Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]#[N:14])[CH3:4].[CH2:20](Br)[Br:21].CCOCC>CN(C)C=O.O>[Br:21][CH2:20][C:12]([C:13]#[N:14])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:3][CH3:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(C#N)c1ccccc1OCC
Reactant: BrCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCC(C#N)(CBr)c1ccccc1OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A 200 ml three-neck flask fitted with a reflux condenser, nitrogen inlet, thermometer and addition funnel was charged with 1.8 grams (0.045 moles, 1.28 ec.) of 60% NaH, washed 2×40 ml of hexane, in 30 ml of dimethyl formamide (DMF). While stirring at room temperature, 1.41 grams of 35% KH (with removal of the mineral oil before washing with hexane, assumed 100% KH, 0.035 moles, 1.0 ec.) in 20 ml of DMF was added. To the reaction was added 8.10 grams (0.0350 moles, 1.0 ec.) of 2-(2-ethoxyphenyl)heptanenitrile in 25 ml of DMF. After stirring at room temperature for 1 hour, 9.15 grams (0.0525 moles, 1.5 eg.) of CH2Br2 in 25 ml of DMF was added dropwise over 10 minutes. The reaction exothermed slightly and was stirred at room temperature overnight after which GLC indicated the reaction was 80% product. An additional 0.7 g of 100% KH (0.5 ec.) was added in 20 ml of DMF, after washing with 20 ml of hexane, and this was followed by an additional 3.0 grams of CH2Br2The reaction was stirred for an additional 3 hours and was complete by GLC. Workup with ether and water gave after concentration 10.97 grams of a thick oil (97.2% yield) which was used directly in the coupling procedure.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)C.[NH3:16]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:16])[N:3]=[N:4][CH:5]=1
Reactant: FC(F)(F)c1cnnc(Cl)c1
Reactant: N
Solvent: CC(C)O
Product: Nc1cc(C(F)(F)F)cnn1
Temperature: 80 °C

Procedure:
3-Chloro-5-(trifluoromethyl)pyridazine (28.0 g, 153 mmol) was dissolved in ammonia in isopropanol (200 mL, 400 mmol, 2.0 M) and heated at 80° C. in a pressure vessel for 3 days. The reaction was cooled to room temperature and concentrated under reduced pressure to take the isopropanol off. The residue was purified by flash chromatography to afford the title compound as an off white solid, 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H); 6.91 (s, 1H); 5.00 (s, 2H, br). LRMS (APCI) calc'd for (CsH4F3N3) [M+H]+, 164.1. found 164.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.[C:13]1(=[O:23])C2C(=CC=CC=2)C=[CH:15][CH2:14]1.C1(O)C2CCC(O)CC=2C=CC=1>>[O:23]1[CH2:13][CH:14]1[CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([OH:12])[CH2:7]2
Reactant: O=C1CC=Cc2ccccc21
Reactant: O=C1CCc2c(O)cccc2C1
Agent: Oc1cccc2c1CCC(O)C2
Product: OC1CCc2c(cccc2OCC2CO2)C1

Procedure:
Employing the procedure of Example 3 a, but substituting a 6-alkoxy-1-tetralone as shown in the left hand (first) column of Table II for 6-methoxy-1-tetralone, a 6-alkoxy-1-naphthol is produced, which is converted as per Example 3 b to the corresponding 5-hydroxy-3,4-dihydro-2(1H)-naphthalenone shown in the middle column of Table II; employing the procedure of Example 3 c the naphthalenone is converted to the corresponding 5,6,7,8-tetrahydro-1,6-naphthalenediol which is reacted with an epoxide of the structure ##EQU13## in accordance with the procedure of Example 3d to form the corresponding 1,2,3,4-tetrahydro-5-[2,3-epoxy-propoxy]-2-naphthol which is reacted with an amine of the structure ##EQU14## in accordance with the procedure of Example 3e to form the corresponding 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(R1, R2 -substituted amino)propoxy]-2-naphthol (formula I) as shown in the right hand (third) column of Table II.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([N+:19]([O-])=O)[CH:18]=2)[NH:15][C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13]3)=[N:6]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:19][C:17]2[CH:18]=[C:10]([C:7]3[S:8][CH2:9][C@@H:5]([CH2:4][C:3]([OH:2])=[O:28])[N:6]=3)[CH:11]=[C:12]3[C:16]=2[NH:15][C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:13]3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)C[C@@H]1CSC(c2cc([N+](=O)[O-])c3[nH]c(-c4ccccc4)cc3c2)=N1
Reactant: O=C1CCCC1
Product: O=C(O)C[C@@H]1CSC(c2cc(NC3CCCC3)c3[nH]c(-c4ccccc4)cc3c2)=N1

