Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1>O1CCCC1>[Br:1][C:13]1[C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:10]([NH2:9])=[N:11][CH:12]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: -5 °C
Yield: 75.9 %

Procedure:
Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to −5±3° C. Charge a nitrogen-flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet/outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0±3° C. throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20±3° C. over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20±3° C. throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp=25° C., 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of tert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30±3° C. and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4×200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of tert-butyl methyl ether. Partially concentrate (57±3° C.) to a volume of 350 mL. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Again, resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 103 g (150 mL) of tert-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45±3° C. throughout the addition. Slowly increase the vacuum and concentrate (internal temp=40° C. to 50° C.) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp=25° C. to 40° C.) to a batch volume of 500 mL. Stir the resulting suspension at 0° C. for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0° C.) heptane (containing 30 ppm Octastat). Dry the solids (40° C., 50 mbar) for 16 h to afford 109.8 g (78.0% yield) 4a as an orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCI (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:9](O)=[O:10]>N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1

Procedure:
49.4 g of thionyl chloride and 0.21 g of pyridine were added to 20 g of 3,5-dichlorobenzoic acid and the mixture was refluxed for 20 hours. Excessive thionyl chloride was removed by distillation. Dry hexane was added to the residue and an insoluble matter was filtered out of the resulting solution and hexane was removed under reduced pressure. The remaining solution was crystallized. 3,5-Dichlorobenzoyl chloride was obtained quantitatively.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[CH3:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: CC(NCCBr)c1ccccc1
Agent: Br
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: CC1NCCc2ccccc21
Temperature: 145 °C
Reaction time: 0.67 h
Yield: 65.4 %

Procedure:
10.0 g (30.1 mmole) of N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 6(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g (96.54 mmole) of anhydrous aluminum chloride was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 2.90 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]1([C:23]([C:29]2[S:33][C:32]([SH:34])=[N:31][CH:30]=2)([OH:28])[C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH:20]1([C:23]([C:29]2[S:33][C:32]([S:34][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)=[N:31][CH:30]=2)([OH:28])[C:24]([F:26])([F:25])[F:27])[CH2:22][CH2:21]1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1

Procedure:
Employing the procedure described in Example 1, Step 3, with 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, (+)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol and potassium carbonate in NMP at 120° C., the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 8.00 (s, 1H), 7.68 (m, 2H), 7.56-7.60 (m, 2H), 7.48 (dd, 1H), 7.39 (t, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 1.65 (m, 1H), 0.82 (m, 1H), 0.54-0.71 (m, 3H); [α]D=+29.4° (c=1, EtOH).
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5]>ClC1C2C(=CC=CC=2)C=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]3[N:5]=[C:4]4[N:10]=[C:1]([C:2]5[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=54)[N:10]=[C:1]4[NH:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]4=[N:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]=2[NH:5]3)[CH:6]=1
Reactant: N#Cc1ccccc1C#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1cccc2ccccc12
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 140 °C

Procedure:
Phthalonitrile (1100 grams) and titanium tetrachloride (813 grams) were suspended in 6800 ml of 1-chloronaphthalene and heated to 215°-220° C. and maintained for 2.5 hours at this temperature. The reaction mixture was cooled to 140° C., and the dark solid was collected, and washed with acetone, and methanol. After drying, the dark blue solid (1090 grams) was refluxed twice in 10 liters of distilled water for two hours, filtered hot each time, and washed with acetone to yield crude titanyl phthalocyanine.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:10].[K+].OO>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(O)(C)C>[C:1]1([CH2:7][C:8]([NH2:9])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: OO
Agent: [Cl-]
Solvent: CC(C)O
Product: NC(=O)Cc1ccccc1
Yield: 95 %

Procedure:
117.2 Grams of phenylacetonitrile (II-2), 56.1 g of a 25% aqueous potassium hydroxide solution, 291.5 g of a 35% aqueous hydrogen peroxide solution and 1.78 g of triethylbenzylammonium chloride were mixed at 50° C. for 4 hours in 351.6 g of isopropanol. After completion of the reaction, isopropanol was distilled off and the formed precipitate was filtered out and washed with water to obtain 128.5 g of phenylacetamide (m.p.: 155° C.) (I-2) in a yield of 95%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.OS(O)(=O)=O.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)nc1

