Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34].O>CS(C)=O>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][CH2:11][CH:12]1[O:26][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:25])[CH2:18]3
Reactant: NCc1cccs1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1cccs1)CO2
Temperature: 90 °C
Yield: 31.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g,2.57 mmole) and thiophene-2-methylamine (1.42 g, 12.6 mmole) were combined in 15 ml of dry DMSO and heated to 90° C. for 6 hours under a nitrogen atmosphere. After cooling to room temperature, 250 ml of water was added and a brown solid precipitated This was dissolved in methylene chloride, dried over MgSO4, filtered and concentrated in vacuum to yield an flaky orange solid, which was column chromatographed on silica gel using 1.5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.27 g) thus obtained was crystallized from isopropanol with the addition of fumaric acid (0.10 g, 0.90 mmole) to give 0.28 g of the (S) enantiomer of the title compound as a light orange solid fumarate, m.p. 211-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[Br:13].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH3:14])=[CH:4][C:3]=1[Br:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Nc1cc2c(cc1Br)CCC(=O)N2
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCc2cc(Br)c(N)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
7-Amino-6-bromo-3,4-dihydro-1H-quinolin-2-one 280 mg (1.16 mmol) was dissolved in 8 ml THF and cooled to 0° C. KHMDS (2.56 ml, 1.27 mmol, 0.5 M in toluene) was then added dropwise, followed by dropwise addition of 80 ml (1.27 mmol) CH3I. The mixture was stirred for 12 hours, then partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 265 mg of 7-amino-6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][S:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(S)CCCCC1.C=O.Cl>C(O)C.O>[CH:14]1([S:13][CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCSC1CCCCC1
Reactant: Oc1ccc(S)cc1
Agent: C=O
Agent: Cl
Agent: SC1CCCCC1
Solvent: CCO
Solvent: O
Product: Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
In 100 g of ethanol were dispersed 12.6 g (0.1 mol) of 4-hydroxythiophenol and 4.0 g (0.1 mol) of sodium hydroxide. The dispersion was heated at 70° C. for dissolution. To the solution, 16.5 g (0.1 mol) of chloromethylcyclohexylsulfide, which was separately prepared from cyclohexanethiol, formaldehyde and hydrochloric acid according to the teaching of U.S. Pat. No. 2,354,230, was added dropwise. The solution was ripened at 70° C. for 4 hours. Thereafter, the solution was cooled, combined with 50 g of water, which was extracted twice with 100 g of dichloromethane. The organic layer was concentrated in vacuum, obtaining 26 g of the crude end product. It was subject to the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2].Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>ClCCl.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[Cl:20][C:18]1[CH:19]=[C:14]([NH:12][C:10]2[CH:11]=[C:5]3[CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7][N:6]3[N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[N:17]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CCN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCN1CCn2nc(Nc3cc(Cl)nn(C)c3=O)cc2C1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
In a 250 mL round-bottomed flask, 5-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (350 mg, 2.11 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (471 mg, 2.11 mmol, Eq: 1.00), cesium carbonate (2.4 g, 7.37 mmol, Eq: 3.50) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (183 mg, 316 μmol, Eq: 0.15) were combined with dioxane (40 ml) and the reaction mixture was flushed with argon. Then bis(dibenzylideneacetone)palladium (90.8 mg, 158 μmol, Eq: 0.075) was added and the reaction mixture was heated at 90° C. for 18 hr. After cooling to room temperature it was diluted with 50 mL dichloromethane and water. The aqueous layer was back-extracted with DCM (2×25 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 3% MeOH in DCM). The pure fractions were triturated with EtOAc. Mixed fractions and filtrate were purified by chromatography to afford pure product, which was combined with the triturated solid to afford the desired product (500 mg). (M+H)+=309 m/e.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH2:5]([O:21][CH2:22][CH:23]=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1.BrC(Br)C.CCOCC>[CH2:5]([O:21][CH2:22][CH:23]([OH:24])[CH:2]=[CH2:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CBr
Reactant: CCCCCCCCCCCCCCCCOCC=O
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)COCCCCCCCCCCCCCCCC
Temperature: 0 °C
Yield: 41.5 %

