Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:18][NH2:19])[N:3]=1.[CH2:20](O)C.[CH3:23][CH:24](C)[C:25](=O)[C:26](=[CH:30]OC)[C:27]([OH:29])=[O:28].COC=C(C)C(CC(OC)=O)=O.CCOCC>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=[C:4]([N:18]2[C:25]([CH2:24][CH3:23])=[C:26]([C:27]([O:29][CH3:20])=[O:28])[CH:30]=[N:19]2)[N:3]=1
Reactant: CCO
Reactant: COc1ccc(CNc2cc(Cl)nc(NN)n2)cc1
Reactant: COC=C(C(=O)O)C(=O)C(C)C
Agent: COC=C(C)C(=O)CC(=O)OC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1c(C(=O)OC)cnn1-c1nc(Cl)cc(NCc2ccc(OC)cc2)n1
Reaction time: 0.5 h

Procedure:
A 2.8 g portion of 4-chloro-2-hydrazino-6-(4-methoxybenzyl)aminopyrimidine was added to an ethanol solution (20 ml) of 1.72 g of methyl 2-(methoxymethylene)propionylacetate (methyl 2-methoxymethylene-3-oxopentanoate) at room temperature and stirred for 30 minutes, and then the mixture was heated under reflux for 3 hours. After concentration of the reaction solution under a reduced pressure, ether and hexane were added to the residue and the precipitate was collected by filtration to obtain 2.53 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:26](OCC)=[O:27]>C1COCC1.CCCCCC>[C:15]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:26]=[O:27])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC=O
Reactant: Cn1nnnc1C=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1C(C=O)=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene (3.75 g; 14.29 mmole) in dry THF (40 mL) was cooled to -78° C. and treated with n-butyllithium (6.3 mL of a 2.5M soln. in hexane; 15.75 mmole) and the resulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (1.5 mL; 18.58 mmole) was added and the mixture stirred at -78° C. for 2 hours. The reaction was quenched with 2N HCl and the solvent removed by evaporation. The residue was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 25-35% EtOAc-hexane as eluent to afford starting material (1.35 g; 36%) and the desired title compound (1.65 g; 39%); m.p.=185°-186° C. (crystallized EtOAc-hexane). MS (EI): m/e=290 for M+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27][CH2:26]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C)C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N,N-dimethylpiperidin-4-amine (1.2 equiv) to give 175 (17.9 mg, M+1 424.1)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[CH3:32][N:33]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](O)=[O:54])=[CH:48][CH:47]=1)[CH2:34][CH:35]([OH:44])[CH:36]([OH:43])[CH:37]([OH:42])[CH:38]([OH:41])[CH2:39][OH:40]>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:53](=[O:54])[CH2:52][C:49]3[CH:48]=[CH:47][C:46]([CH2:45][N:33]([CH3:32])[CH2:34][CH:35]([OH:44])[CH:36]([OH:43])[CH:37]([OH:42])[CH:38]([OH:41])[CH2:39][OH:40])=[CH:51][CH:50]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CN(Cc1ccc(CC(=O)O)cc1)CC(O)C(O)C(O)C(O)CO
Product: CN(Cc1ccc(CC(=O)NCc2ccc(C3C(CCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)cc1)CC(O)C(O)C(O)C(O)CO

Procedure:
The synthesis was carried out analogously to Example XVe), starting with 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 114 mg of (4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetic acid. This gave the product of molecular weight 747.84 (C41H47F2N3O8+); MS (ESI) 748.35 (M+H+).
Reaction SMILES: CCCCCCCC.[F:9][C:10]([F:24])([F:23])[C:11]([F:22])(Br)[C:12](=[O:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].[F:25]C(F)(F)C(=O)C(F)(Br)C(F)(F)C(F)(F)F>>[F:9][C:10]([F:24])([F:23])[C:11]1([F:22])[O:20][C:12]1([F:25])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(C(F)(F)C(F)(F)F)C(F)(Br)C(F)(F)F
Reactant: O=C(C(F)(F)F)C(F)(Br)C(F)(F)C(F)(F)F
Solvent: CCCCCCCC
Product: FC(F)(F)C(F)(F)C1(F)OC1(F)C(F)(F)F

