Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.[C:19]1([CH2:25][C:26](O)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH:1]1([N:4]([C:5]2[S:6][CH:7]=[C:8]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[N:9]=2)[C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]cc(-c3csc(NC4CC4)n3)c2c1
Reactant: O=C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N(c1nc(-c2c[nH]c3ncccc23)cs1)C1CC1
Temperature: 180 °C
Yield: 12.3 %

Procedure:
Cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine (50 mg, 0.39 mmol), phenylacetic acid (63 mg, 0.47 mmol) and N-(1-methanesulfonyl)benzotriazole (93 mg, 0.47 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). 5% DMF-THF (4 mL) was added followed by triethylamine (0.163 mL, 1.17 mmol) and the mixture heated in the sealed tube at 180° C. for 15 minutes. Upon cooling to room temperature the reaction was concentrated and then purified by prepartative TLC (thin layer chromatography) and eluted with ethylacetate and hexane (3:1). Extraction of the silica gel with 5% MeOH-EtOAc was carried out to give product (15 mg, 10%). Alternatively, Cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine (50 mg, 0.39 mmol), phenylacetic acid (63 mg, 0.47 mmol) and fluoro-N,N′,N′,N′-tetramethylformamidiniun hexafluorophosphate (148 mg, 0.59 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). 5% DMF-THF (4 mL) was added followed by triethylamine (0.163 mL, 1.17 mmol) and the mixture heated in the sealed tube at 180° C. for 15 minutes. Upon cooling to room temperature the reaction was concentrated and then purified by prepartative TLC (thin layer chromatography) and eluted with ethylacetate and hexane (3:1). Extraction of the silica gel with 5% MeOH-EtOAc was carried out to give product (18 mg, 12%). The material was isolated as an HCl salt. LC/MS MH+ =375.2, LC/MS RT: 3.39 min. 1H NMR (500 MHz, DMSO-d6, ppm) 11.92 (s,1H), 8.63 (d,1H, J=7.88 Hz), 8.29 (dd,1H, J=4.71, 1.49 Hz), 8.96 (d,J=2.58,1H), 7.44 (s,1H), 7.36-7.19 (m,6H), 4.27 (s,2H), 3.29 (t, 1H,J=3.78), 1.33 (m,2H), 1.06 (m,2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:33][CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:4][N:3]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.N1C=CC=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH2:34][N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: CCN(CC)CC#Cc1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCN(CC)C/C=C\c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Yield: 37.6 %

Procedure:
A solution of N-(4-{4-amino-7-[3-(diethylamino)prop-1-ynyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.135 g, 0.251 mmol) in ethanol/pyridine (15 mL/10 mL) was treated with Lindlar's catalyst (0.027 g), quinoline (0.05 g, 0.38 mmol), and hydrogen (55 psi) in a Parr Hydrogenator. The reaction mixture was shaken for 1H. The catalyst was filtered through celite. The solvent was removed under reduced pressure. The crude material was purified by preparative HPLC to afford 0.051 g (38%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.00–7.98 (d, 1H), 7.81 (s, 1H), 7.71–7.69 (d, 1H), 7.60–7.57 (m, 2H), 7.35–7.33 (m, 2H), 7.21–7.21 (m, 1H), 7.17–7.13 (t, H), 7.10–7.08 (d, 1H), 6.56–6.53 (d, 1H), 5.90–5.88 (dt, 1H), 5.60 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.30–3.28 (m, 2H), 2.49–2.44 (q, 4H), 0.93–0.89 (t, 6H); LCMS (conditions a) Rt 3.28 min (95%), MH+ 540.3.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21](Cl)=[O:22])(=[O:17])[CH3:16].C(SCC(CSC)C(O)=O)(=O)C.S(Cl)(Cl)=O>O>[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:22])(=[O:17])[CH3:16]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CSCC(CSC(C)=O)C(=O)Cl
Agent: CSCC(CSC(C)=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of L-proline (1.44 g.) and sodium carbonate (2.7 g.) in water (25 ml.) in an ice bath, 3-(acetylthio)-2-(methylthiomethyl)propanoic acid chloride (prepared from the acid of Example 72 with thionyl chloride (3.6 g.) is added, and the mixture is vigorously stirred at room temperature for two hours. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to give N-[3-(acetylthio)-2-(methylthiomethyl)propanoyl]-L-proline.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[C:12]1[CH:13]=[C:14]2[C:19](=[O:20])[O:18][C:16](=O)[C:15]2=[CH:21][CH:22]=1.[C:23](O)(=O)C>>[CH3:23][C:13]1[CH:12]=[CH:22][CH:21]=[C:15]2[C:14]=1[C:19](=[O:20])[N:1]([CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:16]2=[O:18]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)O
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Product: Cc1cccc2c1C(=O)N(C(CCC(=O)O)C(=O)O)C2=O