Procedure:
To a stirring mixture of 5.67 g of magnesium in 25 ml of tetrahydrofuran was added 10 drops of dibromoethane as an initiator. After the reaction began another 100 ml of tetrahydrofuran was added followed by the dropwise addition of a solution of 49.85 g of vinyl bromide in 250 ml of tetrahydrofuran at a rate to maintain reflux. After all of the magnesium had reacted, the solution was cooled to 0° C. and a solution of 44.2 g of (hexadecyloxy) acetaldehyde, prepared by the procedure of Example 3, in 175 ml of ether was added dropwise over 1/2 hour. After 1 hour at room temperature dilute hydrochloric acid was added. The tetrahydrofuran was removed and the residue was extracted with ether. The ether layer was washed with brine, dried and the solvent removed. The residue was purified by HPLC [hexane: ether (9:1), two columns, two passes] giving an oil which was distilled via a Kugelrohr apparatus (185°-190° C., 0.2 mm) giving a colorles oil which solidified on standing to give 20.17 g of the desired compound.
Reaction SMILES: ClC[C:3](=O)[C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]2=[O:20].[OH-].[K+].S([O-])(O)=O.[Na+].Cl>O>[OH:20][C:13]1[CH:14]=[N:15][C:16]2[C:12]([C:3]=1[C:4]([OH:6])=[O:5])=[CH:11][C:10]([O:9][CH3:8])=[CH:18][CH:17]=2
Reactant: O=C(O)C(=O)CCl
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: COc1ccc2ncc(O)c(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 21.5 %

Procedure:
3-Chloro-2-oxo-propionic acid (11.46 g, 91.10 mmol, 1.61 eq) is added portionwise at room temperature to a stirred solution of 5-methoxy-1H-indole-2,3-dione (10.0 g, 56.45 mmol, 1.0 eq) and potassium hydroxide (30.5 g, 543.6 mmol, 9.6 eq) in water (60 mL). After 6 days stirring at room temperature, a solution of sodium hydrogen sulfite (2.3 g, 22.10 mmol, 0.4 eq) in water (4 mL) is added and the reaction mixture is acidified by the addition of concentrated hydrochloric acid (12N, 30 mL). The resulting yellow precipitate is collected by filtration, washed with a saturated sulfur dioxide aqueous solution and water, then purified by column chromatography (silica gel, eluent:ethyl acetate:acetonitrile:methanol:water, 70:5:2.5:2.5, v/v/v/v) to afford 3-hydroxy-6-methoxyquinoline-4-carboxylic acid as a light brown solid (2.66 g, 21% yield).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[CH3:10][N:11]1[C:17]2=[CH:18][S:19][CH:20]=[C:16]2[C:15](=[O:21])[NH:14][C:13]2[CH:22]=[CH:23][CH:24]=[N:25][C:12]1=2>CN(C)C=O>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:14]1[C:15](=[O:21])[C:16]2=[CH:20][S:19][CH:18]=[C:17]2[N:11]([CH3:10])[C:12]2[N:25]=[CH:24][CH:23]=[CH:22][C:13]1=2
Reactant: CN1c2cscc2C(=O)Nc2cccnc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)c2cscc2N(C)c2ncccc21
Reaction time: 18 h

