Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O.C(O)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 50 °C
Yield: 91 %

Procedure:
4-vinyl benzoyl chloride was synthesized from 4-vinyl benzoic acid (obtained from Trans World Chemicals). The 4-vinyl benzoic acid was dissolved in chloroform with a small (0.16 mole/mole 4-vinyl benzoic acid) amount of nitrobenzene added as an inhibitor to prevent cross-linking. A large excess of thionyl chloride (six times the moles of benzoic acid) was added dropwise while stirring and gently heating to 50° C. Once the thionyl chloride was completely added, and the solution was at a temperature of 50° C., it was allowed to stir for one hour. The solution was then distilled (rotary evaporator) to remove the bulk of the chloroform and unreacted thionyl chloride. The impure 4-vinylbenzoyl chloride was then vacuum distilled to further purify it. At <1 mm mercury the 4-vinylbenzoyl chloride distills at around 70° C. The composition of the product was checked by NMR and was confirmed to be 4-vinylbenzoyl chloride. The yield was 91%.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.CN(C)C1C=CC=CC=1.C[Si](C)(C)Cl.Cl[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].Cl>ClCCl.C(N(CC)CC)C>[CH:36]([S:37]([NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:11][CH:12]=1)(=[O:39])=[O:38])=[CH2:35]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: C=CS(=O)(=O)NCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
276 mg of triethylamine was added to a dichloromethane suspension (4 ml) containing 100 mg of 6-[4-(3-aminopropoxy)phenyl]pyridazin-3(2H)-one hydrobromide and 37 mg of dimethylaniline, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, 86 mg of trimethylchlorosilane was added thereto, and the mixture was stirred at room temperature for 2 hours. Again, under ice cooling, a dichloromethane solution (1 ml) containing 65 mg of chloroethylsulfonyl chloride was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. 5 ml of 1M hydrochloric acid was added to the mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol (30:1)) to obtain 73 mg of 6-[4-(3-vinylsulfonylaminopropoxy)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Br[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[CH3:3][CH:4]([O:7][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]#[CH:6]
Reactant: COC(=O)CBr
Reactant: C#CC(C)O
Agent: [H-]
Agent: [Na+]
Product: C#CC(C)OCC(=O)OC

