Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12].ClCCl.O>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNC
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue obtained was added with dichloromethane and water, and then was shaken for mixing. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24].[Cl:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]([C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])=[C:2]3[OH:1])[CH:38]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n(C)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(-c3cc(Cl)ncn3)ccc2n(C)c1=O
Temperature: 70 °C

Procedure:
To a 10 ml reaction vial was charged ethyl 2-(4-hydroxy-1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroquinoline-3-carboxamido)acetate (200 mg, 465 μmol) in 1,4-dioxane (5 ml), 4,6-dichloropyrimidine (69 mg, 465 μmol), tetrakis(triphenylphosphine) palladium(0) (27 mg, 23 μmol) and sodium carbonate (0.7 ml, 1395 μmol), and the reaction vial was heated to 70° C. After reaction was complete, the reaction mixture was concentrated on a roto-evaporator, extracted with EtOAc, washed with water and brine (3× ea.) then dried with MgSO4 and concentrated on a roto-evaporator. The yellow solid was washed with EtOH and filtered and the solid was washed with ether. Yield=55 mg.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].CN([CH:26]=[O:27])C.[NH4+].[Cl-].Cl>C1COCC1.C(OCC)C>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: COc1cc(F)ccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COc1c(Br)ccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (6.89 g, 9.6 mL, 68.3 mmol) in THF (100 mL) at −78° C. was added n-butyl lithium (33.5 mL of 1.6 M solution in hexane, 53.6 mmol) over 3 mins. After stirring at −78° C. for 10 mins, 2-bromo-5-fluoroanisole (10 g, 48.8 mmol) in THF (20 mL) was added dropwise over 15 mins. After completion of the addition, the mixture was stirred at −78° C. for 1 hr and then DMF (3.91 g, 4.12 mL, 53.6 mmol) was added dropwise over 3 mins and stirring was continued at −78° C. for 45 mins. Saturated NH4Cl solution was added and the mixture allowed to each room temperature. Diethyl ether and 2M HCl were added, the product was extracted into diethyl ether and the combined extracts were washed with brine, dried and evaporated. Chromatography on silica gel followed by trituration of the product with diethyl ether gave the title compound (D18) as a yellow solid (6.84 g)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([Br:19])[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20]>>[ClH:20].[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: Cl
Product: Brc1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(4-Bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 3. mmol) in ETOAc (4 ml) was added sat. ETOAc in HCl (5 ml) and the reaction mixture stirred at room temperature for 2 h. The solvent removed in vacuo and re-evaporated with toluene to give the product (0.68 g), which was used without further purification MS: [M+H]+=230
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[F:14][C:15]([F:38])([F:37])[C:16]1[NH:20][C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[C:30]([NH2:36])[C:31]([NH:34][CH3:35])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[N:18][CH:17]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C.O>[CH3:35][N:34]1[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([C:19]4[NH:20][C:16]([C:15]([F:37])([F:14])[F:38])=[CH:17][N:18]=4)[CH:26]=3)=[CH:29][C:30]=2[N:36]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: CNc1ccc(Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)cc1N
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(-c4ncc(C(F)(F)F)[nH]4)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
4-Trifluoromethylphenyl isothiocyanate (200 mg, 1 mmol) was added to a mixture of 4-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N1-methylbenzene-1,2-diamine (350 mg, 1 mmol) in 3 mL of acetonitrile. After stirring for 20 min at ambient temperature, HPLC analysis showed complete conversion. Triethylamine (0.3 mL, 2.2 mmol) was added followed by 2-chloro-1-methylpyridinium iodide (270 mg, 1.05 mmol). The reaction mixture was heated to 50° C. for 5 h. The heating was stopped and 1.5 mL of water was added. After stirring the mixture for 2 h, the solid was collected by filtration and washed with 2:1 acetonitrile/water (3×1 mL) to afford 317 mg (61%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=O.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(F)cnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.8 %

Procedure:
A suspension of crude compound 3 (65 g, 372.4 mmol) and Et3N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 0° C. and TFAA (57 mL, 409.6 mmol) was added dropwise. The resulting yellow solution was stirred for 90 minutes at 0° C., diluted with DCM, washed with sat. aq. NaHCO3 and brine, and dried (Na2SO4). The mixture was filtered and concentrated. Kugel Rohr distillation of the residue (˜70° C./1 mbar) gave 50 g (86%) of compound 4 as a beige solid. Compound 4 can also be purified by column chromatography (SiO2, 8:1 heptane:EtOAc). 1H NMR (CDCl3, 300 MHz): δ 7.78 (dd, 1H); 8.49 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([NH:11][C:12]1[NH:18][C:17]2[N:19](C(C)=O)[CH:20]=[N:21][C:16]=2[C:14](=O)[N:13]=1)=[O:10].P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[C:9]([NH:11][C:12]1[N:18]=[C:17]2[C:16]([NH:21][CH:20]=[N:19]2)=[C:14]([Cl:27])[N:13]=1)(=[O:10])[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc(=O)c2ncn(C(C)=O)c2[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
60.0 g (0.36 mol) of tetraethylammonium chloride and 20.3 g (0.2 mol) of triethylamine are added to a suspension of 42.6 g (0.18 mol) of 2,9-diacetylguanine in 450 ml of acetonitrile. 165.3 g (1.08 mol) of phosphorus oxychloride are then added at a temperature of the reaction mixture of 0° C. to 5° C. The mixture is stirred at 25° C. for 20 hours and then worked up as in Example 1. 30.9 g of 2-acetamido-6-chloropurine are obtained.
