Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32]>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[S:21][CH:25]=[CH:24][N:23]=2)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: NCCOCCCc1nccs1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Temperature: 60 °C
Yield: 60.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (3.4 mL, 24 mmol) was added dropwise to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (4.50 g, 20.4 mmol) in anhydrous DMF (45 mL). 2-[3-(1,3-Thiazol-2-yl)propoxy]ethylamine (4.55 g, 24.4 mmol) was then added, and the addition funnel was rinsed with additional DMF (15 mL). The reaction was heated at 60° C. for 3.5 hours. The volatiles were then removed under reduced pressure, and the residue was partitioned between water (100 mL) and diethyl ether (250 mL). The organic layer was washed with water (2×50 mL) and brine (3×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an orange oil. The crude product (7.41 g) was purified by column chromatography on silica gel (375 g, eluting with 50:50 hexane:ethyl acetate) to provide a solid, which was dried overnight under high vacuum at room temperature to provide 4.6 g of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>Cl.O>[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[CH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Yield: 41.4 %

Procedure:
4-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (133 mg, 0.709 mmol) and 2-fluoro-4-iodoaniline (172 mg, 0.726 mmol) were combined in a round bottom flask equipped with magenetic stir bar. The flask was immersed in an ice bath and lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 5.0 mL, 5.0 mmol) was added slowly (5 min) with vigorous stirring under an atmosphere of nitrogen. The reaction mixture was further stirred for 1 h at 0° C. and 1 h at ambient temperature. The reaction mixture was diluted with 1 M hydrochloric acid and water and was extracted with ethyl acetate (3×). The extracts were dried over magnesium sulfate and concentrated in vacuo. Upon concentrateion, 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (114 mg, 41% yield) was isolated directly from the ethyl acetate by filtration and drying in vacuo: 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (v br s, 1H), 9.66 (s, 1H), 8.52 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.59 (br d, J=8.5 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.49 (s, 1H), 3.41 (s, 3H); MS (APCI+) 388.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][CH:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 72.7 %

Procedure:
Following general N—C coupling procedure 1, tert-butyl-3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (119 mg, 0.359 mmol) was combined with 2-chloro-7-cyclobutyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.359 mmol) which gave tert-butyl 3-(6-(7-cyclobutyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (150 mg) in 73% yield. MS m/z 575.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1nc2c([nH]1)CCCC2
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a solution of 1.20 g (4 mmol) of 2-(2-methylaminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in chloroform was added under chilling with ice 0.85 g (4 mmol) of 80% m-chloroperbenzoic acid for 20 min. The 30 mixture was then stirred for 15 min. The chloroform portion was washed with a saturated aqueous NaHCO3 solution. The chloroform portion was then extracted with two portions of diluted aqueous NaOH solution. The aqueous extracts were combined, and an excess amount of aqueous NH4Cl was added to the combined extracts to precipitate a crystalline product. The crystalline products were collected by filtration and sufficiently washed. The thus obtained crude crystalline product was recrystallized from dichloromethane/hexane to give 0.32 g of the desired compound as a white crystalline product, yield 25%.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14].[BH3-]C#N.[Na+].[OH-].[Na+]>CC(O)=O>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)C1=NCCc2c(I)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)C(C)C1NCCc2c(I)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
A mixture of methyl 2-(5-iodo-3,4-dihydroisoquinolin-1-yl)propanoate (1.15 g, 3.35 mmol) in glacial AcOH (12 mL) was treated with NaBH3CN (421 mg, 6.70 mmol) at RT under N2. The mixture was stirred at RT for 16 h, and then poured onto H2O. The mixture was rendered basic with a 50% aqueous solution of NaOH and extracted with AcOEt. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.17 g) that was used as it is. UPLC-MS: MS 346.1 (M+H+); UPLC rt 0.65 min.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)c1ccnc(I)c1
Reactant: OB(O)c1ccc(F)cc1F
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: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccnc(-c2ccc(F)cc2F)c1
Temperature: 90 °C
Yield: 78.3 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (3 g, 12 mmol), 2,4-difluorophenylboronic acid (2.3 g, 14.5 mmol) and K2CO3 (6 g, 43.5 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated. The crude compound was purified by column chromatography (SiO2, CHCl3 then CHCl3/MeOH, 97/3) to afford 2.2 g (78%) of the titled compound as a slightly yellow oil, which solidify upon standing. If some impurities remains, the compound can be purified by following the acidic extraction followed by basic recovery as performed before for 2-phenyl-4-dimethylaminopyridine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25].O>C(OCC)C>[Br:25][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 14.1 %