Procedure:
Sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol), (±)-3-butyn-2-ol (21 g, 0.30 mol), and methyl bromoacetate were processed as described in Example 43A to provide the title compound. 1H NMR (CDCl3) δ 1.51 (d, 3H), 2.46 (d, 1H), 3.76 (s, 3H), 4.25 (AB q, 2H), 4.39 (dq, 1H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]([CH3:15])=[O:14].OS(O)(=O)=O>CCOCC>[CH3:12][C:13]([OH:14])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: CC(C)=O
Reactant: BrCCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 8.8 g. (0.37 mol.) of magnesium turnings and 150 ml of dry ether was placed in a 3-necked flask fitted with a nitrogen inlet, a reflux condenser and an addition funnel containing 73.7 g (0.37 mol) of 1-bromo-3-phenylpropane. A small amount of the bromo compound was added to the reaction mixture and the mixture warmed in order to initiate reaction. The reaction mixture was treated with 150 ml of dry ether and then the bromo compound was added at such a rate as to maintain gentle reflux. The reaction mixture was heated at reflux for a further 15 minutes and then treated slowly with 21.5 g (0.37 mol) of acetone. The mixture was heated at reflux for a further 30 minutes, cooled and then poured slowly into 300 g of crushed ice. The resultant white precipitate was dissolved by the addition of 20% H2SO4. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo. The residue was distilled (120° C.; 6 mm) to give the captioned compound as a colorless oil. PMR (CDCl3): δ 1.18 (6H, s), 1.44-1.53 (2 H, m), 1.62-1.72 (2H, m), 2.61 (2H, t, J~7.6 Hz), 7.16-7.30 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:42][CH2:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[N:47][N:48]3[CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
2-Chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) was suspended in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Example 12; 91 mg, 0.393 mmol) with a 2×0.25 mL wash of dichloromethane. Diisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min at ˜0° C. The mixture was stirred at ˜0° C. for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl, sodium hydrogen carbonate solution, and brine (10 mL each), then dried (MgSO4), filtered, and concentrated. Ethyl acetate/petroleum ether was added and the insoluble material was filtered off to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (93 mg, 55%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18](=O)[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>COC(OC)C>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:18]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: COC(C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethyoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22-341. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate which can be used without further purification.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1Cl)=[O:12]>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH:4]([C:2]#[N:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 86.7 g of sodium in 4,500 ml of anhydrous ethanol is added at 15° C. to a solution of 528 g of ethyl cyanoacetate in 500 ml of anhydrous ethanol. After one hour, the mixture is cooled to 0° C. and a solution of 620 g of 2-chloro-4-fluoroacetophenone in one liter of ethanol is added to the solution obtained. The reaction mixture is left for 12 hours at room temperature, then hydrolyzed with 200 ml of water and concentrated. The residue is taken up in one liter of water and this aqueous phase is neutralized to pH 7 and extracted with dichloromethane, followed by concentration.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:17])[CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[C:19]1([Li])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl[Sn]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:4][CH:3]=3)[C:6]3[C:11]([C:12]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]([Br:17])=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Reactant: [Li]c1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Brc1ccc2c(-c3ccccc3)c3cc(Br)ccc3c(-c3ccccc3)c2c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
36.6 g (100 mmol) of 2,6-dibromoanthraquinone are dissolved in 600 ml of THF, the solution is cooled to −75° C., and 100 ml of a 2 M phenyllithium solution in THF are added dropwise. After 2 h, the mixture is allowed to come to RT, 50 ml of 4 M HCl are added, the mixture is partitioned between toluene and water, the organic phase is dried over Na2SO4, and the solvent is removed in vacuo. The residue is taken up in 350 ml of DMF, 68 g (350 mmol) of SnCl2 are added, and the mixture is brought to an internal temperature of 140° C. for 2 h. 180 ml of 2 M HCl are then added at about 40° C., and the precipitate is filtered off with suction, washed with water, EtOH and ethyl acetate and dried at 80° C. in vacuo. Recrystallisation from toluene gives 30.8 g (63 mmol, 63%) of an ochre solid, which is homogeneous according to TLC and 1H-NMR and is employed in this form in the subsequent reaction.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.3.). Starting with 2.49 g (8.15 mmol) of tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate (isomer 1), described in Example 12 (step 12.1.) and 1.07 g (16.31 mmol) of sodium azide, the product is obtained, which is used in the following step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: Cc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1ccccc1N1CCOCC1
Yield: 39.5 %

Procedure:
According to the general procedure B, 2-bromotoluene (171 mg, 1.00 mmol) reacted with morpholine (104 mg, 1.20 mmol) using 1 mol % of catalyst and sodium tert-butoxide (134 mg, 1.40 mmol) at room temperature for 43 h to give the title compound (70 mg, 40%) as an oil after purification: 1H-NMR (300 MHz, CDCl3): δ 7.22-7.18 (m, 2H), 7.06-7.00 (m, 2H), 3.87 (t, 4H, J=4.5 Hz), 2.93 (t, 4H, J=4.5 Hz), 2.34 (s, 3H). GC/MS(EI): m/z 177 (M+).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)C>[CH2:11]([O:19][C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:6][CH:5]=1)[CH3:10]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
1 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H), 10 ml ethanol and 0.4 ml concentrated sulphuric acid were heated at about 80-120° C. for about 24 hours. The mixture was evaporated to dryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (hydrogen sulphate salt). Spectroscopic data as in Example 44.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br>O1CCOCC1>[Br:11][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of 4-hydroxyacetophenone (2.5 g, 18.3 mmol) (Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine (3.22 g, 20.1 mmol) in dioxane (20 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was recrystalized from methanol to provide 2-bromo-1-(4-hydroxyphenyl)ethanone (1.73 g, 44% yield).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
107 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 5A; 300 mmol, 1 equivalent) were dissolved in 2.8 l of THF/methanol (1:1), 1.5 l of 1 N aqueous lithium hydroxide solution (1.5 mol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The organic solvents were removed under reduced pressure and the resulting aqueous solution was adjusted in an ice bath to pH 3-4 using 1 N aqueous hydrochloric acid. The resulting solid was filtered off, washed with water and isopropanol and dried under reduced pressure. This gave 92 g (95% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>CO>[OH:39][C:37]([C:36]([F:41])([F:40])[F:35])=[O:38].[CH3:1][CH:2]([CH3:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[CH:20]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)[CH2:19][CH2:18]4)[N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CN(C2CCc3cc(-c4noc(-c5ccc(CC(C)C)cc5)n4)ccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc(-c2nc(-c3ccc4c(c3)CCC4N3CC(C(=O)O)C3)no2)cc1
Reaction time: 2 h

