Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@H]1CCNC1

Procedure:
To (3S)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((S)-pyrrolidin-3-yl)acetamide. (33 mg, 0.069 mmol)
Reaction SMILES: [BrH:1].C(O)(=O)C.O=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:8][S:9][C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:10]1[S:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A 25% hydrogen bromide/acetic acid (35 ml) solution was added to a solution of 2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl thiocyanate (3.88 g, 15.8 mmol) in acetic acid (35 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.88 g (59.1%) of the desired product as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1>[C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1ccc(C(=O)O)o1)n2Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of the compound obtained in Example 30 (6) (0.003 g) in 1,4-dioxane (0.5;ml), a 10% aqueous lithium hydroxide solution (0.5 ml) was added at −5° C. under argon atmosphere and the mixture was stirred for 2 hours. To the reaction solution was then added a 10% aqueous hydrochloric acid solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain 0.001 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.17 g, 0.85 mmol), acetonitrile (4 mL), sodium carbonate (0.11 g, 2.12 mmol) and iodoethane (0.13 g, 0.85 mmol) was stirred at ambient temperature for 72 h. Water (30 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.11 g). [α]D=−21.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 111-112° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C[Si](Cl)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>N1C=CC=CC=1>[C:22]([NH:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:1]2[O:8][C@H:5]([CH2:6][O:7][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:54][CH:53]=3)[C@@H:3]([OH:4])[CH2:2]2)[C:10](=[O:11])[N:12]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
2′-Deoxycytidine (5.82 g, 25.6 mmol) was dried by evaporation with dry pyridine (2′50 mL) and taken up in dry pyridine (100 mL). To this suspension, trimethylsilyl chloride (11.5 mL, 90.6 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was cooled using an ice water bath and benzoyl chloride (4.60 mL, 39.6 mmol) was slowly introduced. The ice-water bath was removed and the mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched by adding methanol (15 mL), concentrated to one half of the original volume and filtered. To the filtrate, water (30 mL) was added and the solution was evaporated to an oil. Additional evaporations with water (3×30 mL) were performed to remove pyridine, and the resulting residue was partitioned between water and ethyl acetate. After vigorous stirring, the product crystallized from the aqueous layer. The crystals were washed with cold water and ethyl acetate, and they were used in the next step without further purification. TLC: Rf(B)=0.7. Crude N4-benzoyl-2′-deoxycytidine was dried by evaporation with dry pyridine (3×50 mL), and then dissolved in the same solvent (100 mL). 4,4′-Dimethoxy-tritylchloride (7.4 g, 22 mmol) was added portion-wise to the reaction mixture, and the stirring was continued overnight at ambient temperature. The reaction mixture was evaporated to an oil and dissolved in CH2Cl2 (100 mL). The organic phase was washed with saturated aqueous NaHCO3 (50 mL) and water (3×100 mL), and dried with anhydrous Na2SO4. After coevaporation with toluene, the residue was applied onto a silica gel column and eluted with a gradient of MeOH in CH2Cl2 (0-8% MeOH). The title compound (6) was obtained in 65% yield (9.0 g) starting from 2′-deoxycytidine.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl([O-])=[O:14].[Na+].O1CCOCC1.S(=O)(=O)(O)N>O>[F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
In a round bottom flask, 2-fluoro-3-nitro-benzaldehyde (15, 1.02 g, 6.03 mmol) is combined with sodium chlorite (1.26 g, 11.15 mmol), 60 mL of 1,4-dioxane, 20 mL of water, and sulfamic acid (4.47 g, 46.0 mmol) and the reaction is stirred at room temperature for 30 minutes. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified on column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum, then suspended in dichloromethane. The resulting solid is collected by filtration to provide the desired compound (16, 151 mg). MS (ESI)[M−H+]−=184.4.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1.C[I:18].[CH2:19](OCC)C>C(O)C>[I-:18].[CH3:1][N+:2]([CH3:19])([CH3:16])[CH2:3][C:4]1[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)Cc1ccccc1-c1ccccc1
Reactant: CCOCC
Reactant: CI
Solvent: CCO
Product: C[N+](C)(C)Cc1ccccc1-c1ccccc1
Product: [I-]
Reaction time: 16 h
Yield: 100 %