Procedure:
2-[(R)-2-(7-nitro-2-phenyl-1H-indol-5-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester prepared in Step B and cyclopentanone were reacted according to the same procedures as Examples 1 and 30 to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][O:23][C:22]2[CH:26]=[C:27]([NH2:30])[CH:28]=[CH:29][C:21]1=2.[I-].[Na+]>CC#N>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:30][C:27]4[CH:28]=[CH:29][C:21]5[N:20]([CH3:19])[CH2:25][CH2:24][O:23][C:22]=5[CH:26]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCOc2cc(N)ccc21
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCOc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 180 °C
Yield: 16.3 %

Procedure:
4-Chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (112 mg, 0.36 mmol) and 3,4-dihydro-4-methyl-2H-benzo[b][1,4]oxazin-7-amine (130 mg, 0.72 mmol) were dissolved in CH3CN (3 mL), Sodium iodide (10 mg, 0.06 mmol) was added and the reaction was heated via microwave at 180° C. for 40 minutes. Solvent was removed and the residue was purified by preparative TLC to obtain the product as a beige foam (24 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([CH2:11][CH3:12])[C@@H:7]1[C:13]([OH:15])=O.O1CCCC1.C(N(CC)CC)C.[N+:34](=[CH2:36])=[N-:35]>CCOCC>[N+:34](=[CH:36][C:13]([C@@H:7]1[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[C:9](=[O:10])[C@H:8]1[CH2:11][CH3:12])=[O:15])=[N-:35]
Reactant: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@@H]1C(=O)N(Cc2ccc(OC)cc2OC)[C@H]1C(=O)C=[N+]=[N-]
Temperature: -15 °C
Yield: 58 %

Procedure:
To a solution of 14.65 g (50 millimoles) of trans-1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2-azetidinecarboxylic acid prepared according to the preceding paragraph in 150 ml of anhydrous tetrahydrofurane 7.3 ml (52.5 millimoles) of triethyl amine are added and to the solution under stirring and ice-cooling 5.1 ml (52.5 millimoles) of ethyl-chloro-formiate are added. The mixture is cooled to -15° C., stirred at this temperature for 20 minutes and the precipitated triethyl amine salt is filtered off under argon. To the filtrate a cold solution of 22.5 g (150 millimoles) of diazomethane and 230 ml of ether is added. The solution is allowed to warm to room temperature under stirring and after 2 hours the reaction mixture is evaporated to dryness. The residue is a mixture comprising predominantly trans-4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-3-ethyl-2-azetidinone and some methyl-trans-1-(2,4-dimethoxybenzyl)-3-ethyl-4-oxo-2-azetidine-carboxylate. The mixture thus obtained can be used as starting material in Example 3 directly, without purification. The benzene solution of the evaporation residue can be, however, subjected to column chromatography, if desired. (Adsorbent: Kieselgel 60. diameter 0.063-0.200 mm, eluant: benzene-acetone 7:2). Thus 9.2 g of trans-4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-3-ethyl-2-azetidinone are obtained. Yield: 59%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1)C.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][O:3][C:4](=[O:15])[C:5]([C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1)=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1nnc(C(F)(F)F)s1
Product: COC(=O)C(=CN(C)C)c1nnc(C(F)(F)F)s1