Procedure:
A solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 100 mg; 0.39 mmol) in dehydrated diethyl ether (1.0 mL) was added with dehydrated pyridine (69.4 mg, 0.89 mmol) under an argon atmosphere. The mixture was slowly added dropwise with a solution of phosphorus tribromide (117.2 mg, 0.43 mmol) in dehydrated diethyl ether (0.5 mL) at −15 to −20° C., and the mixture was stirred at the same temperature for 2 hours, and then left standing at −5° C. for 48 hours. Then, the reaction mixture was added with cooled water (3 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes, and then extracted with diethyl ether (10 mL). The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, 3.0 g; developing solvent, n-hexane) to obtain 17.6 mg of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=CC=1)([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:36]=1>O1CCCC1>[N+:22]([C:18]1[CH:17]=[C:16]([C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)NCCCCc1cccnc1
Yield: 84.3 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.950 g) and 3-pyridinebutanamine (0.34 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was crystallized from ethyl acetate-hexane to yield 0.82 g of (E)-5,5-bis(3-nitrophenyl)-N-[4-(3-pyridinyl)butyl)-2,4-pentadienamide mp 158°-159° C. Anal. Calculated for : C26H24N4O5 : C, 66.09; H, 5.12; N, 11.86 Found: C, 65.91; H, 5.34; N, 11.82.
Reaction SMILES: P(CNCC(O)=O)(O)(O)=O.P(C[N:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])(O)(O)=O>>[NH:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=C(O)CNCP(=O)(O)O
Product: O=C(O)CNCC(=O)O

Procedure:
N-phosphonomethylglycine (glyphosate) is an important broad spectrum herbicide. One conventional precursor to glyphosate is N-phosphonomethyliminodiacetic acid having the following structure: ##STR1## Conventional routes to compound (I) typically involve phosphonomethylating iminodiacetic acid (IDA), the latter obtained by recovering (IDA) from the crude hydrolysate of iminodiacetonitrile (IDAN) by acidification with a mineral acid, crystallization of IDA, filtration thereof, and drying. Such processes result in waste in that the alkali metal salt solution separated from IDA upon the filtration step contains unrecovered IDA. Indeed, fractional crystallization is necessary to precipitate the alkali metal salt, which can then be separated from the IDA solution by centrifugation. In U.S. Pat. No. 3,808,269, disclosed is a process of recovering IDA from an aqueous solution of sodium sulfate and the amino acid by adjusting the pH of the solution to 1.5-3 to form an IDA precipitate and a first mother liquor, and separating and recovering the IDA precipitate therefrom. Sodium sulfate can then be precipitated from the first mother liquor by concentrating the liquor and adjusting the temperature so as to prevent the concomitant precipitation of IDA. The process can then be repeated. However, at some point successive fractional crystallization steps become uneconomical, notwithstanding the presence of additional product in the solution. U.S. Pat. No. 3,852,344 discloses a similar process wherein the sulfuric acid is replaced with hydrochloric acid, with sodium chloride being recovered as the by-product instead of sodium sulfate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: O=Cc1cccs1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (100 mg, 0.552 mmol) in methylene chloride (5 mL) was added thiophene-2-carbaldehyde (62 mg, 0.552 mmol), sodium triacetoxyborohydride (351 mg, 1.66 mmol) and drop of acetic acid. The solution was stirred for 4 hr. The solvent was removed under vacuum, and the crude product was loaded on a Isco 12 g column. Elution with 0% to 10% methanol in methylene chloride over 15 column volumes afforded the title compound (95 mg, 61% yield). Exact mass calculated for C13H15N3O2S 277.3. found 278.2 (ESI, M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.58 (d, J=5.05 Hz, 1H) 7.33 (d, J=3.03 Hz, 1H) 7.07-7.16 (m, 1H) 4.63 (s, 2H) 4.47 (s, 2H) 4.24 (s, 2H) 3.94 (t, J=5.56 Hz, 2H) 2.73 (t, J=5.56 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)=[C:21]([F:36])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][OH:28])=[C:21]([F:36])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)c(F)c3)cc3ccccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3ccc(OCCO)c(F)c3)cc3ccccc23)CC1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-{3-fluoro-4-[2-(tert-butyldimethylsilyloxy)ethoxy]phenyl}isoquinoline (0.62 g) was dissolved in tetrahydrofuran (6 ml), to which was then added 1.0M tetrabutylammonium fluoride/tetrahydrofuran solution (1.46 ml), and the mixture was stirred for 2 hr. The solvent was evaporated, and the resulting residue was dissolved in ethyl acetate, washed with water (three times) and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.42 g of the free compound of the title compound as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[CH:64]=[CH:63][C:48]([CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)=[CH:47][CH:46]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([CH2:49][N:50]3[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:57])[CH2:52][CH2:51]3)=[CH:63][CH:64]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(Br)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromobenzoic acid (1, 685.0 mg, 3.4 mmol) and HATU (1298.1 mg, 3.4 mmol) are partially dissolved in DMF (10 mL) at rt. DIEA (560 μL, 3.4 mmol) is added to this mixture to give a pale yellow solution. After stirring at rt for 30 min, tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (2, 992.9 mg, 3.4 mmol) is added and the resulting reaction mixture is heated at 60° C. for 20 h, allowed to cool to rt, and poured into water (100 mL). This mixture is extracted with Et2O (3×150 mL). The combined organic extracts are evaporated to dryness to give a white solid, which is washed with water (50 mL) and dried in vacuo. This material is used in the next synthetic step without further purification. HPLC: tR 1.67 min (method 1). LC-MS m/z calcd for C23H2879BrN3O3 ([M]+), 473. found, 474 ([M+H]+). 1H NMR (CD3OD): δ 1.46 (s, 9H), 2.96 (m, 4H), 3.59 (m, 4H), 4.05 (br s, 2H), 7.46 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H), 7.85 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([CH:18]=O)([CH2:11]3)[CH2:9]1)[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:18]([C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH2:15]3)[CH2:9]1)[CH2:11]2)#[CH:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C=O)(C3)C1)C2
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC12CC3CC(C1)CC(NC(=O)OC(C)(C)C)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a solution of tert-butyl-3-formyl-1-adamantylcarbamate (600 mg, 2.1 mmol) and K2CO3 (590 mg, 4.2 mmol) in methanol (60 mL) under N2 atmosphere was added dimethyl (1-diazo-2-oxopropyl)phosphonate (490 mg, 2.5 mmol). After stirring at room temperature for three hours the clear reaction solution was partitioned between ethyl acetate (100 mL) and 5% NaHCO3 (100 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 600 mg (100%) of the title compound, tert-butyl 3-ethynyl-1-adamantylcarbamate as a colorless oil. ESI-MS m/z: 220 (M-55)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([ClH:21]O)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:21][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reaction time: 5 h