Reaction SMILES: C1(C([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[CH:24]([C:29]4[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CC(C)=O>[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[CH:24]([C:29]3[N:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12.[CH3:51][C:41]1[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: CCOC(=O)n1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)n1nnnc1C1N2C(=O)C(N)[C@H]2SC1(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 554 mg. of 6-(triphenylmethylamino)-2,2-dimetyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam in 2 ml. of acetone is added a solution of 190 mg. of p-toluenesulfonic acid of 1 ml. of acetone. Stirring is continued for a further 3 hours, and then the acetone is removed by evaporation in vacuo. The residue is slurried in ether, filtered and dried, to give the title compound as its p-toluenesulfonate salt.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(N)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Further, to ethyl 4-nitrophenoxyisobutyrate (12 g) were added ethanol (150 ml) and 5 % palladium/carbon (1 g), the mixture was subjected to catalytic reduction at room temperature overnight. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 4-aminophenoxyisobutyrate (10.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:51])[CH2:10][C:11]1[CH:50]=[CH:49][CH:48]=[CH:47][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:45][CH3:46])[N:16]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:46][O:45][C:27]1[CH:28]=[C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:17]1[N:16]=[C:15]([CH2:14][CH2:13][C:12]2[CH:47]=[CH:48][CH:49]=[CH:50][C:11]=2[CH2:10][C:9]([NH2:8])=[O:51])[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][N:18]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I23) (185 mg, 0.301 mmol) in DCM (10 mL) and the resulting solution was stirred at room temperature for 2 hours. DCM (20 mL) and 10% NaHCO3 solution (10 mL) were added then the organic layer was dried (MgSO4) and evaporated to dryness under reduced pressure to give the title compound (2) (125 mg, 81%) as a colourless solid; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.28-7.12 (m, 3H), 6.94 (bs, 2H), 6.85 (d, J=8.2 Hz, 1H), 6.78 (dd, J=11.8, 3.1 Hz, 1H), 6.35 (s, 1H), 5.94 (s, 1H), 3.88 (s, 3H), 3.65 (s, 2H), 3.42 (d, J=12.3 Hz, 2H), 3.24-3.02 (m, 4H), 2.91 (t, J=11.3 Hz, 2H), 2.75-2.61 (m, 1H), 2.10-1.83 (m, 4H). LCMS Method C: rt 4.92 min; m/z 514.1 [M+1]+, 521.1 [M−1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.CN[C@@H]1CCCC[C@H]1NC>O.C(OCC)(=O)C.[Cu](I)I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]ncc12
Reactant: Fc1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 1H-indazole-4-carboxylic acid methyl ester (5.0 g, 28 mmol), copper iodide (5.7 g, 3.0 mmol), potassium carbonate (4.15 g, 30.0 mmol) and 4-fluoroiodobenzene (3.47 g, 30.0 mmol) is charged in a sealed tube at room temperature. The tube is evacuated, back-filled with argon and dimethylformamide (20 mL) is added followed by rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.93 g, 6.5 mmol). The solution is stirred at 120° C. for 3 hours, then cooled to room temperature and diluted with water (50 mL) and ethyl acetate (80 mL). The organic layer is separated, washed with brine (30 mL), and dried over sodium sulfate. The crude product is filtered, concentrated and purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[NH2:16]OS(O)(=O)=O>CN(C)C=O.O>[NH2:16][N:11]1[CH:12]=[CH:13][C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:10]1
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-benzoylpyrrole (4.92 g) in 50 ml of dry dimethylformamide was added milled potassium hydroxide (8.06 g). Hydroxylamine-O-sulfonic acid (4.23 g) was added to the suspension in 4 portions over a period of 1 hour with stirring at room temperature. After the addition was completed the reaction mixture was stirred for 30 minutes at room temperature, and subsequently diluted with 50 ml of water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate, 5:1), affording starting material (1.44 g) and the desired product as the second fraction. Recrystallization from ethyl ether/hexane gave the product as crystals (1.80 g), which was combined with material obtained from a 36.9 mmol scale reaction and recryslized from DCM/hexane affording 3.20 g of crystals, m.p. 82°-83° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7]Br)(=[O:3])[CH3:2].[N-:9]=[N+:10]=[N-:11].[Na+]>O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:9]=[N+:10]=[N-:11])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCBr
Agent: [Na+]
Solvent: O