Procedure:
3.05 g (13.5 mmol) 5-(trifluoromethyl)-1,3,4-thiadiazol-2-ylacetic acid ethyl ester [for preparation see DE 42 40 168-A1] are heated in 6.9 ml (40.5 mmol) dimethylformamide diethyl acetal overnight at 100° C. After cooling, the mixture is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)(=O)C>[Br:22][C:23]1[CH:28]=[C:27]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[N:3]=3)[NH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Cl)cnc32)cc1
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cnc2[nH]cc(-c3cccc(Br)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 ml round bottom flask was charged under nitrogen with 2-chloro-7-iodo-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (6) (950 mg, 2.2 mmol), 3-bromophenyl boronic acid (440 mg, 2.2 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.04 mmol), 2M aqueous potassium carbonate (2.2 ml, 4.4 mmol) in a toluene/ethanol mixture (15/3 ml) under nitrogen. The reaction mixture was refluxed for 18 h, then allowed to cool to room temperature. The solution was diluted with ethyl acetate (˜70 ml). The organic was washed with brine, dried over magnesium sulfate and concentrated in vacuo, The residue was triturated in dichloromethane/methanol. A pale yellow solid was removed by filtration (300 mg). The residue was taken up in a tetrahydrofuran/methanol/1M NaOH mixture (4/1/1 ml) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in methanol. A solid was filtered off as the title compound (10 mg, 1%). 1H NMR (DMSO-d6): 7.35-7.45 (2H, m), 8.10-8.15 (1H, d), 8.35 (1H, s), 8.4 (1H, s), 8.6 (1H, s). MS (ES+): 310, 312.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:28][CH:27]([N:29]([CH3:31])[CH3:30])[CH2:26][C:25]2([CH3:33])[CH3:32])[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[C:25]([CH3:33])([CH3:32])[CH2:26][CH:27]([N:29]([CH3:30])[CH3:31])[CH2:28]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)C1CN(c2nc(Cl)nc(NN)c2F)C(C)(C)C1
Reaction time: 72 h
Yield: 95.5 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-6-[4-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (2.2004 g, 3.648 mmol) in MeOH (22 mL) was added 4 N HCl in dioxane (22 mL). The solution was stirred for 3 days and then concentrated in vacuo. The residue was azeotroped with MeOH (50 mL), and then partitioned between DCM (100 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with fresh DCM (2×50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,5,5-tetramethyl-3-pyrrolidinamine (1.0552 g, 96%) as an orange foam. LCMS: (M+H)+: 303.1.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][C:23]1[CH:52]=[CH:51][C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]3[CH2:43][O:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[O:29][C:25]=2[CH:24]=1>CO>[ClH:1].[CH3:22][C:23]1[CH:52]=[CH:51][C:26]2[N:27]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]3[CH2:43][O:44][C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[O:29][C:25]=2[CH:24]=1
Reactant: Cc1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)oc2c1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCNCC3COc3cccnc3)oc2c1
Reaction time: 2 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (91.1 mg, 0.140 mmol) in MeOH (1 mL). After 2 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH, and brine (20 mL) was added. This was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 33.0 mg of the free-base of the desired product. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.025 mL) was added. The mixture was concentrated under reduced pressure to give 35.5 mg (70%) of the desired product as the hydrochloride salt. LC-MS: RT=4.40 min, [M+H]+=325.1.
Reaction SMILES: [Si](Cl)(Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=O)=[CH:13][CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[N:6]=[N:7][NH:8][N:20]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: Brc1ccc(Cc2nn[nH]n2)cc1
Temperature: 85 °C
Yield: 75.3 %

Procedure:
Stir a mixture of SiCl4 (1.7 g, 10 mmol, 2 eq.) and NaN3 (1.95 g, 30 mmol, 6 eq.) in 50 mL of acetonitrile for 2 hours. Add 1.07 g of 2-(4-bromophenyl) acetamide (5 mmol, 1 eq.) and heat to 85° C. for 5 hour. Cool to room temperature and filter off the solid wash the solid with EtOAc. Wash the ester layer with water, saturated aq. sodium chloride, dry over MgSO4 and evaporate the solvent to afford 900 mg title compound (80%). MS (m/e): 237.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1.[CH3:29][SH:30].[Na]>O1CCCC1>[CH3:22][C:15]1[N:14]=[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[S:30][CH3:29])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cc([N+](=O)[O-])ccc1SC
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.4 %

Procedure:
To a solution of tetrahydrofuran (25 ml), methylmercaptan-diemthylformamide solution (methylmercaptan 66 g/DMF 306 g) (5 ml) and ethyl 4-(2-chloro-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (2 g), sodium methylmercaptan (0.42 g) was added, stirred for 3 h at ambient temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel, eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the object compound were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to afford ethyl 6-methyl-4-(2-methylthio-5-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (0.4 g).
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])[CH:28]=[CH: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: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1cc2c(cc1OC)[C@@H](COS(C)(=O)=O)C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 7, 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-dihydro-2H-3-benzazepin-2-one, there is obtained a compound which is hydrogenated by following the procedure described in patent specification EP 0 534 859 (Example 1, Step D) to yield 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: Cl.C([NH:5][C:6]1[S:7][C:8]2[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:13][C:14]=2[N:15]=1)(=O)C.Cl>>[NH2:5][C:6]1[S:7][C:8]2[CH2:9][CH2:10][N:11]([CH2:16][CH:17]=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:12][CH2:13][C:14]=2[N:15]=1
Reactant: CC(=O)Nc1nc2c(s1)CCN(CCCc1ccccc1)CC2
Agent: Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1)CC2

