Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:17](=[O:20])[NH2:18])([CH3:16])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C#N)CC1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(N)=O)CC1
Temperature: 40 °C
Yield: 309.7 %

Procedure:
To a cooled (ice/water bath) solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (102.9 mg) in dry DMSO was added K2CO3 (9.8 mg) followed by 28% hydrogen peroxide solution (200 μL) dropwise. The resultant was heated at 40° C. overnight. Water was added and the white solid collected, washed with water and air dried to give 4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (59.6 mg). (See Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C1(CCN)CCCCC=1.C1(=O)CCCCC1.C([O:48][C:49](=[O:52])[CH2:50][CH3:51])C.Cl.CCN(C(C)C)C(C)C>>[C:23]1([CH2:22][CH2:21][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:51][CH2:50][C:49]([OH:52])=[O:48])=[CH:13][N:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: Cl
Agent: NCCC1=CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C1CCCCC1
Product: O=C(O)CCSc1cnc(NC(=O)N(CCC2=CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-(1-cyclohexenyl)ethylamine hydrochloride, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].O.[CH3:18][CH2:19][CH2:20]CCC>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:20][C:19]#[CH:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCOCCOCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 5-(t-butyldimethylsilyloxy)-3-oxa-1-pentanol (2.16 g, 9.8 mmol) in dry tetrahydrofuran (20 ml) was added sodium hydride (432 mg, 60% in oil, 10.8 mmol) at room temperature. The mixture was stirred for 30 minutes, and propalgyl bromide (2.9 g, 19.6 mmol) was added thereto. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=8:1) to give the title compound (950 mg, yield: 38%).
Reaction SMILES: [NH3:1].S([O-])([O-])=O.[NH4+:6].[NH4+].[CH:8]1[CH:9]=[CH:10][C:11]2[C:17]([C:18]3[C:27](O)=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][CH:22]=[CH:23]4)=[C:16]([OH:29])[CH:15]=[CH:14][C:12]=2[CH:13]=1>>[CH:22]1[CH:23]=[C:24]2[CH:25]=[CH:26][C:27]([NH2:1])=[C:18]([C:17]3[C:11]4[C:12](=[CH:13][CH:8]=[CH:9][CH:10]=4)[CH:14]=[CH:15][C:16]=3[OH:29])[C:19]2=[CH:20][CH:21]=1.[CH:22]1[CH:23]=[C:24]2[CH:25]=[CH:26][C:27]([NH2:6])=[C:18]([C:17]3[C:11]4[C:12](=[CH:13][CH:8]=[CH:9][CH:10]=4)[CH:14]=[CH:15][C:16]=3[NH2:1])[C:19]2=[CH:20][CH:21]=1
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: [NH4+]
Reactant: N
Agent: O=S([O-])[O-]
Product: Nc1ccc2ccccc2c1-c1c(N)ccc2ccccc12
Product: Nc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 200 °C

Procedure:
Although it is reported that 2-naphthylamine can be obtained in high yield when 2-naphthol was heated to 150° C. in the presence of concentrated aqueous ammonia and ammonium sulfite for 8 hours, no reaction was observed when the same conditions were subjected to BINOL. When the temperature was increased to 200° C. and more ammonium sulfite was employed, NOBIN was exclusively formed without detectable amounts of BINAM. Thus, by extending the reaction time to 5 days and increasing the amount of ammonium sulfite to 10 equivalents, the starting material disappeared completely. The produced solid was simply filtered and washed with water. A 91% isolated yield of NOBIN was obtained by recrystallization from benzene. Thus, a practical procedure for the synthesis of NOBIN from BINOL in a single-step via a process that can be scaled-up in high yield is provided.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2.000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][CH3:34])(=[O:32])=[O:31])[C:20]([Cl:35])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][CH3:34])(=[O:32])=[O:31])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCN(C)C3=O)ncc1Cl
Temperature: 120 °C
Yield: 54 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (50 mg, 0.24 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (#) (89 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 120° C. in the microwave for 40 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a white foam (65 mg, 53%). LCMS: m/z=503.20 (M+H+), 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.68 (s, 1H), 8.40 (t, J=7.1 Hz, 2H), 7.97 (m, 2H), 7.62 (t, 7.6 Hz, 1H), 7.27 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 5.88 (m, 1H), 3.38 (m, 4H), 3.21 (s, 3H), 2.82 (s, 3H), 2.67 (d, J=5.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:25]1([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[C:34]([F:47])[CH:33]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@H:19]4[CH3:24])[C:5]4[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[C:34]([F:47])[CH:33]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 78 %