Procedure:
A mixture of glutamic acid (10 mmol) and 4-methyphthalic anhydride below (10 mmol) in 20 mL of acetic acid is heated to reflux. The cooled reaction is then concentrated in vacuo. The residue is slurried in ethyl acetate and the resulting slurry filtered to afford the desired product. As an alternative to slurry filtering, column chromatography can be used to purify the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.CCOCC.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][CH:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 3,4-dichloroaniline (5 g), N-tert-butoxycarbonyl4-piperidone (11.7 g), sodium triacetoxyborohydride (19.7 g) and acetic acid (7 ml) in dichloroethane (150 ml) was stirred for 16 hours. 2M NaOH solution and ether were added, the organic phase separated, dried and concentrated. The residue was triturated under an isohexane:ethyl acetate, 4:1 mixture and the sub-titled product collected as a solid (7.25 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:28])([F:27])[C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH2:8][NH:9][CH:10]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.[CH3:38]CCCCC.C(OCC)(=O)C>CN(C)C=O.CCOCC>[CH3:38][N:9]([CH2:8][C:7]1[CH:24]=[CH:25][CH:26]=[C:5]([C:4]([F:3])([F:27])[F:28])[CH:6]=1)[CH:10]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH:16]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCCCC
Reactant: COC(=O)C(NCc1cccc(C(F)(F)F)c1)c1c[nH]c2ccccc12
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(c1cn(Cc2ccc(Cl)cc2)c2ccccc12)N(C)Cc1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a magnetically stirred suspension of sodium hydride (60% oil dispersion washed two times with hexane, 80 mg, 2.0 mmol) in 5 mL of dimethylformamide (DMF) under nitrogen was added methyl α-[3-(trifluoromethyl)benzylamino]-indole-3acetate (752 mg, 2.0 mmol) dissolved in 2 mL DMF. Stirring was continued at room temperature for 10 minutes. At the end of this time, 0.322 g (2.0 mmol) of parachlorobenzyl chloride was added and the reaction stirred at room temperature for one hour. The reaction was diluted with ether and the ether solution was washed two times with water. The ether extract was then washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Flash chromatography of the crude product with 100 g of silica gel and using hexane-ethyl acetate (4:10) as the eluent afforded 419 mg of the title compound.
Reaction SMILES: [OH-].[Na+].NC1[S:5][C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:7]=2[N:8]=1>O.C(O)CO>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]=1[SH:5]
Reactant: Nc1nc2ccc3ccccc3c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Nc1ccc2ccccc2c1S