Procedure:
A mixture of 0.20 g. of 55% sodium hydride-mineral oil dispersion and 0.3 g. of dimethylaminoethylchloride hydrochloride in 12 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.23 g. of 5,10-dihydro-10-methyl-6H-pyrido[3,2-b]thieno[3,4-e] [1,4]diazepin-6-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloro form. The dried chloroform extracts are concentrated to give an amber oil, which is crystallized from hexane to give an off-white solid, m.p. 129°-130°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([C:32]([CH3:34])=[CH2:33])=[CH:20][C:10]=1[C:11]([N:13]([CH2:17][C:18]#[CH:19])[CH2:14][C:15]#[CH:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([OH:40])[CH2:36][CH2:37][C:38]#[CH:39].CCCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]([C:32]([CH3:34])=[CH2:33])=[CH:20][C:10]=1[C:11]([N:13]1[CH2:17][C:18]2[C:15](=[CH:16][CH:39]=[C:38]([CH2:37][CH2:36][CH2:35][OH:40])[CH:19]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: C#CCN(CC#C)C(=O)c1cc(C(=C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CCCO)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 2,4-bis-benzyloxy-5-isopropenyl-N,N-di-prop-2-ynyl-benzamide (0.545 g, 1.21 mmol) in ethyl acetate (10 mL) was added 4-pentyn-1-ol (0.30 mL, 3.2 mmol) and RhCl(PPh3)3(0.161 g, 0.17 mmol). Solvent was removed under vacuum, and the mixture stirred at room temperature overnight. Additional 4-pentyn-1-ol (2.5 mL, 26 mmol) and RhCl(PPh3)3 (0.155 g, 0.17 mmol) were added and the mixture stirred for 48 hours. The mixture was loaded onto a silica gel column and eluted with 7:3 ethyl acetate:heptane to yield the desired product (0.254 g, 39% yield). LC/MS: m/z 534.25 [M+H]+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:33]1([NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH2:39].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(#N)C>[NH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[NH:40][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:18]2[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH:11][CH:12]=3)[CH:21]=[CH:20][N:19]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
To a solution of 21 (crude from the previous step) in dry acetonitrile (50 mL) was added 1,2-phenylenediamine (1.83 g, 16.9 mmol) followed by Et3N (2.65 mL, 19.0 mmol), HOBt.H2O (1.03 g, 7.6 mmol) and EDCI.HCl (1.62 g, 8.5 mmol). The mixture was stirred at room temperature for 72 h, filtered to remove salts and filtrate was concentrated to form a residue, which was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98 to 5/95). Trituration of this material with a mixture of EtOAc/CH2Cl2, allowed affording the title compound 22a (696 mg, 1.3 mmol, 31% yield over 2 steps) as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 9.55 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.77 (t, J=6.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.92 (td, J=7.6, 1.6 Hz, 1H), 6.73 (dd, J=8.0, 1.6 Hz, 1H), 6.55 (td, J=7.4, 1.2 Hz, 1H), 4.85 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.13 (t, J=5.6 Hz, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.68 (t, J=5.6 Hz, 2H), 2.45 (t, J=4.4 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.CC[O:13][C:14]([CH2:16][CH:17]1[C:22](=O)[CH2:21][CH2:20][CH2:19][CH2:18]1)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:13])[CH2:16][CH:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: CCOC(=O)CC1CCCCC1=O
Solvent: CC(=O)O
Product: O=C1CC2CCCCC2=NN1c1ccc(Cl)cc1F

Procedure:
8.0 Parts of 4-chloro-2-fluorophenylhydrazine and 9.2 parts of ethyl 2-cyclohexanoneacetate [bp 92°-93°, 0.5 mm Hg; prepared by the method described by A. Sergre, et al., J. Amer. Chem. Soc., 79 3503 (1957)] were dissolved in 75 parts of glacial acetic acid, and the resulting solution was refluxed for 16 hours. The reaction solvent was removed under a reduced pressure of 300 mm Hg, and the residual brown oil was dissolved in 150 parts of methylene chloride. The organic solution was washed with saturated aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate and the solvent was removed under a reduced pressure of 300 mm Hg to give 2-(4-chloro-2-fluorophenyl)-4,4a,5,6,7,8-hexahydro-3(2H)-cinnolinone as a brown oil that solidified on scratching. Purification was achieved by recrystallization from cyclohexane to yield 5.9 parts of tan solid, mp 110°-112°.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Cl)c(CNc2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2,5-dichlorobenzylbromide (528 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5. Yield: 0.045 g (15.4%); MS m/z: 292.2/294.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.32 (d, 2H, 3J=6.1 Hz); 6.20 (br s, 1H); 6.43 (br s, 1H); 6.60 (dd, 1H, 4J=1.6 Hz, 3J=8.8 Hz); 7.30-7.33 (m, 2H); 7.40 (d, 1H, 4J=2.6 Hz); 7.49 (d, 1H, 3J=8.5 Hz); 7.86 (s, 1H), 11.83 (br s, 1H); HPLC (METHOD [A]): rt 12.97 min (100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:17]=1)[C:5]2([CH3:25])[CH3:24].[Cl:26][C:27]1[C:28]([C:33](O)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:33]([C:28]4[C:27]([Cl:26])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:34])[CH2:20][CH2:19]3)[CH:17]=1)[C:5]2([CH3:25])[CH3:24]
Reactant: O=C(O)c1ncccc1Cl
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CCN(C(=O)c3ncccc3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of 5-chloro-3,3-dimethyl-2-(5-piperazin-1-yl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one (example 455 [C]) (52 mg, 0.146 mmol), 3-chloro-pyridine-2-carboxylic acid (25.3 mg, 0.161 mmol), HATU (83.3 mg, 0.219 mmol) and Et3N (29.5 mg, 0.292 mmol) in DCM (5 mL) was stirred for 2 hours at room temperature. The mixture was treated with water, and extracted with DCM. The organic layer was dried over anhy. Na2SO4 and after removal of solvent, the residue was purified by preparative HPLC to afford the title compound (33 mg, 45%) as a white solid. MS: 496.3 (M+H+).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:14][C:13]2[C:8]1=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)(=O)=O.[CH3:19][O:20][C:21]1[C:37]([O:38][CH3:39])=[CH:36][C:24]2[CH2:25][C:26](=[O:35])[N:27]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[CH3:34][N:33]([CH2:6][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH2:14]1)[CH2:32][CH2:31][CH2:30][N:27]1[C:26](=[O:35])[CH2:25][C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[C:37]([O:38][CH3:39])[CH:36]=2)[CH2:29][CH2:28]1
Reactant: COc1cc2c(cc1OC)[C@@H](COS(C)(=O)=O)C2
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 5, starting from (7S)-(iodomethyl)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene (or from (7S)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl methanesulphonate) and from 7,8-dimethoxy-3-[3-(methylamino)-propyl]-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, there is obtained ivabradine base, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: [N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38](O)=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[NH2:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:81]([NH:83][C@H:84]([C:97]([O:99][CH3:100])=[O:98])[CH2:85][CH2:86][CH2:87][CH2:88][NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=[O:82])[CH2:75][C:76]1[N:80]=[CH:79][NH:78][CH:77]=1)=[O:72])[C@H:67]([CH2:69][CH3:70])[CH3:68])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:59])[CH3:58].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:81]([NH:83][C@H:84]([C:97]([O:99][CH3:100])=[O:98])[CH2:85][CH2:86][CH2:87][CH2:88][NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=[O:82])[CH2:75][C:76]1[N:80]=[CH:79][NH:78][CH:77]=1)=[O:72])[C@H:67]([CH2:69][CH3:70])[CH3:68])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:58])[CH3:59])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@@H](N)CC(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 5 h