Procedure:
In 70 ml of MeOH was suspended 12.0 g (0.086 mole) of 6-hydroxynicotinic acid followed by addition of 4 ml of concentrated H2SO4. The mixture was refluxed for 10 hours. After cooling, MeOH was distilled off and the residue was adjusted to pH about 8 with a saturated aqueous solution of sodium hydrogen carbonate. The precipitate was collected by filtration, rinsed (twice) with water and dried to give 10.5 g of methyl 6-hydroxynicotinate as pale yellow crystals. This product was in the pyridone structure.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20]>C1CCCCC1>[C:19]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[O-:34])([CH3:22])([CH3:21])[CH3:20].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1CCCCC1
Product: Cc1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 1 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum was purged with nitrogen. Operating in an atmosphere of nitrogen, the vessel was charged with a cyclohexane solution (500 ml) which contained 50 grams poly(iso-butylene-co-para-bromomethylstyrene) (Mv=10k, 4.6% para-bromomethylstyrene). A cyclohexane solution of tetrabutylammonium 2,6-di(t-butyl)-4-methylphenoxide was prepared in a second flask under nitrogen by placing 100 ml cyclohexane, 30 ml tetrabutylammonium hydroxide (1M in methanol) and 6.6 g 2,6-di(t-butyl)-4-methylphenol into the flask and concentrating this solution down to half its volume. This solution was then added to the flask containing the poly(iso-butylene-co-para-bromomethylstyrene). Then 2.5 ml methacrylic acid was added to the polymer solution and the temperature of the solution was raised to 50° C. The reaction was complete in one hour and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg and 40° C. GPC of the recovered polymer (50 g, 100% yield) was identical to that of the starting poly(iso-butylene-co-para-bromomethylstyrene). The analysis for the methacrylate content (FTIR and NMR) indicate that the modified polymer had 0.58 meq/gram which is consistent with the complete conversion of methacrylic acid to methacrylic ester.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>>[C:1]([CH2:2][CH2:3][N:7]([CH2:3][CH2:2][C:1]#[N:4])[CH2:6][CH2:5][N:8]([CH2:3][CH2:2][C:1]#[N:4])[CH2:3][CH2:2][C:1]#[N:4])#[N:4]
Reactant: NCCN
Reactant: C=CC#N
Product: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
53.03 g of acrylonitrile was dropwise added to an aqueous solution (50 ml) of 12.01 g of ethylenediamine under room temperature over 2 hours and the mixture was stirred at 80° C. for 2 hours. After excessive acrylonitrile was distilled off under reduced pressure, 100 mL of ethyl acetate was added thereto and the mixture was washed with water. The organic layer obtained by liquid separation was dried with anhydrous magnesium sulfate and the solvent was distilled off to give 46.56 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CN(C)C=O.C(O)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In the same manner as that described under (a), 111 g of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (crude product) in a mixture of 640 ml of dimethylformamide and 160 ml of glacial acetic acid are reduced with 4.5 g of sodium borohydride and worked up. The title compound having the properties mentioned under (a) is obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.Br[C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:27]([CH2:34][O:35][CH2:36][CH3:37])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1>[Cu]I.O1CCOCC1>[CH2:36]([O:35][CH2:34][C:27]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([N:9]4[CH:13]=[CH:12][CH:11]=[N:10]4)=[CH:24][C:23]=3[N:22]=[C:21]([NH2:25])[C:20]=2[N:26]=1)[CH3:37]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(-n4cccn4)ccc3c2n1CCCOC
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 25 %

