Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Br:12])[CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(C)=O>[Br:12][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(CBr)c1ccc(F)c(Br)c1
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Product: Fc1ccc(-c2cn3ccccc3n2)cc1Br
Reaction time: 8 h

Procedure:
In analogy to the method as described in J. Heterocyclic Chem. 1988, 25, 129-137, 2-Bromo-1-(3-bromo-4-fluoro-phenyl)-ethanone (89 mg, 0.3 mmol) and 2-Aminopyridine (28 mg, 0.3 mmol) were dissolved in 2 ml of acetone and shaken overnight. The solvent was evaporated and and the residue was dissolved in 1 ml of DMF. The title compound (m/e=292.6, [M+H+]) was isolated from this solution by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10-95% CH3CN in 0.1% TFA (aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(O)(=O)C(O)=O.[CH2:56]1C2(CNC2)[CH2:58][O:57]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][C:26]3([CH2:58][O:57][CH2:56]3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1NCC12COC2
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.3]heptane oxalate and isolated as white solid (10.8 mg, 57%). MS(m/e): 399.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:15][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1)[CH2:14][CH2:13][S:12][CH2:11]3.[C:19]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:15][C:7]=2[C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1)[CH2:14][CH2:13][S:12][CH2:11]3
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCSC1)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCSC1)O2
Reaction time: 8 h
Yield: 14.2 %

Procedure:
A suspension of 7-methoxy-4′,5′-dihydro-spiro[1,3-benzodioxole-2,3′-(2H)-thiophen]-4-carboxylic acid (161 mg, 0.600 mmol), K2CO3 (166 g, 1.20 mmol) and dimethyl sulphate (74 μL, 0.78 mmol) in acetone (1 mL) was kept at 50° C. overnight. At room temperature water (15 mL) was added and the aqueous phase was extracted with ethyl acetate (2×20 mL). The organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded compound 505 (24 mg, 14%). 1H NMR (CDCl3) δ 7.44 (d, 1H), 6.56 (d, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.32 (d, 1H), 3.24 (d, 1H), 3.05 (t, 2H), 2.49 (td, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1COCC1.C(N(CC)CC)C.[Br:21][C:22]1[C:23]([F:32])=[CH:24][C:25](F)=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:25]1[CH:24]=[C:23]([F:32])[C:22]([Br:21])=[CH:27][C:26]=1[N+:28]([O-:30])=[O:29])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Yield: 65.9 %

Procedure:
By using 7.61 g (54.5 mmol) of glycine ethyl ester hydrochloride, 15 ml of THF, 7.64 ml of triethylamine, 10 ml of DMF and 11.8 g (49.6 mmol) of 5-bromo-2,4-difluoronitrobenzene, 10.5 g (60%) of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (7.5 g, 30.6 mmol), MeOH (24 mL) and H2SO4 (0.8 mL) was stirred at 75° C. for 17 h. The reaction mixture was concentrated. The residue was poured into H2O and extracted with CH2Cl2. The organic layer was washed with brine, dried (NaSO4), filtered and concentrated to afford the title compound. tR: 0.99 min (LC-MS 2).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[O:12])[S:8][CH:9]=1)=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[O:12])[S:8][CH:9]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN=[N+]=[N-])cs2)c(C(=O)C2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1

Procedure:
To a solution of (1-(4-azidomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea) (7.7 g, 20 mmol) in EtOH (100 mL) was added catalytic amount of palladium on charcoal (200 mg) and the reaction mixture was hydrogenated (1 atmos) for 3-4 hours to give 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea. This crude product was then purified by flash column chromatography with DCM:EtOAc (80:20 to 50:50) as eluent to give the desired amine (5.7 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2S[C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].NCCC(O)=[O:38].CO.C(Cl)Cl>C(O)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[O:38][C:30](/[CH:32]=[C:3]3/[NH:4][C:5](=[S:18])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:2]/3=[O:1])=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: NCCC(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)/C(=C\c2ccc(-c3ccc(Cl)c(Cl)c3)o2)NC1=S
Temperature: 80 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.110g, 0.416 mmol) and 5-(3,4-dichloro-phenyl)thiophene-2-carbaldehyde (0.100 g, 0.416 mmol) in acetic acid 10 mL is added β-alanine (1.8 mg, 0.021 mmol) and heat to 80° C. for 16 h. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.070 g, 0.144 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. The product is further purified by recryatallization in hexane and DCM mixture and got pure E-isomer. 1H-NMR (CDCl3/CD3OD/300 MHz): 7.84 (d, J=2.1 Hz, 1H), 7.60 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.17 (m, 6H), 6.85 (m, 1H), 6.42 (s, 1H), 5.61 (dd, J=11.1, 5.4 Hz, 1H), 3.66 (dd, J=14.1, 12.6 Hz, 1H), 3.53 (dd, J=14.1, 5.1 Hz, 1H). MS (ES−, m/z): 585.3 (M−, 100.0).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[NH:15][C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12]2)=[CH:7][CH:6]=1.[H][H].[Cl:26][CH2:27][CH2:28]Cl>CCOCC.O.CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[N:15]([CH2:28][CH2:27][Cl:26])[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12]2)=[CH:9][CH:10]=1
Reactant: ClCCCl
Reactant: [H][H]
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCCl)C(=O)[C@@H]2O)cc1
Reaction time: 0.75 h
Yield: 24.9 %