Product: CC(=O)OCCCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromopropyl acetate (1.0 g, 6.0 mmol) in water (10 mL) was added to sodium azide (780 mg, 12.1 mmol). The solution was stirred at 90° C. overnight. The solution was extracted three times with 15 mL CH2Cl2 and dried with MgSO4. Solvent was removed under reduced pressure to afford 3-azidopropyl acetate as a pale yellow oil. A solution of tripropargylamine (12.3 mg, 0.941 mmol) in tetrahydrofuran (6.5 mL) was added to 3-azidopropyl acetate (0.672 g, 4.71 mmol) and Cu(I) acetate (5.8 mg, 5 mol %). The solution was refluxed overnight under inert atmosphere. Solvent was removed under reduced pressure. Silica chromatography purification (Rf=0.5, 5-10% MeOH in CH2Cl2) afforded acetyl-protected THPTA as a yellow oil.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]1([CH3:12])[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=1.BrBr>CO>[OH:11][C:10]1[CH:9]=[CH:8][C:7]([S:1][C:2]#[N:3])=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1ccccc1O
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SC#N)ccc1O

Procedure:
Sodium thiocyanate (23.5 g, 0.29 mole) was added to a solution of ortho-cresol (31.4 g, 0.29 mole) in methyl alcohol (225 ml) and cooled by an ice bath. A solution of bromine (46.4 g, 0.29 mole) in methyl alcohol (50 ml) was added dropwise over 45 minutes. The reaction was filtered and poured into water (400 ml). Sodium thiosulfate was added to eliminate the color (yellow). The product was extracted into ethyl ether (2×200 ml). The ethyl ether extracts were washed with water (100 ml), 1N hydrochloric acid (200 ml) and saturated sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated. The product was purified by chromatography on silica. The structure was confirmed by NMR and IR spectroscopy.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][C:12]([S:15]([N:17]=[C:18]1[CH2:21][O:20][CH2:19]1)=[O:16])([CH3:14])[CH3:13]>O1CCCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:18]1([NH:17][S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH2:21][O:20][CH2:19]1
Reactant: c1cscn1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7) (500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with anhydrous sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (EI): m/e=261.0 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(CCCO)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A suspension of 1-acetylpiperazine (3.85 g, 30 mmol), potassium carbonate (8.3 g, 60 mmol) and 3-bromo-1-propanol (4 ml, 45 mmol) in acetonitrile (30 ml) was heated and stirred at 80° C. for 5 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethanol. The fractions containing the expected product were combined and evaporated to give 3-(4-acetylpiperazin-1-yl)propan-1-ol (3.15 g, 56%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][O:32][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(O)=O>[C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][OH:32])=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OC(C)c1c(CO)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the crude ether from Step 5 in THF (10 mL) at 0° C. was added HOAc, (4 drops) followed by n-Bu4NF (1M, THF, 1.4 mL). The reaction mixture was stirred 2 hr at 0° C. then quenched with a saturated solution of NH4Cl and diluted with Et2O. The organic phase was washed with H2O, brine, dried over MgSO4, and the solvent evaporated. The residue was purified by chromatography on silica gel using hexane/EtOAc 7:3 to give the title product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][C:16]=1[Cl:22]>C1COCC1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:22])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension of potassium tert-butoxide (110.9 g) in THF (900 mL) at room temperature and under nitrogen. The mixture was heated at reflux and 1,2-dichloro-4-fluorobenzene (98 g) added dropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled down to room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1M hydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by addition of a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to yield the sub-title compound as a dark oil which was used as such in the next step.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([OH:9])=[O:8].[CH2:25](O)[CH3:26]>C(OCC)(=O)C.CO>[NH2:5][C@H:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][CH2:25][CH3:26])=[O:8]
Reactant: CCO
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: -25 °C
Reaction time: 3 h

Procedure:
3.9 cm3 of thionyl chloride are added to a stirred suspension of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid (Ns-CBZ-D-lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature in the region of −25° C. The mixture is stirred for 3 hours at this temperature and is then allowed to warm to about 20° C. After leaving for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 0° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with aqueous sodium carbonate solution and then with aqueous sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-=carbonyl]amino}hexanoate are obtained in the form of a pale yellow oil. (αD20=−11.7±0.6 at a concentration of 0.5% in methanol).