Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([CH:9]1[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11][N:10]1[C:19](OC1C=CC=CC=1)=[O:20])[CH3:8]>O1CCCC1>[CH2:7]([CH:9]1[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11][N:10]1[C:19]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:20])[CH3:8]
Reactant: CCC1c2nccnc2CCN1C(=O)Oc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1c2nccnc2CCN1C(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (11.0M in tetrahydrofuran, 0.7 mL, 0.7 mmol) was added over 3 min to a solution of phenyl 5-ethyl-7,8-dihydropyrido[3,4-b]pyrazine-6(5H)-carboxylate (91 mg, 0.32 mmol) in tetrahydrofuran (1.8 mL) cooled in a −20 to −30° C. bath. After 30 min, the bath was removed and stirring was continued for 75 min. The mixture was added to saturated aqueous sodium bicarbonate solution (10 mL) which was then extracted with two portions of ethyl acetate (35 mL and 15 mL). The organic layers were washed in succession with saturated aqueous brine (10 mL), dried over sodium sulfate, decanted, and evaporated. Purification by flash column chromatography (silica gel, 15% ethyl acetate/hexanes) gave the title compound as a colorless oil. 1H NMR (500 MHz, CD3OD) δ 8.43 (d, 1H, J=2 Hz), 8.40 (d, 1H, J=2 Hz), 5.17-5.02 (bm, 1H), 4.40-4.25 (bm, 1H), 3.37-3.20 (bm, 1H), 3.04 (ddd, 1H, J=17, 12, 6 Hz), 2.90 (dd, 1H, J=17, 4 Hz), 2.10-2.00 (m, 1H), 1.87-1.76 (m, 1H), 1.49 (s, 9H), 1.04 (bt, 3H). LC/MS 208 (M+1-56).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:15]=1[O:16][CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:14]1[CH:28]=[C:27]([O:29][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[CH:26]=[CH:25][C:15]=1[O:16][CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: CCCOC(=O)C(C)Oc1ccc(O)cc1F
Reactant: Fc1ccc2nc(Cl)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1F
Temperature: 120 °C
Yield: 41.8 %

Procedure:
A mixture of 2-chloro-6-fluoroquinoxaline (1.0 g; 5.48 mmole), n-propyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (1.33 g; 5.49 mmole), anhydrous potassium carbonate (0.8 g) and anhydrous dimethylformamide (40 ml) was stirred and heated at a temperature of 120° C. for a period of 3.5 hours. The solvent was evaporated from the reaction mixture under vacuum, the residue was treated with water and the mixture was extracted with diethyl ether. The etherial extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under vacuum to give a brown oil. The product was purified by preparative thin layer chromatography over silica gel (eluant chloroform/ethanol, 95:5) to give the title compound (0.89 g; 41.8%) as a solid; mp 49°-51° C.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].[C@@H]1(N)CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1>O1CCOCC1.CCOC(C)=O.[Cu]I>[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([OH:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=3)[CH:8]=[N:9]2)=[CH:33][CH:32]=1
Reactant: CC(C)c1cc2[nH]ncc2cc1O
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1cc2c(cnn2-c2ccc(F)cc2)cc1O
Yield: 29 %

Procedure:
6-Isopropyl-1H-indazol-5-ol was dissolved in 20 mL dry dioxane in a stainless steel pressure tube. Trans-1,2-cyclohexanediamine (0.35 mL, 2.88 mmol) was added followed by CuI (110 mg, 0.58 mmol) and then K3PO4 2.2 g, 10.4 mmol). After the addition of 4-fluoro-1-iodobenzene (0.7 mL, 6.0 mmol), the reactor was sealed and heated at 100 C for 24 h. The reactor was cooled and the contents were taken up in EtOAc, filtered through a SiO2 plug using EtOAc as the eluent and concentrated in vacuo. The crude product was chromatographed on SiO2 using 1:3 EtOAc/hexanes to give 453 mg (29% yield) of 1-(4-fluorophenyl)-6-isopropyl-1H-indazol-5-ol. MS found: (M+H)+=271.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:26])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[P:29](Cl)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:32]([O:31][P:29](=[O:30])([O:34][CH2:35][CH3:36])[O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:12]3[C:11]([CH3:27])=[CH:10][N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:28])[C:13]=3[N:14]=[C:15]([CH3:26])[N:16]=2)[CH2:19][CH2:20]1)[CH3:33]