Procedure:
A 4 dram vial containing a stir bar was charged sequentially with copper(I) iodide (0.003 g), potassium phosphate (0.890 g), pyrazole (0.164 g), 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.786 g), (1)-trans-1,2-diaminocyclohexane (0.030 mL), and anhydrous 1,4-dioxane (2 mL). The vial was flushed with nitrogen, capped, and placed in an oil bath at 110° C. After 15.5 hours, the reaction was cooled to room temperature and purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. Subsequent recrystallization from acetonitrile yielded 0.190 g of 2-ethoxymethyl-1-(3-methoxypropyl)-7-(pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 159.0-160.0° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>C(OCC)(=O)C>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C@H:5]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 120 ml ethyl acetate is added 10 g (0.032 moles) of racemic N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, followed by 5.95 g (0.015 moles) of Di-para-toluoyl-L-tartaric acid at 25° C.-28° C. The resultant clear solution is stirred at room temperature for about 2-3 hrs so as to crystallise the acid addition salt of the desired enantiomer of N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine. The product is filtered, washed with 100 ml ethyl acetate and dried at 60-70° C. Yield: 7.8 g, about 98% ee.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 2,2-diphenylpropionic acid (0.200 mmol, 45.2 mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.200 mmol, 60.7 mg), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide (EDC, 0.400 mmol, 62.0 mg) and 4-dimethylaminopyridine (5.00 mg) was dissolved in CH2Cl2/DMF (1.00/0.100 mL) and the mixture was shaken on an orbital J-KEM shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, purified by preparative TLC [silica, CH2Cl2:ammonia (2.0 M in methanol) 100:5] to afford the desired product (43.8 mg, 42% yield): 1H NMR (400 MHz, CDCl3) δ 7.50–7.43 (br, 1H), 7.43–7.39 (br, 1H), 7.39–7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (br, 1H) 3.42–3.32 (m, 2H), 2.85 (d, 2H, J=10.8 Hz), 2.50 (quintet, 1H, J=7.4 Hz), 2.45–2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.96–1.82 (m, 2H), 1.78–1.60 (m, 4H), 1.60–1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.I[CH3:11]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(O)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ncc(C)cc1Br
Temperature: 55 °C
Reaction time: 3 h

Procedure:
3-Bromo-2-hydroxy-5-methylpyridine (5.012 g, 26.7 mmol), silver carbonate (9.58 g, 34.7 mmol), and iodomethane (5 mL, 80.0 mmol) were combined in CHCl3 (75 mL) and stirred at 55° C. for 3 hours. The mixture was cooled and filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give 3-bromo-2-methoxy-5-methyl-pyridine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:21].CC(O)C>[Pd].CCO>[ClH:21].[ClH:21].[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2cccnc2F)CCC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Fc1ncccc1C1CCCNC1
Reaction time: 0.08 h

Procedure:
To a N2 purged round bottomed flask containing tert-butyl 5-(2-fluoropyridin-3-yl)-3,4-dihydropyridine-1(2H)-carboxylate (673 mg, 2.418 mmol) was added 10% Pd/C (50 mg, 0.470 mmol) and EtOH (15 mL). After stirring for 5 minutes, 5N HCl in iPrOH (4.0 mL, 20.00 mmol) was added and the flask capped with a balloon of H2. After 16 hours, LC-MS shows ˜30% conversion. The balloon was refilled. After a further 5 days, LC-MS shows complete consumption of starting material. The reaction was filtered through a celite cartridge and the cartridge rinsed with DCM:10% EtOH (50 mL). The filtrate was concentrated in vacuo to give 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride as a yellow foam. The material was carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>C(O)(=O)C.Cl.O>[Br:14][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Yield: 109.9 %

Procedure:
To a stirred solution of the acetophenone prepared in Step 2 (11.91 g, 60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11 ml) at ambient temperature, was added a soluton of bromine (8.22 g, 51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours. The reaction mixture was diluted with water (500 ml) and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and concentrated in vacuo to give 15.66 g of crude 2-bromo-4′-(methylsulfonyl)acetophenone: 1H NMR (CDCl3) δ3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[OH:13][NH2:14].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:13][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=NO)c1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Nitrobenzaldehyde (3.00 g, 19.9 mmol) and hydroxyamine HCl (1.79 g, 25.8 mmol) were dissolved in 60 mL of ethyl alcohol/water (1/1, v/v) solution. While stirring the reaction mixture, Na2CO3 (2.74 g, 25.8 mmol) was added slowly at below 0. The reaction was continued for 1 hr in an oil bath preheated to 60-65. After the reaction was completed, 3.0 g (92%) of the target product was obtained by extracting with ethyl acetate, drying over anhydrous MgSO4 and removing the solvent under reduced pressure.