Procedure:
To a solution of 30.0 g sodium hydroxide in 30 mL of water and 140 mL of ethylene glycol was added 18.0 g of 2-aminobenzo[g]benzothiazole. The mixture was heated at reflux under nitrogen for 20 hours and diluted with 80 mL of water. After cooling, the mixture was filtered, then the filtrate was chilled in an ice-bath and neutralized with acetic acid. The aqueous suspension was extracted with ether (3×200 mL) and the combined extracts were dried (magnesium sulfate). Removal of the solvent gave the product to which heptane (3×150 mL) was added and the solvent was removed under reduced pressure. (This step removed traces of acetic acid). The yield of the 2-aminonaphthalene-1-thiol was 15.4 g (97%), mp 108°-110°. A sample of this compound was recrystallized from ethanol, mp 109°-110°. This compound is sensitive to air and therefore was used immediately in the next step of the synthetic scheme.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22]O.CC([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]#[N:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1csc(-c2cc3cc(C#N)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (4.46 g), hydroxylamine hydrochloride (3.96 g) and sodium acetate anhydrous (5.0 g) in acetic acid (40 ml) was stirred at ambient temperature for 3 hours. Subsequently, acetic anhydride (13 ml) was added to the mixture. After being stirred for 30 minutes at the same temperature, the reaction mixture was stirred at 120° C. for 2 hours. After being cooled, the mixture was poured into water, followed by collecting by filtration. The precipitates were washed with water and air-dried at ambient temperature. The crude products were washed with petroleum ether to give 4-tert-butyl-2-(5-cyanobenzofuran-2-yl)thiazole (4.44 g).
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][S:6][C:5]=12
Reactant: CCOC(=O)c1cn2c(n1)SCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cn2c(n1)SCCC2
Temperature: -70 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Ethyl 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine2-carboxylate (2.12 g, 10 mmol) was dissolved in dry dichloromethane (40 ml) under argon and cooled to −70°. Diisobutylaluminium hydride (1.5M toluene, 12 ml, 18 mmol) was added below −68° C. and the reaction mixture stirred at −70° C. for 1 h. Water was added carefully and the cooling remove. The reaction mixture was stirred vigorously at ambient temperature for 15 minutes and Celite (2 g) added. The mixture was filtered through Celite, the filter bed washed with dichloromethane and water, the filtrate and the washings combined and evaporated to dryness under reduced pressure. The residue was evaporated from ethanol (2×) to give the title compound as a white solid (1.31 g, 78%); νmax (CH2Cl2) 1685, 1543 and 1453 cm−1; δH (250 MHz; CDCl3) 2.34-2.43 (2H, m), 3.20 (2H, t, J 6 Hz), 4.17 (2H, t, J 6 Hz), 7.58 (1H, s), 9.75 (1H, s).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.Cl.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>CN(C=O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reaction time: 3 h

Procedure:
2.18 ml (15.5 mmol) of triethylamine are added to a colorless suspension of 1.28 g (5 mmol) of 4-bromobenzyl bromide and 944 mg (5.5 mmol) thiomorpholine-1,1-dioxide hydrochloride in 15 ml DMF. After 3 h at RT, the reaction mixture is partitioned between CH2Cl2 and H2O. The aqueous phase is re-extracted four times with CH2Cl2. The combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:19](OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)([OH:9])[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=C(c1ccc(Br)cc1)C1CCCCC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C1CCCCC1
Temperature: 0 °C

Procedure:
A solution of (4-bromophenyl)(cyclohexyl)methanone (step 63.2) (3.1 g, 11.60 mmol) in THF (30 ml) was immersed in an ice-bath, followed by dropwise addition of MeMgBr (3M) in diethylether (7.74 ml, 23.21 mmol). The yellow reaction solution was stirred in the ice-bath for 1.5 hrs. The reaction mixture was quenched carefully with saturated aqueous NH4Cl solution and taken up in ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]([NH2:18])=O)[CH:4]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH3:1][N:2]([CH3:19])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]#[N:18])[CH:4]=1
Reactant: CN(C)c1cc(C(N)=O)nn1Cc1ccccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN(C)c1cc(C#N)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.33 g of 5-(dimethylamino)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxamide 1-10-1 (5.07 mmol, 1.0 eq.) were dissolved in 74 mL of dry THF. 1.03 mL of pyridine (12.7 mmol, 2.50 eq.) were added. Then 1.79 mL of trifluoroacetic anhydride (12.7 mmol, 2.50 eq.) were added dropwise. The reaction mixture was stirred for 24 hours at rt. Then the reaction mixture was partitioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane/ethyl acetate) to provide 406 mg (1.66 mmol, 33%) of analytically pure target compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70]([NH:72][C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:72][C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-4-yl-urea hydrochloride (Example 108). MS (ES+) m/e 715.54 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1C)([CH3:3])[CH3:2].[C:12]([OH:16])(=[O:15])[CH2:13]C.[C:17]([OH:29])(=[O:28])[CH2:18][C:19]([CH2:24][C:25]([OH:27])=[O:26])([C:21]([OH:23])=[O:22])[OH:20]>>[C:12]([CH2:13][C:8]1[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:22][C:21]([C:19]([OH:20])([CH2:18][C:17]([OH:29])=[O:28])[CH2:24][C:25]([OH:27])=[O:26])=[O:23])=[C:6]([OH:10])[CH:7]=1)([OH:16])=[O:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1c(O)cccc1C(C)C
Reactant: CCC(=O)O
Product: CC(C)c1cc(CC(=O)O)cc(O)c1OC(=O)C(O)(CC(=O)O)CC(=O)O