Procedure:
A solution of methyl 1-(5-(5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate, Enantiomer 1 (from Step A, 0.10 g, 0.23 mmol) and sodium hydroxide (1N aqueous solution, 0.6 mL) were heated in methanol (1 mL) at 60° C. After 2 h, the reaction was cooled and acidified with trifluoroacetic acid. HPLC purification (HPLC B) gave the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 8.19 (s, 1H), 8.13–8.15 (m, 3H), 7.74 (d, J=7.8 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 5.06 (dd, J=2.5, 7.8 Hz, 1H), 4.52–4.60 (m, 2H), 4.41–4.48 (m, 2H), 3.71 (m, 1H), 3.27 (dt, J=8.15, 16.7 Hz, 1H), 3.13 (ddd, J=3.7, 9.2, 16.7 Hz, 1H), 2.56–2.66 (m, 3H), 2.22–2.30 (m, 1H), 1.92–2.00 (m, 1H), 0.96 (d, J=6.6 Hz, 6H); ESI-MS 418.1 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH:23]1[C:33]2[CH:32]=[CH:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH:31]=[CH:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the product of step (i) (50 g) in dry tetrahydrofuran (11) at −78° C. was added n-butyllithium (69 ml of a 2.5 M solution in hexanes) dropwise. After 0.5 hours a solution of 5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) was added. The reaction mixture was stirred at −78° C. for three hours and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (400 ml) was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give the crude 5-[2,4-bis[1,1-dimethylethoxy]pyrimidin-5-yl]-5H-dibenzo[a,d]cyclohepten-5-ol which was used directly.
Reaction SMILES: CSC.B.[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](O)=[O:15].S(C)C>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=C(O)CCc1ccccc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCc1ccccc1Br
Temperature: 0 °C

Procedure:
Borane-dimethyl sulfide complexe (2.2 eq.) was added to a stirred solution of commercially available 3-(2-bromophenyl)propanoic acid (1 eq.) in THF (0.15M). The mixture was reflux for 3 h. without a condensor allowing the SMe2 to escape. The final reaction concentration was 0.3M. The mixture was cooled to 0° C. and quenched with a slow addition of HCl 1N. The resulting mixture was extracted with Et2O. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated to afford the desired material as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:11].O=O>CC([O-])=O.CC([O-])=O.[Cu+2].O.O>[CH:8]1[CH:7]=[C:5]2[N:6]=[C:2]([S:1][S:1][C:2]3[S:3][C:4]4[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:11]=3)[S:3][C:4]2=[CH:10][CH:9]=1
Reactant: Sc1nc2ccccc2s1
Reactant: N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Temperature: 50 °C

Procedure:
Following the procedure of Example 24, 50 g (0.3 mole) of 2-mercaptobenzothiazole, 8 mg (0.04 mMole) of Cu(OAc)2.H2O, 40.8 g (2.4 moles) of ammonia and 300 g of water were heated to 50° C., intensively stirred and placed under an oxygen pressure of 4 bars. Uptake of oxygen was immediately recorded and a deposit of dibenzothiazolyl disulphide was formed. After a reaction time of 2.5 hours, the 2-mercaptobenzothiazole conversion amounted to 95.4% and the yield of dibenzothiazolyl disulphide to 94.1% of the theoretical yield (selectivity: 98.6%).
Reaction SMILES: [CH3:1][N:2]([CH2:22][C@@H:23]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[CH2:24]1)[CH2:3][CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[CH2:8][CH2:7]1.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>C(OCC)(=O)C.CC(C)=O>[CH3:1][N:2]([CH2:22][C@@H:23]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[CH2:24]1)[CH2:3][CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[CH2:8][CH2:7]1.[C:35]([O-:40])(=[O:39])[C:36]([O-:38])=[O:37]
Reactant: O=C(O)C(=O)O
Agent: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Ivabradine (44 g) was dissolved in ethyl acetate (700 ml) and to this oxalic acid (22 g) in acetone (50 ml) was added slowly and stirred for 3-4 hours at ambient temperature. The ivabradine oxalate, thus obtained was filtered, washed with ethyl acetate (100 ml) and recrystallized in acetonitrile (350 ml). XRD pattern shows that isolated ivabradine oxalate was crystalline in nature and depicted in FIG. 2.