Procedure:
Method as described for example 147 using (R)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (from step 1) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) as starting materials. Reaction solvent was removed in vacuo. The residue was then partitioned between DCM (100 ml) and water (80 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by flash chromatography using 20-100% ethyl acetate/petroleum ether 40-60 to yield an off white solid (1.107 g, 2.16 mmol, 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26]Cl)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid [2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide (18 mg) in acetonitrile (1 mL) at room temperature was added morpholine (15 μL), potassium carbonate (7 mg) and potassium iodide (2 mg). The reaction mixture was stirred at 80° C. for 72 h and allowed to cool to room temperature before quenching with water (30 mL) and extracting into dichloromethane (2×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give the title compound as an off-white solid (7 mg). NMR: CDCl3: 1.96 (m, 2H), 2.43-2.37 (m, 6H), 2.87 (s, 3H), 3.05 (m, 2H), 3.84 (t, J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.60 (s, 2H), 7.21-7.27 (m, 2H), 7.39 (s, 1H), 7.42-7.47 (m, 2H), 8.11 (d, J=7.2, 1H), 8.25 (s, 1H). MS: (ESI+): MH+ 571
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:12][CH:11]=1.[CH3:40][NH:41][CH2:42][CH2:43][OH:44].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:41]([CH2:42][CH2:43][OH:44])[CH3:40])=[CH:11][CH:12]=3)[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCN(C)CCO)cc1
Temperature: 60 °C

Procedure:
A solution of 4-(8-bromooctyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (36.3 mg, 0.06 mmol, e.g. which can be as prepared in Intermediate 41) in N,N-dimethylformamide (6 ml) was treated with 2-(methylamino)ethanol (0.0195 ml, 0.24 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (7 mg). LCMS showed MH+=593; TRET=2.37 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH:34]=[N:35][NH:36]3)O1>>[NH:36]1[C:37]2[C:33](=[C:32]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:40]=[CH:39][CH:38]=2)[CH:34]=[N:35]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(C)(=O)=O

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification on silica yielded 273. NMR: (400 MHz, CDCl3) 10.20 (br s, 1H), 9.02 (br s, 1H), 8.28 (d, J=7.4, 1H), 7.60 (d, J=8.3, 1H), 7.51 (t, J=7.7, 1H), 7.47 (s, 1H), 4.67 (s, 2H), 4.09 (t, J=4.8, 4H), 3.92 (t, J=4.8, 4H), 2.95 (s, 3H), 2.93 (s, 3H). MS: (ESI+):[M+H]+ 459.06
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[OH-].[NH4+:32]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:32])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol) in toluene (4.8 mL) and N,N-dimethylformamide (12 μL) at 25° C. was treated with a 2.0 M solution of oxalyl chloride in methylene chloride (0.36 mL, 0.73 mmol). This solution was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated dropwise with a 30% aqueous ammonium hydroxide solution (0.59 mL, 5.24 mmol). The resulting suspension was allowed to gradually warm to 25° C. and stirred at 25° C. for 1 h. The reaction mixture was then extracted with ethyl acetate (3×25 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage Flash 40S column, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (175 mg, 88%) as a colorless oil: [α]23589=−45.8° (c=0.096, chloroform); EI-HRMS m/e calcd for C15H20ClNO3S (M+) 329.0852, found 329.0851.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:19][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[CH:17][N:16]=1
Reactant: Nc1cc(Br)ccn1
Reactant: OB(O)c1cc(F)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cc(F)ccc2O)ccn1
Temperature: 85 °C
Yield: 86.7 %