Procedure:
An antimicrobial compound was formed by combining the isopropyl-o-cresol from Example 2 with propionic acid and citric acid. 3-{[4-(carboxymethyl)-2-hydroxy-6-isopropylphenoxy]carbonyl}-3-hydroxypentanedioic acid (citro-propiono-cresol or CPC), was formed by combining 50 grams isopropyl-o-cresol with 25 ml propionic acid (90% purity) and 25 ml citric acid (95% purity). The mixture was heated to a temperature of 80° C. and mixed in a high speed turbo mixer for 3 minutes at a speed of 1,000 revolutions per minute.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([S:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To a stirred ice-cooled solution of tert-butyl 1-piperazinecarboxylate (0.88 g, 4.7 mmol), triethylamine (1.3 mL, 9.4 mmol), and 4-dimethylaminopyridine (0.0058 g, 0.047 mmol) in DCM (10 mL) was added 6-chloropyridine-3-sulfonyl chloride (1.0 g, 4.7 mmol) in one portion. The resulting mixture was stirred at 0° C. and gradually warmed up to ambient temperature for 1.5 h. Upon workup, the mixture was directly subjected to combi-flash column chromatography (methanol/DCM) to give compound 360 (1.44 g, 84% yield) as a white solid.
Reaction SMILES: [Na].[F:2][C:3]([F:10])([F:9])[C:4]([O:6]CC)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1>C(O)C>[F:10][C:3]([F:2])([F:9])[C:4]([CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:19]#[N:20])=[O:6]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: N#CC(C(=O)C(F)(F)F)c1ccc(F)cc1
Yield: 90.6 %

Procedure:
Dry ethanol (15 ml) was added to sodium metal (1.22 g, 0.0530 mole) and the mixture was heated under reflux to dissolve sodium metal perfectly. A mixture of ethyl trifluoroacetate (7.53 g, 0.0530 mole) and p-fluorophenylacetonitrile (6.76 g, 0.0500 mole) was added dropwise over 30 minutes. The mixture, after being heated under reflux for 10 hours, was extracted with methylene chloride to remove neutral and basic components. To the mixture was then added 36% hydrochloric acid to adjust below pH 2 and the mixture was extracted with diethyl ether again. After being dried, the solvent was distilled off under reduced pressure to give the crude title compound (10.47 g, 84.0%). The product showed a single spot on thin-layer chromatography. The product was recrystallized from benzenecyclohexane to recover the monohydrate of the title compound (8.97 g, 77.0%) as pale yellow prisms. The structure of this compound was confirmed by IR and NMR.
Reaction SMILES: C1(C[N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]2[OH:27])CC2C=CC=CC=2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:16][C@@H:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]1[OH:27]
Reactant: CCCCN1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCN1CC[C@@H](CN)[C@H](O)C1
Yield: 93.8 %

Procedure:
A mixture of intermediate (72) (0.079 mol) in methanol (250 ml) was hydrogenated with palladium-on-carbon (10%) (2 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered over celite and the filtrate was evaporated, yielding 13.8 g of (trans)-4-(aminomethyl)-1-butyl-3-piperidinol (intermediate 73).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:3]([C:11]([F:12])([F:13])[F:14])=[CH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of 17 mmol 2-methyl-3-nitrobenzotrifluoride and 43 mmol N,N-dimethylformamide-dimethylacetal in 30 ml N,N-dimethylformamide was held at 120° C. overnight. The reaction mixture is concentrated in vacuo to give the crude title compound. Yield=83%. MS (m/e): 261.1 ([M+H]+, 90%).