Procedure:
Under a dry nitrogen atmosphere, 6.1 g (0.027 mole) of N,N-dimethyl-[1,1'-biphenyl]-2-methanamine was dissolved with stirring in 6.4 ml of anhydrous ethanol. To this solution 5.1 g (0.036 mole) of methyl iodide was added slowly. After complete addition, the reaction mixture was heated at reflux temperature for 45 minutes, then cooled. Diethyl ether was added until the mixture was cloudy, then the whole was placed in a freezer for 16 hours. An oil which had formed in the mixture was separated then dissolved in ethanol, and the solution was concentrated under reduced pressure to give 10.0 g (100% yield) of N,N,N-trimethyl-[1,1'-biphenyl]-2-methanaminium iodide as a brittle yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:42]=[C:43]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[CH:45][C:46]=1[Cl:47]>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([C:43]1[CH:44]=[CH:45][C:46]([Cl:47])=[C:41]([Cl:40])[CH:42]=1)(=[O:50])=[O:49])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 3,4-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OC)=O.CO>O>[C:1]1([S:7][CH2:8][CH:9]([OH:10])[CH2:11][N:12]=[N+:13]=[N-:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(SCC2CO2)cc1
Agent: [Na+]
Solvent: COC=O
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCC(O)CSc1ccccc1
Yield: 91.9 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 7.2 g of phenylthiomethyloxirane (prepared as described in Preparation 85), 14 g of sodium azide, 65 ml of methyl formate and 270 ml of an 8:1 by volume mixture of methanol and water were used, to give 8.33 g of the title compound as a colorless oil having an Rf value of 0.23 (on silica gel thin layer chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: O1C2C=CC(C3(C(NC4C=CC(CC5C=CC=CC=5)=CN=4)=O)CC3)=CC=2OC1.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1.[Cl-].[Cl:52][C:53]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[C:54]=1[CH2:55][Zn+]>>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]3([C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([CH2:55][C:54]5[C:53]([Cl:52])=[CH:60][CH:59]=[CH:58][C:57]=5[Cl:61])=[CH:46][N:45]=4)=[O:42])[CH2:40][CH2:39]3)=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1ccc(Cc2c(Cl)cccc2Cl)cn1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2,6-dichlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with (2,6-dichlorobenzyl)zinc(II) chloride.
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCCl.C(Cl)(Cl)Cl>[C:1]([NH:6][C:7](=[O:8])[O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)N=C=O
Reactant: Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)Oc1ccccc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 0.1 mol) in 1,2-dichloroethane (50 ml) was dropise added to a solution of dry phenol (9.4 g; 0.1 mol) in chloroform (20 ml) under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure. The residue (20.5 g) was recrystallized from a mixture of hexane and benzene to give phenyl N-methacryloylcarbamate as colorless needles. M.P., 94°-95° C.
Reaction SMILES: [Na].[CH:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11]>COCCOCCOC.C(OCC)C>[CH3:11][CH2:10][C:9](=[O:12])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCC
Reactant: CCC(=O)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCCCCC#CC(=O)CC
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
A 1-liter reactor was loaded with 345 mL of diglyme (RN 111-96-6) and 17.2 g (748 mmoles) of sodium (RN 7440-23-5) cut into pieces. After heating to a temperature slightly above the melting point of sodium accompanied by thorough stirring, 71.7 g (745 mmoles) i.e. 97.5 mL of 1-heptyne (RN 628-71-7) in solution in 100 mL of diglyme is then added four times at hourly intervals. The medium thickens to form a beige suspension. Stirring is continued for another 2 hours 30 minutes at the same temperature. The mixture is cooled down to 25-30° C. and poured slowly into a stirred solution of 64.8 g (700 mmoles) i.e. 61.0 mL of propionyl chloride (RN 79-03-8) in 600 mL of ethyl ether. An exothermic reaction takes place followed by stirring for 1 hour at no particular temperature.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])=[O:19]
Reactant: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 93.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 0.83 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 195 (0.21 g, 95%) as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:12][C:7]1[CH:6]=[C:3]([C:2]([OH:1])=[CH:9][C:8]=1[O:10][CH3:11])[CH:4]=[O:5]
Reactant: [Br-]
Reactant: COc1ccc(C=O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A mixture of 2-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and tetrabutylammonium tribromide (6.40 g, 20 mmol) in anhydrous dichloromethane (200 mL) was stirred at room temperature for 24 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40M cartridge, eluting with 5% ethyl acetate/95% hexane to give 3-bromo-6-hydroxy-4-methoxy-benzaldehyde as a white solid (3.50 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu](Br)Br>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: Brc1ccccc1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1-c1ccccc1
Temperature: 156 °C