Procedure:
Under a nitrogen blanket, 7.47 g of 80 percent sodium hydride (Aldrich; 0.249 mol) and 600 mL of anhydrous dimethyl sulfoxide (DMSO) were added to a 2-L round bottom flask, which had been fitted with a reflux condenser, nitrogen adapter and magnetic stirrer. The resulting solution was stirred for 45 minutes, and then 50.0 g of dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy -1,5-benzothiazepin-4(5H)-one (0.166 mol) was added in two portions over a ten minute period. A fairly vigorous evolution of hydrogen gas ensued. The reaction mixture was stirred for 50 minutes, and then 40 mL of anhydrous 1,2-dichloroethane (Aldrich; 0.508 mol) was added all at once. The reaction mixture was stirred for 40 hours, whereupon 750 mL of cold water was added thereto. Ether was used to extract the desired alkylated product, which was dried over drying agent. This product was taken up with dichloromethane, and it was dried further. The product was chromatographed on 70-230 mesh silica gel column, with a 2:1 hexane to ethyl acetate eluent. Concentration under high vacuum yielded 15.05 g of dl-cis-2-(4-methoxyphenyl) -2,3-dihydro-3-hydroxy-5-(2-chloroethyl)-1,5-benzothiazepin -4(5H)-one (24.9 percent of theory).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([N:10]([CH3:33])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[CH3:33][N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH:9]1[CH2:8][O:7][CH2:6][CH:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)C1COCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3COCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid methyl ester (0.160 g, 0.3 mmol) and lithium hydroxide (0.082 g,. 3.4 mmol) in THF:methanol:water (3: 2:2 mL) was stirred at 25° C. for 19 h. The solution was then washed with ethyl acetate (2×30 mL) and the aqueous layer was acidified with 2N HCl to pH ˜2. The aqueous layer was washed with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to produce 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid as a crude solid (0.160 g, 100%). MS: 457 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([N:19]=[C:20]=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)c(O)c2)no1
Temperature: 70 °C

Procedure:
A mixture of 5-amino-2-chlorophenol (1.0 g, 6.97 mmol) and 5-tert-butyl-3isocyanatoisoxazole (1.16 g, 6.97 mmol) in toluene (40 mL) was heated at 70° C. overnight. It was purified by silica gel chromatography with 0-25% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-hydroxyphenyl)urea as solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[C:3]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]=3)=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cnc(Cl)c(Br)c1
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(Br)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-Bromo-2-chloro-5-methoxypyridine (0.30 g, 1.35 mmol), 4-(5-methylpyridin-2-ylamino)phenol (0.68 g, 3.37 mmol), and cesium carbonate (1.32 g, 4.05 mmol) were mixed in NMP (4 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography. The isolated product contained a significant impurity. The impurity was removed by reverse phase HPLC. The desired product was partitioned between DCM and sat. aqueous sodium bicarbonate. The organic layers were separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-(4-(3-bromo-5-methoxypyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 386.1 and 388.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][NH:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([N:23]([O:22][CH3:21])[CH3:24])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Yield: 81 %

Procedure:
2-Allyloxycarbonylamino-succinic acid 4-tert-butyl ester, 100, (43.4 g, 0.159 mol) is dissolved in CH2Cl2(900 mL). To this solution O,N-dimethyl-hydroxylamine hydrochloride (18.6 g, 0.191 mol), 4-Methyl-morpholine (21.0 mL, 19.3 g, 0.191 mol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.6 g, 0.191 mol) are added. After the consumption of the starting material, the solution is washed with 1.0 N HCl (2×400 mL) and brine (1×250 mL). The organic layer is concentrated in vacuo and the residue purified over silica (hexanes/ethyl acetate 65:35) to afford 40.8 g (81% yield) of the desired product as a clear oil. 1H-NMR, (300 MHz, CDCl3): δ 1.43 (s, 9H), 2.50–2.74 (m, 2H), 3.22 (s, 3H), 3.79 (s, 3H), 4.55–4.57 (d, J=4.8, 2H), 4.97–5.04 (m, 1H), 5.17–5.32 (m, 2H), 5.67–5.70 (d, J=9.0, 1H), 5.83–5.94 (m, 1H); 13C-NMR (75.5 MHz, CDCl3): δ 28.20, 32.58, 38.48, 61.83, 65.93, 81.53, 117.85, 132.88, 155.84, 169.46, 171.83; MS (ESI): m/e=317.11 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]([C:31]1([CH2:36][CH3:37])[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30]>>[CH2:29]([C:31]1([CH2:36][CH3:37])[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32]1)[CH3:30]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CCC1(CC)CCNC1
Product: CCC1(CC)CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3-diethylpyrrolidine via General Procedure E to give 26.5 mg of 301 following reverse phase purification. MS (Q1) 4892 (M)+
Reaction SMILES: O[CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8].S(Cl)([Cl:15])=O.C1C=CC=CC=1>CN(C)C=O>[Cl:15][CH2:2][CH:3]([CH3:12])[CH2:4][CH2:5][CH:6]([O:10][CH3:11])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(CCC(C)CO)C(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(CCC(C)CCl)C(C)C