Procedure:
Prepared from 2-acetylamino-6-(3-phenyl-propyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine-hydrochloride with semi-concentrated hydrochloric acid. The foam obtained by evaporating to dryness is crystallised from concentrated ethanolic solution with the addition of a little acetone. Yield: 66% of theory, Melting point: 221°-225° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:35])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH2:27]CC(F)(F)F)[CH2:21][C:20]2([CH3:34])[CH3:33])[CH:9]=1.[CH3:36][C:37]1(C)N(CC2C=C(C3C=CC(O)=CC=3F)N=C3NN=C(C)C=23)CC2(CCCC2)NC1.C=O>>[F:1][C:2]1[CH:3]=[C:4]([OH:35])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]2[NH:14][N:15]=[C:16]([CH3:17])[C:11]2=[C:10]([CH2:18][N:19]2[CH2:24][C:23]3([CH2:26][CH2:37][CH2:36][CH2:25]3)[N:22]([CH3:27])[CH2:21][C:20]2([CH3:33])[CH3:34])[CH:9]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC4(CCCC4)NCC3(C)C)c12
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c12
Agent: C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC4(CCCC4)N(C)CC3(C)C)c12

Procedure:
The title compound was prepared in analogy to Example 65 (3-Fluoro-4-{3-methyl-4-[2,2,5,5-tetramethyl-4-(3,3,3-trifluoro-propyl)-piperazin-1-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-6-yl}-phenol) using 4-[4-(8,8-Dimethyl-6,9-diaza-spiro[4.5]dec-9-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-3-fluoro-phenol and aqueous formaldehyde.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39]([NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione hydrochloride (2 g, 4.6 mmol) and 2-t-butoxycarbonylamino propionic acid (0.87 g, 4.6 mmol) in dimethyl formamide (10 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (1.139 g, 5.5 mmol) was added to this solution and stirring was continued for 2 h at ambient temperature. Water (200 ml) was added to the reaction mixture, stirred for 15 minutes, ethyl acetate (250 ml) added and stirring was continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to furnish the crude compound which was purified by column chromatography (0.95 g, yield 36.3%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4])#[N:2].S(=O)(=O)(O)[OH:22].N>>[NH2:2][C:1]([C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)c1ccc2nc(-c3ccncc3)[nH]c2c1
Agent: N
Product: CC(C)(C(N)=O)c1ccc2nc(-c3ccncc3)[nH]c2c1

Procedure:
3.7 g. of the 5-(2-cyanopropan-2-yl)-2-(4-pyridinyl)benzimidazole (prepared in Example 15) are stirred for 3 hours at 50° C. in 40 ml. 80% sulphuric acid, the compound thereby slowly going into solution. The reaction mixture is then poured on to ice, rendered alkaline with ammonia, filtered off with suction and recrystallised from ethanol. There are obtained 2.4 g. (61% of theory) of the title compound in the form of colourless crystals; m.p. 274°-276° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CN(C(O[N:21]1N=N[C:23]2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.COC(OC)CN.OS(O)(=O)=O.[OH-].[Na+]>S1(CCCC1)(=O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:11][CH3:12])[C:6](=[O:8])[NH:21][CH:22]=[CH:23]2
Reactant: COc1cc(C(=O)O)ccc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(CN)OC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Product: COc1cc2c(=O)[nH]ccc2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
A solution of 4-fluoro-3-methoxybenzoic acid (1.30 g, 7.64 mmol) and TEA (1.25 mL, 8.97 mmol) in sulfolane (6.0 mL) was treated with HATU (3.25 g, 8.55 mmol). After 10 minutes, aminoacetaldehyde dimethylacetal (0.925 mL, 8.58 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then treated with conc. H2SO4 (15 mL) and stirred at 60° C. for 2 days. The reaction mixture was poured over ice and brought to pH˜4 with 10M NaOH (˜55 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 6-fluoro-7-methoxyisoquinolin-1(2H)-one (Cpd L, 1.32 g, 89%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[CH:21][N:20]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)ccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)ccn2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 4-chloro-2-(tributylstannyl)pyridine (0.893 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol) in toluene (4 mL) to give 4-chloro-2-(4-chloropyridin-2-yl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=325.0 (M+1).