Procedure:
5.5 g (22.31 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate, 6.16 g (44.62 mmol) of anhydrous potassium carbonate, 77.53 g (52 ml, 493.8 mmol) of bromobenzene and 1.6 g (11.15 mmol) of copper bromide are stirred under reflux (about 156° C.) for 5 days. The reaction mixture is then filtered, and the residue on the frit is washed with toluene. The collected filtrates are concentrated, dried under high vacuum and purified by flash chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: CCOC(=O)CCCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 84 %

Procedure:
In the same manner as described in Example 38, 0.50 g (1.171 mmol) of the product of Example 37 and 0419 mL (2.927 mmol) of ethyl 4-bromobutyrate provided 0.530 g (84%) of the desired product as a colorless oil. Electrospray Mass Spec: 542.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cncc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of ethyl-5-bromonicotinate (30 g, 130.40 mmol), triethylamine (78 mL) and ethyl acetate (130 mL) is degassed for 15 min. Add trimethylsilylacetylene (88.46 mL, 625.92 mmol), bis(triphenylphosphine)palladium (II) dichloride (4.57 g, 6.52 mmol) and copper (I) iodide (0.25 g, 1.30 mmol) and stir at 50° C. under-nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give the title compound (27.7 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.CO.C(OCC)(=O)C>O>[CH3:17][C@H:13]([NH:12][CH2:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[C:14]([NH2:16])=[O:15]
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene-amino]propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50% H2O) Pt/C5% (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35° C. for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40° C., until two clear phases are obtained. These two phases are separated and the aqueous layer is extracted with 50 mL of ethyl acetate at 40° C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20° C. The solid formed is collected by filtration, washed with n-heptane (15 mL) and dried under reduced pressure to give 15.2 g (94.8% yield) of safinamide with a HPLC purity of 99.8 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide lower than 0.005% by weight measured by HPLC see Example 17B).
Reaction SMILES: O[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)O)O)[OH:6])=[O:4].C(O)(=O)[CH2:14][C:15](CC(O)=O)([C:17](O)=[O:18])[OH:16].[C:26]([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>>[CH3:26][O:6][C:5]1[CH:7]=[CH:9][CH:11]=[CH:2][C:3]=1[O:4][CH2:14][CH:15]([OH:16])[CH2:17][OH:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: COc1ccccc1OCC(O)CO

Procedure:
The maltitol was similarly admixed with Phase F to form Phase G to which the ammonium glycyrrhizinate was added with another about 5 minutes mixing time being used. The flavors and colorants were then admixed, with a mixing time of about 5 minutes, followed by addition of a sufficient amount of liquid fructose to make the desired volume and mixing to homogeneity. The pH value was thereafter adjusted to be between 4 and 5 using a citric acid or sodium citrate solution. This composition provides 100 mg of guaifenesin per 5 mL (teaspoon).