Procedure:
To a solution of 5.0 g p-(3,5-difluorophenoxy)phenol in 50 mg of carbon tetrachloride, there were added dropwise 2.45 of tert-butylhypochlorous acid with stirring and ice-cooling, and stirring was continued at room temperature for 5 hours. The reaction mixture was concentrated and extracted with 200 ml of ethyl acetate. The extract was washed with 5% aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.31 g of 2-chloro-4-(3,5-difluorophenoxy)phenol. Yield, 92%. nD25 : 1.5639
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1B1OC(C)(C)C(C)(C)O1)[C:13]([O:15]C)=[O:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]([OH:15])=[O:14]
Reactant: Cc1ncccc1Br
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
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: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)O)ccc1-c1cccnc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A mixture of 3-bromo-2-methylpyridine (0.13 mL; 1.16 mmol; 1 eq.), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (353 mg; 1.28 mmol; 1.1 eq.), potassium carbonate (803 mg; 5.81 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (134 mg; 0.12 mmol; 0.1 eq.) in toluene (1 mL) and water (1 mL) was refluxed for 2 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of Celite® which was further washed with toluene (20 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (10 mL). The organic layer was washed with a sat. aq. NaHCO3, water and brine, dried over MgSO4 and concentrated in vacuo. The residue (250 mg; 1.04 mmol; 1 eq.) was taken up in EtOH (7.5 mL) and sodium hydroxide (5M; 0.62 mL; 3.11 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours then concentrated in vacuo. The residue was taken up in water (50 mL) and the aqueous phase was washed with Ethyl acetate (2×20 mL) then acidified pH 2 with conc. HCl. The solution was concentrated in vacuo to ca. 15 mL, the precipitate filtered off and washed with ACN to afford the title compound (190 mg, 72%) as a beige solid.