Procedure:
480 mg of Boc-Pro-His-Pro-Phe-His-OH (for manufacture see Example 1, stage 1.9), 340 mg of H-Sta-Ile-His-Lys(Boc)-OMe and 150 mg of HONB are dissolved, while heating, in 3.5 ml of DMF. After cooling to 0°, 170 mg of DCCI are added, whereupon stirring is carried out for 5 hours at 0° and the whole is left to stand at room temperature for 20 hours. The condensation product is precipitated by the addition of 35 ml of diisopropyl ether and filtered off. It is purified by Craig partitioning over 1000 stages in the same solvent system as described in stage 2.4 (K=0.6), yielding Boc-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe; Rf (A)=0.22; Rf (B)=0.21; Rf (E)=0.54.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH:11]=O)=[C:9](Cl)[N:8]=[CH:7][N:6]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]2[NH:2][N:3]=[CH:11][C:10]=12
Reactant: NN
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Clc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 830.2 %

Procedure:
Hydrazine hydrate (11.5 mL, 23.7 mmol) was slowly added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (40.0 g, 22.6 mmol) and triethylamine (30 mL, 22 mmol) in 1,4-dioxane (600 mL) with cooling to maintain an internal temperature below 20° C. After the addition was completed, the reaction was warmed to rt. After 1 hr, the reaction was filtered. The solvent was removed in vacuo to afford the title intermediate (29 g, 83%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ14.52 (br. s, 1H), 8.83 (s, 1H), 8.45 (s, 1H). MS m/z 155 [M+1]+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:38])[CH2:8][CH2:9][N:10]([CH2:18][C:19]1[CH:37]=[CH:36][C:22]2[N:23]=[C:24]([NH2:35])[N:25]([CH2:26][C:27]3[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]=3)[C:21]=2[CH:20]=1)[C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)C>O.O1CCCC1>[NH2:35][C:24]1[N:25]([CH2:26][C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]=2)[C:21]2[CH:20]=[C:19]([CH2:18][N:10]([C:11]3[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:8][C:7]([OH:38])=[O:6])[CH:37]=[CH:36][C:22]=2[N:23]=1
Reactant: CCOC(=O)CCN(Cc1ccc2nc(N)n(Cc3nc(C)ccc3O)c2c1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(N(CCC(=O)O)Cc2ccc3nc(N)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.9 %

Procedure:
Lithium hydroxide hydrate (0.00093 mol) was added to a solution of 3-{[2-amino-3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-m-tolylamino}-propionic acid ethyl ester (0.000464 mol) in a mixture of water (10 ml) and tetrahydrofuran (10 ml). The reaction was stirred at room temperature for 12 hours. The tetrahydrofuran was removed under reduced pressure and the solution was acidified to pH 4 with a 1N solution of HCl in water. The precipitate was filtered off, rinsed with water, then with diethyl ether and dried, yielding 0.157 g of 3-{[2-amino-3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-m-tolyl-amino}-propionic acid (76%, compound 161, melting point 165° C.).