Procedure:
The distillate was subjected to flash chromatography on silica gel using octane as an eluant. The column effluent containing primarily octane and the mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone was then subjected to two vacuum distillations at a pressure of 56 and 100 torr, respectively, to separate the bromoperfluoroketones from the bulk of the octane. The low-boiling fractions from the vacuum distillations were then re-distilled at atmospheric pressure. The fractions collected at a head temperature of 71.2-72.8° C. were combined. The product was a mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone in molar ratio of 1.0 to 1.12 with overall purity of >98 GC area %.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[C:14]([Br:28])[C:13]([CH3:17])=[N:12]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1cc(Cl)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
The solution of 12.5 g (0.043 mol) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-5-chloropyrazole in the mixed solvent made of 100 ml of chloroform and 100 ml of acetic acid was added with 3.9 g (0.047 mol) of sodium acetate, followed by 7.2 g (0.045 mol) of bromine at 10° C. After stirred at the same temperature for 2 hours, the reaction mixture was poured into ice water and the chloroform layer was separated. The chloroform layer was washed with an aqueous sodium bicarbonate and water and concentrated to obtain 13.0 g of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4-bromo-5-chloropyrazole as pale yellow crystals, melting point: 135° to 137° C. in yield of 82%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C(N(CC)C(C)C)(C)C.[NH2:20][C@@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>C(O)CCC>[C@@H:21]1([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol) was dissolved in 1-butanol (60.0 mL) and N,N-diisopropylethylamine (3.57 mL, 20.5 mmol) was added followed by (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol). The mixture was heated to reflux for 60 h, cooled down to rt and the solvent was evaporated to dryness. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to afford the title compound (2.72 g, 80%). LC/MS: Rt=1.42 min, ES+ 251 (AA standard).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].C1COCC1.CO.C1C(=O)N([Br:37])C(=O)C1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:37])=[CH:17][C:16]=2[CH3:21])=[C:12]([F:22])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
7-Fluoro-6-o-tolylamino-1H-benzoimidazole-5-carboxylic acid methyl ester 7a (2.00 g, 6.68 mmol) is suspended in 1:1 THF/MeOH (60 mL) and cooled to −78° C. under a nitrogen atmosphere. A solution of NBS (1.20 g, 6.75 mmol) in 1:1 THF/MeOH (5 mL) is added followed by a MeOH (5 mL) solution of TsOH.H2O (1.9 g, 10.0 mmol). After 30 minutes, the reaction mixture is warmed to 0° C. and then after 1 hour warmed to room temperature. After 16 hours, more NBS (0.12 g, 0.67 mmol) is added and the reaction mixture is allowed to stir for 3 hours. The reaction mixture is quenched by the addition of 10% Na2S2O4 solution. After 30 minutes, the reaction mixture is diluted with water and ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The recovered solid is triturated with methylene chloride to give 2.00 g (79%) pure desired product: MS APCI (+) m/z 380, 378 (M+1 Br pattern) detected.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([C:23]#[N:24])[C:7]=1[S:25][C:26]([F:29])([F:28])[F:27].OO.[OH:32]S(O)(=O)=O>O>[CH:15]1[C:14]([C:18]([F:19])([F:20])[F:21])=[CH:13][C:12]([Cl:22])=[C:11]([N:10]2[N:9]=[C:8]([C:23]#[N:24])[C:7]([S+:25]([O-:32])[C:26]([F:29])([F:28])[F:27])=[C:6]2[NH2:5])[C:16]=1[Cl:17]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: OO
Solvent: ClCCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 7.5 °C
Yield: 80.1 %

Procedure:
3.0 liter of ethylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was cooled to a temperature of about 5-10° C. 95.0 gms of H2O2 (50.0% w/w) & 2000.0 gms H2SO4 (85.0% w/w) were simultaneously added over a period of 3-4 hours. The reaction temperature was maintained at 12-15° C. for about 2.0 hours with monitoring of reaction conversion. The reaction mass obtained thereafter was slowly added into 800 ml of chilled water at a temperature of about 10-20° C. over a period of 2.0 hours. This mass was heated to a temperature of about 60-65° C. to separate the aqueous and organic layers. The organic phase was washed with water & then with 5% NaHCO3, followed by water wash, till a neutral pH was obtained. The crude yield of fipronil after removal of solvent was 435.0 gms. The crude fipronil was then crystallized to yield 350.0 gms of fipronil with 95.50% purity.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>CN(C)C=O>[ClH:1].[C:31]([O:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(OCC(O)CN2CCC(COc3ccccn3)CC2)c2[nH]cnc12
Agent: Cl
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1ccc(OCC(CN2CCC(COc3ccccn3)CC2)OC(=O)c2ccccc2)c2[nH]cnc12

Procedure:
4.87 g. 4-{2-Hydroxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole (preparation see Example 13), 19.5 g. benzoic acid and 2.12 g. benzoic anhydride are heated under reflux for 2 hours in 100 ml. benzene and 25 ml. dimethylformamide. After removing the solvent, the residue is taken up in 100 ml. water, rendered alkaline with concentrated aqueous ammonia solution and extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulphate and evaporated. The residue is taken up in ethanol and mixed with ethereal hydrochloric acid. After adding isopropanol and diethyl ether, there crystallize out 2.1 g. (41% of theory) 4-{2-benzoyloxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole hydrochloride; m.p. 178°-181° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:9]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:16][CH3:17])=[C:8]([C:10]#[CH:11])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.9 %