Reactant: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)OCC1CCN(c2nc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Under nitrogen atmosphere, to a solution of {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (0.50 g) and 4-dimethylaminopyridine (0.55 g) in CH2Cl2 (50 mL) at 0° C. diethyl chlorophosphate (0.38 g) was added dropwise and the reaction is slowly heated up to room temperature. The reaction mixture is poured on ice-water and extracted with CH2Cl2. After the usual work-up the residue is purified over silica gel on a glass filter (eluent: CH2Cl2/MeOH=98:2) yielding product 3-017 (0.31 g).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27].C(N(CC)CC)C.Cl>C(#N)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 18 h
Yield: 38.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 4-cyanophenylisocyanate (0.14 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (40 mL). The crude product was purified by prep-HPLC (MeCN/H2O, 10/90 to 90/10 gradient over 15 min). The product fractions were combined, triturated in Et2O then filtered and dried in vacuo to give 1-(4-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.16 g, 38% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.31 min (97.64%); mp: 258-260° C.; 1H NMR (DMSO-d6) δ 1.86-2.06 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.78-3.03 (m, 1H, CHH), 4.31 (d, J=17.2 Hz, 1H, CHH), 4.38-4.59 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.00 (t, J=5.7 Hz, 1H, NH), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 7.56-7.63 (m, 2H, Ar), 7.64-7.82 (m, 3H, Ar), 9.23 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.12, 51.56, 102.50, 117.56, 119.40, 121.89, 122.96, 126.91, 130.36, 133.15, 142.39, 144.39, 144.84, 154.68, 167.92, 170.98, 172.85; LCMS: MH=418; Anal Calcd for C22H19N5O4: C, 62.76; H, 4.64; N, 16.63. Found: C, 62.65; H, 4.55; N, 16.69.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:15])[N:5]=1)[CH3:3].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O.CCOC(C)=O>CN(C=O)C>[Cl:14][C:13]1[C:4]([CH:2]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH3:3])=[N:5][C:6]2[C:11]([N:12]=1)=[C:10]([Cl:15])[CH:9]=[CH:8][CH:7]=2
Reactant: CC(Br)c1nc2cccc(Cl)c2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1nc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a solution of 2-(1-bromoethyl)-3,5-dichloroquinoxaline (1.00 Kg, 3.27 mol) in DMF (8.2 L) was added potassium phthalimide (1.21 Kg, 6.54 mol). The reaction mixture was stirred for 3 h. At this time LC-MS analysis showed that the reaction was complete. The mixture was transferred to a 50 L separatory funnel and water (12 L) and EtOAc (6 L) were added to it with stirring. A large amount of white solid crashed out and was collected by filtration. The aqueous. phase was separated and extracted again with EtOAc (2×4 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the volume was reduced to 5 L under reduced pressure. After cooling to rt, the product was obtained as a white solid. The white solid was filtered, triturated with hexane and dried under vacuum to give 2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (1.24 Kg). 1H NMR (DMSO-d6) δ ppm 8.02-8.21 (2H, m), 7.83-8.02 (m, 5H), 5.89 (q, J=6.8 Hz, 1H), 1.87 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI) m/z=372.0 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:27]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>C1COCC1.O>[F:27][C:4]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=C(OCc1ccccc1)C1CCOCC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(F)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of the compound (0.22 g) obtained in step 1 in THF (3.5 mL) was added dropwise at −78° C. lithium bis(trimethylsilyl)amide (1.1M THF solution, 1.82 mL), and the mixture was stirred for 30 min. The mixture was warmed to 0° C. and stirred for 15 min. The reaction mixture was cooled to −78° C., a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.63 g) in THF (2.0 mL) was added dropwise, and the mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→20% ethyl acetate/hexane) to give benzyl 4-fluorotetrahydro-2H-pyran-4-carboxylate (0.10 g, 44%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:21](=[O:22])[NH:20][C@H:4]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:3])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: c1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)N[C@@H](C)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with (S)-1-isocyanato-ethyl)-benzene (25 mg) to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure I. This product (25 mg) was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 882.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27](=[NH:33])[N:28]2[CH:32]=[CH:31][CH:30]=N2)=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:38].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27]([NH:28][CH2:32][CH2:31][CH2:30][OH:38])=[NH:33])=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: NCCCO
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[imino(1H-pyrazol-1-yl)methyl]acetamide (0.240 g, 0.50 mmol) in CH2Cl2 (5 mL) was added 3-aminopropanol (0.112 g, 0.12 mL, 1.50 mmol) and diisopropyl ethylamine (0.193 g, 0.26 mL, 1.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide as a white solid. mp 49-50° C.; MS (ES) m/z 486.09 ([M+H]+). MS (ES) m/z 971.26 ([2M+H]+). Anal. Calcd for C25H28ClN3O3S.0.10 C6H14: C, 62.16; H, 5.99; N, 8.49. Found: C, 62.41; H, 5.70; N, 8.45.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)(=O)C(Cl)=O.[CH:31]1[CH:36]=[CH:35][CH:34]=CC=1>>[C:1]([O:24][CH2:34][CH:35]1[CH2:31][CH2:36]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC1CC1

Procedure:
In a 500 ml. flask is stirred 3.2 g. of docosanoic acid in 250 ml. of dry benzene until most of acid dissolves. Oxalyl chloride (3.5 g.) is added and mixture stirred for 2 hours at room temperature under nitrogen. Solvent is removed in vacuo and fresh benzene added and 1.3 g. of cyclopropylmethyl alcohol. The reaction product is worked up by washing with water and brine, drying over calcium sulfate and evaporation of solvent to yield cyclopropylmethyl docosanoate m.p. 44°, which can be further purified by recrystallization from methanol.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+]>C(Cl)(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:7][CH2:8][CH3:9])[CH2:6][CH2:5][CH3:12])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 146.5 %

Procedure:
Commercially available 4-nitrobenzylamine hydrochloride (manufactured by Tokyo Kasei Kogyo., Ltd.) (1.82 g) was suspended in chloroform (15 ml). Then, a 1 mol/l sodium hydroxide aqueous solution (15 ml) was added to the suspension and the aqueous layer was then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off, followed by dissolving the residue in anhydrous methanol (20 ml). Subsequently, the solution was added with propionaldehyde (1.66 ml) and sodium cyanoborohydride (1.81 g) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 21 hours. After completion of the reaction, the solvent was distilled off. The residue was added with 1 mol/l sodium hydroxide and then subjected to chloroform extraction. The extract was dried with anhydrous magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.67 g) as a yellow oily substance.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Product: Clc1cc(N2CCCC2)nc(NC2CCCC2)n1
Yield: 72.4 %

Procedure:
The reaction of 2-cyclopentylamino-4,6-dichloropyrimidine with pyrrolidine as described in Example 13 gives the title compound as an oily product in a yield of 72.4%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])[CH:17]=1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Reactant: Nc1cccnc1
Product: CC1CC(=O)c2c(C(=O)Nc3cccnc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 3-aminopyridine, General Procedure B provided the title compound:
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)([CH3:4])[CH3:3].[CH:37](I)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C.CN(C=O)C>[CH:2]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C@:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH3:37])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc([C@]3(O)CCCN(C)C3)n(C)c2n1