Procedure:
Argon was bubbled through a suspension of (5-fluoro-2-hydroxyphenyl)boronic acid (55.0 mg, 0.35 mmol), 4-bromopyridin-2-amine (67.1 mg, 0.39 mmol) and sodium carbonate (0.15 g, 1.4 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.04 mmol) was added. The resulting mixture was heated at 85° C. for 22 hours then cooled to ambient temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automated silica gel flash chromatography (0% to 100% ethyl acetate in hexanes gradient elution) to afford the title compound as a light tan solid (62 mg).
Reaction SMILES: ClCCl.[OH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.CCOCC>[CH3:24][S:25]([O:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:27])=[O:26]
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(Cc1ccccc1)OS(C)(=O)=O
Yield: 93 %

Procedure:
A dichloromethane solution of methyl 2-hydroxy-3-phenylpropionate (33) is treated with triethylamine (1.1 equiv) and methanesulfonyl chloride (1.1 equiv) at 0° C. Upon completion of reaction, the mixture is dissolved in dichloromethane/ether and washed with saturated aqueous solution of sodium chloride, dried and concentrated. Purification of crude material by flash column chromatography (40% ethyl acetate in hexane) gives methyl 2-methanesulfonyloxy-3-phenylpropionate (1.6 g, 93%). 1H NMR (300 MHz CDCl3): δ 7.358-7.233 (m, 5H), 5.173 (dd, 4.26 Hz, 8.8 Hz, 1H), 3.793 (s, 3H), 3.301 (dd, 4.23 Hz, 14.38 Hz, 1H), 3.1295 (dd, 8.8 Hz, 14.3 Hz, 1H), 2.766 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[CH:11]1(OS(C)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[CH:14]1([N:3]2[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]2)[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: Cc1n[nH]c(C)c1I
Reactant: CS(=O)(=O)OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C2CC=CC2)c(C)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 3,5-dimethyl-4-iodo-1H-pyrazole (5.00 g, 22.5 mmol) in DMF (15 mL) was added NaH (60%, 1.08 g, 27 mmol) in portions and stirred at room temperature for 1 h. To this was added methanesulfonic acid cyclopent-3-enyl ester (4.00 g, 24.7 mmol) and heated at 60° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (60 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography using 5-10% ethyl acetate in hexane to give the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ=5.75 (s, 2H), 4.97 (m, 1H), 2.79 (d, 4H, J=7.2 Hz), 2.28 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N+:17]([O-])=O)=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)([OH:7])[CH3:6])[CH3:2].C([O-])=O.[NH4+].C1COCC1.CO>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:9]=[N:10][C:11]([NH2:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)([OH:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(O)c1cnc([N+](=O)[O-])c(OCC)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1cnc(N)c(OCC)c1
Yield: 74.2 %

Procedure:
A mixture of 2-(6-nitro-5-ethoxy-pyridin-3-yl)-2-hydroxy-propionic acid ethyl ester (1.3 g), ammonium formate (1.5 g), and 10% Pd/C (100 mg) was stirred in a 1:1 mixture of THF/methanol overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate evaporated to yield an oil. The oil was dissolved in EtOAc, washed with water and brine, and the organic layer separated and dried over magnesium sulfate. Evaporation furnished 863 mg of the title compound. LC/MS+=255.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][NH:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:14][N:15]([CH2:16][CH:17]=[O:18])[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][N:8]=1)=[O:13]
Reactant: CNCC=O
Reactant: O=C=Nc1nnc(C2CCCC2)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCC2)s1

Procedure:
A mixture of 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-ureido]acetaldehyde.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].O[C:8]1C=CC=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>CN(C)C=O>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:4][C:2]1[CH:3]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:1]=1
Reactant: COC(=O)c1ccccc1O
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
3.9 g (35 mmol) of potassium tert-butoxide were added a little at a time to 5 g (33 mmol) of methyl hydroxybenzoate in 200 ml of dimethylformamide. After about 15 min, a further 7.3 g (33 mmol) of 2-(bromomethyl)naphthalene were added and the reaction mixture was heated to 100° C. for about 3 h. The reaction mixture was then poured into ice-water and the product was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. 8.4 g (88%) of the product were obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NCCCN
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)C(=O)NCCCN
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Methacryloyl chloride (8.0 g, 0.078 mmol) in methylene chloride (10 ml) was added to a solution of 1,3-diaminopropane (35 ml) in methylene chloride (200 ml) at 0° C. After 15 min. stirring at 0° C. and 16 hours at 25° C. the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silicagel, chloroform/methanol (8:2)) to give (72%) of the title compound.