Procedure:
Add a solution of potassium hydroxide (3.28 g, 58.5 mmol) in water (30 mL) dropwise over 25 minutes to a stirred solution of (5-chloro-2-methoxy-phenylethynyl)-trimethylsilane (13.7 g, 57.4 mmol) in methanol (275 mL) and stir at room temperature for 2 hours. Concentrate, add brine to residue, and extract with EtOAc (×2). Dry organic layer over MgSO4 and concentrate to get 13 g of a black oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford the title compound (8.98 g, 94%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:46][CH:47]1[C@H:51]2[C@H:52](OC3CCCCO3)[N:53](C(OC(C)(C)C)=O)[C:54]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@H:19]2[C@H:20](OC3CCCCO3)[N:21](C(OC(C)(C)C)=O)[C:22]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:46][CH:47]1[C@@H:51]2[CH:52]=[N:53][C:54]3[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@@H:19]2[CH:20]=[N:21][C:22]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 88.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8d (174 mg, 0.17 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9d (86 mg, 0.15 mmol, 88%) as a solid: [α]20D=+500° (c=0.09, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.39-1.55 (m, 4H, 14-H, 14′-H), 1.72-1.89 (m, 4H, 13-H, 13′-H), 1.91-2.05 (m, 4H, 2-H, 2′-H), 2.17-2.31 (m, 4H, 1-H, 1′-H), 3.45-3.56 (m, 2H, 3-H, 3′-H), 3.62-3.69 (m, 2H, 11a-H, 11a′-H), 3.70-3.79 (m, 2H, 3-H, 3′-H), 3.83 (s, 6H, 7-OMe, 7′-OMe), 3.95-4.13 (m, 4H, 12-H, 12′-H), 6.73 (s, 2H, 9-H, 9′-H), 7.43 (s, 2H, 6-H, 6′-H), 7.58 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.7, 29.0, 29.6, 46.6, 53.7, 56.0, 69.0, 109.6, 112.5, 120.2, 140.5, 147.1, 151.7, 162.8, 164.6; IR (neat): 3385, 2945, 1622, 1599, 1506, 1447, 1387, 1261, 1217, 1093 cm−1; MS (FAB) m/z (relative intensity) 639 ([M+2×MeOH]+., 4), 607 ([M+MeOH]+., 12), 575 (M+., 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Br)cc(OC(F)(F)F)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Br)cc(OC(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607 mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture, then stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 30, which was purified through flash chromatography by using 100-200 mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexane to afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolved in methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude des-brominated compound 31. The crude 31 was purified by flash chromatography using 100-200 mesh silica gel. Compound 31 was eluted as des-brominated compound at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one 31. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).
Reaction SMILES: C(OC([N:11]1[C@H:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:28]>C(O)C.[H][H].[Pd]>[ClH:28].[CH2:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH2:22][C@@H:23]([CH2:24][C:25]([OH:27])=[O:26])[NH:11]1
Reactant: O=C(O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 72 %

Procedure:
0.55 g of (3S)-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-acetic acid is dissolved in 12 ml of 80% aqueous ethanol. 0.5 g of 10% Pd-C and 3 ml of 10% HCl are added to the solution. The mixture is subjected to catalytic reduction in hydrogen gas under atmospheric pressure at room temperature. The catalyst is filtered off, and washed with ethanol. The filtrate and the washings are combined, and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate. 290 mg of (3S)-1,2,3,4-tetrahydro-β-carboline-3-acetic acid hydrochloride are obtained as pale yellow needles. Yield: 72%
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11][C:12](=[O:14])[CH3:13].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:20])([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:15][OH:16]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 47 h
Yield: 95.8 %

Procedure:
A 10 l reaction vessel was charged with 110 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol, 11 g of Lipase made by SEIKAGAKU CORPORATION, (derived from Rhizopus delemar, Enzyme No. 3), 2.8 l of 50 mM acetate buffer (pH 5) and 2.8 l of cyclohexane. The resulting mixture was stirred at 30° C. for 47 hours. The obtained reaction mixture was extracted twice with 3 l of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 90 g of (R)-2-(2,4-difluorophenyl)-3-acetoxy-1,2-propanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([O-:12])=O)[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([C:10]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=1
Reactant: COc1cc(Cl)cc(C(=O)[O-])n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylate, 411 mg (3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 μL (6.60 mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11]B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1OCCOC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
2-Chloro-3-nitropyridine (20 g, 126.18 mmol), methane boronic acid (9.8 g, 164 mmol), tetrakis(triphenylphosphine)palladium (11.66 g, 10 mmol) and potassium carbonate (51.48 g, 378.6 mmol) were all mixed in 1-4 dioxane (500 mL), degasified and heated to 100° C. for 48 h under N2. Work up was carried out by allowing the reaction mass to cool to ambient temperature and quenched with water and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid. The solid was further purified by silica gel column chromatography using 6% of ethyl acetate in hexane as eluent to give 2-methyl-3-nitropyridine as an off white solid: 1H-NMR (CDCl3) δ: 2.9 (s, 3H), 7.4 (m, 1H), 8.3 (d, 1H), 8.7 (d, 1H).