8 mol) in 50 minutes. The mixture was stirred at 60° C. for an additional 15 minutes. The cooled mixture was diluted with dichloromethane (400 mL), washed with sodium bicarbonate (100 mL×3), and concentrated under reduced pressure. The mixture was purified by flash chromatography to afford the desired product as a brown oil.