Procedure:
A mixture of 3.4 g. of 1-hydroxy-5-methoxy-2,6-dimethylheptane and 3 g. of thionyl chloride and 60 ml. of dry benzene is treated with 0.2 ml. of dry dimethylformamide and then refluxed for 6 hours. After cooling, the mixture is decanted and 1-chloro-5-methoxy-2,6-dimethylheptane isolated by filtration through silica gel and distillation.
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44]C(O)=O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3,4-dimethoxy-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3](C(C)C)C(C)C)[CH3:2].[O:10]=[C:11]([S:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([OH:16])=[O:15].[Cl-].[NH4+]>BrCC#N>[O:10]=[C:11]([S:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:12][C@H:13]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([O:16][CH2:2][C:1]#[N:3])=[O:15]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCCc1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCCC(=O)N[C@@H](CC(=O)SCCc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.187 ml, 1.07 mmol) was added to a solution of ((S)-4-oxo-2-(pent-4-enamido)-4-(phenethylthio)butanoic acid (Compound 1f-IE) (300 mg, 0.894 mmol) in 2-bromoacetonitrile (1.87 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-oxo-2-(pent-4-enamido)-4-(phenethylthio)butanoate (Compound 1g-IE) (295 mg, 88%).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23]Br)=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([O:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:23][C:1]#[N:2])=[N:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2c(CBr)nn(OC(=O)OC(C)(C)C)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(CC#N)nn(OC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
KCN (5.73 g, 88 mmol) in 23 ml of H2O was added dropwise at 0° C. to 1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-bromomethyl-1H-indazole (10.5 g, 30.08 mmol) in 80 ml of ethanol and stirred at room temperature for 1 h30. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4. Concentration and precipitation in diisopropyl ether gave the expected product (4.42 g, 50% as solid).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:23]>CO.C1(OC)C=CC=CC=1.C(OCC)C>[ClH:23].[ClH:23].[ClH:23].[F:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2F)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: COc1ccccc1
Product: Fc1cnccc1CCN1CCNCC1
Reaction time: 1 h
Yield: 84 %

Procedure:
1-Boc-4-[2-(3-fluoropyridin-4-yl)ethyl]piperazine (6.0 g, 19.4 mmol) was dissolved in methanol (20 mL) and anisole (6 mL). To this solution, concentrated hydrochloric acid (15 mL) was added and the mixture stirred for 1 h. The solvents were removed under vacuum to provide a yellow solid. The residue was suspended in diethyl ether and sonicated for 1 h. The product was recovered by vacuum filtration, and the solid dried under vacuum to provide 1-[2-(3-fluoropyridin-4-yl)ethyl]piperazine trihydrochloride (5.2 g, 84%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1([C:23]([NH2:25])=[O:24])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:13])[CH2:4][CH2:3]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27].CN(C=O)C>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][C:2]3([NH:1][C:26](=[S:27])[NH:25][C:23]3=[O:24])[CH2:7][CH2:6]2)[CH:19]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1C(=O)CCCCN1CCC(N)(C(N)=O)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)CCCCN1CCC2(CC1)NC(=S)NC2=O
Yield: 29 %

Procedure:
A mixture of 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]-piperidine-4-carboxamide (0.36 g, 1 mmol), prepared as in Example 21, 1,1'-thiocarbonyldiimidazole (0.23 g, 1.3 mmol), and DMF (3 mL) was heated 5 hours at 50°-60° C. and then diluted with water. The mixture was extracted with ethyl acetate and the extract was dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with methylene chloride/methanol+ammonium hydroxide (95:5) to give 8-[5-(5-chloro-2-methoxyphenyl)-5-oxopentyl]-2-thioxo-1,3,8-triazaspiro[4.5]decane-4-one (0.12 g, 0.29 mmol), m.p. 152°-154° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].Cl.Cl.[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[NH3:9].[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:22]2[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]2)=[O:13])=[N:9][CH:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(C(C)C)CC2)nc1
Product: N
Reaction time: 18 h
Yield: 149.8 %
Yield: 2 %

Procedure:
To a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester (1.00 g, 5.50 mmol) and 1-isopropyl-piperazine dihydrochloride (1.20 g, 6.10 mmol) in DCM (100 mL) was added 1-hydroxybenzotriazole hydrate (HOBt, 1.10 g, 8.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.60 g, 8.30 mmol), and N-methyl morpholine (2.9 mL, 27.0 mmol). After 18 h, the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 2-5% 2 M NH3 in MeOH/DCM) gave the title compound (1.20 g, 74%).