Temperature: 75 °C

Procedure:
The HCl salt of 3-(2-(2-isopropyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)piperidin-3-ol (80 mg) was reacted with isopropyl iodide (1.5 eq) and potassium carbonate (5 eq) in a 1:1 mixture of DMF and Acetonitrile (2 mL). The reaction was heated at 75° C. for 18 hours until complete. The reaction mixture was diluted with Ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated to give 581 [4.6 mg; MS (Q1) 491.3 (M)+] and 582 [4.7 mg; MS (Q1) 491.3 (M)+] following reverse phase purification and subsequent chiral separation.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[S:6][C:7]([C:10]([NH:12][C:13]2[S:14][C:15]([C:18](=O)[NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[N:24]=3)=[CH:16][N:17]=2)=O)=[CH:8][N:9]=1)[CH2:2][CH3:3]>C1COCC1>[CH2:1]([NH:4][C:5]1[S:6][C:7]([CH2:10][NH:12][C:13]2[S:14][C:15]([CH2:18][NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[N:24]=3)=[CH:16][N:17]=2)=[CH:8][N:9]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ncc(C(=O)Nc2ncc(C(=O)Nc3nc(-c4ccc(C)cc4)cs3)s2)s1
Solvent: C1CCOC1
Product: CCCNc1ncc(CNc2ncc(CNc3nc(-c4ccc(C)cc4)cs3)s2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
BMS (0.015 mL, 0.15 mmol) was added to a solution of 2-(propylamino)-N-(5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-yl)thiazole-5-carboxamide (15 mg, 0.03 mmol) in THF (1 mL) at RT. The resulting solution was stirred at RT overnight. The reaction was then quenched with MeOH (0.5 mL). 1N HCl was added until pH=2. After stirring the reaction mixture at RT for 12 hrs, the organic solvents were evaporated and the aqueous solution was neutralized with a NaHCO3 saturated aqueous solution, extracted with AcOEt, dried with Na2SO4 and concentrated. The crude product was purified by column chromatography (0%-5% MeOH/AcOEt), yielding N-propyl-5-((5-((4-p-tolylthiazol-2-ylamino)methyl)thiazol-2-ylamino)methyl)thiazol-2-amine (5 mg, 32%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][N:4]1[CH2:27][CH2:26][C:7]2[N:8]([CH2:16][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)(O)[CH3:18])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1>S(Cl)(Cl)=O>[CH3:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8](/[CH:16]=[C:17](/[C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)\[CH3:18])[C:7]3[CH2:26][CH2:27][N:4]([CH2:3][C:2]([F:28])([F:29])[F:1])[CH2:5][C:6]=3[C:14]=2[CH:13]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(CC(F)(F)F)C1
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CC(F)(F)F)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-(2,2,2-Trifluoroethyl)-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (200 mg, 0.4 mmol) was dissolved in thionyl chloride (2 mL), and stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure; the residue was cooled in ice water and basified with saturated aqueous NaHCO3. The product was extracted with EtOAc and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. Yield: 195 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 8.10 (d, 2H), 7.70 (s, 1H), 7.22 (s, 1H), 7.05 (m, 2H), 3.95 (s, 2H), 3.40 (m, 2H), 3.10 (m, 2H), 2.82 (m, 2H), 2.42 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [F:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][C:4]([O:6]C)=[O:5].Cl>C(O)(=O)C>[F:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCC[C@H](F)CC(=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCC[C@H](F)CC(=O)O
Temperature: 90 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
In a two-necked round-bottomed flask, 98 mg (0.52 mM) of methyl (S)-3-fluorononanoate and 1 ml of acetic acid were placed. To the mixture, 1 ml of concentrated hydrochloric acid was added, followed by stirring for 4 hours at 90° C. After the reaction, ice water was added to the reaction mixture, followed by extraction with Et2O. The organic layer was sufficiently washed with distilled water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent under reduced pressure to obtain 78 mg (0.44 mM) of (S)-3-fluorononanoic acid.