Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)[CH2:48][CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=1)[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH2:47][CH2:48][CH3:49])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CCCc1nc(C(=O)O)cs1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.25 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.16 g), 2-propylthiazole-4-carboxylic acid (example 56, step c) (0.09 g) and triethylamine (0.29 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the mixture evaporated to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCCCCl)c1ccccc1F
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:7]([C:6]3[C:2]([Cl:1])=[N:3][N:4]([C:10]4[N:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cn(-c2ncccn2)nc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 1-adamantan-1-ylmethan-amine (36 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol) The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with CH2Cl2 (5 mL). The CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient from 30% EtOAc/hexane to 60% EtOAc/hexane) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (1H, s), 8.91 (2H, d, J 4.8), 8.18 (1H, bs), 7.56 (1H, t, J 4.8), 2.92 (2H, d, J 5.6), 1.92 (3H, s), 1.60 (6H, m), 1.47 (6H, s). MS (M+1)=372.18; RT=1.35 min. *IC50.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:14]CCC.CI.[NH4+].[Cl-]>C1COCC1>[CH3:14][N:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCc2ncccc2N1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 1.0 eq of 96 in 30 mL of dry THF was cooled to −78° C. While stirring, 1.1 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction solution was warmed to 0° C. and stirred for 1 hr. The solution was then cooled to -78° C. and 1.2 eq of methyl iodide was slowly added. The mixture was stirred, as the solution warmed to rt. After 17 hrs, 50 mL of saturated NH4Cl was added and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to afford a dark orange colored solid as 97.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][NH:9][CH2:10][C:11]1([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C=NOCc2ccccc2)CCCC1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: O=C(O)C1(CNOCc2ccccc2)CCCC1
Temperature: 0 °C

Procedure:
To a solution of 1-(benzyloxyimino-methyl)-cyclopentanecarboxylic acid (1.91 g, 7.72 mmol) in methanol (70 mL) at 0° C. under a nitrogen atmosphere was added a trace amount of methyl orange. A solution of saturated methanolic HCl was added until a persistent red color was observed. Sodium cyanoborohydride (0.58 g, 9.27 mmol) was added portionwise alternately with methanolic HCl to maintain the red color. The reaction mixture was maintained at 0° C. for an additional 3 h and the volatiles were removed in vacuo. The residue was purified by preparative reverse-phase HPLC to yield the title compound as a pale, yellow oil (1.1 g, 57%). MH+250.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[C:12](=[O:24])[CH2:11]1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N(C)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([CH:29]=[CH:28][CH:27]=1)[O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[C:12](=[O:24])[CH2:11]1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)C
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(Oc2cccc(Cl)c2)c1
Reaction time: 24 h
Yield: 17.9 %

Procedure:
3-[4-(2-Hydroxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzamide (32 mg, 0.1 mmol), 3-chlorobenzeneboronic acid (19 mg, 1.2 eq), and copper acetate (1 eq) were added to a dry tube. The mixture was charged with 2 mL CH2Cl2, (CH3)3N (3 eq) followed by addition of 4 Å MS. The mixture was stirred for 24 h and diluted with 10 mL CH2Cl2. After filtration, the mixture was washed with NH4Cl, water, and brine, and then dried. After concentration, the residue was purified by preparative LC-MS to give 7.8 mg of the desired product. Yield: 18%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](Cl)=[N:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.[NH3:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)[NH2:20]
Reactant: N
Reactant: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(I)cc1
Solvent: C1CCOC1
Product: NC(=NNc1ccc(I)cc1)c1c(F)cccc1Cl

Procedure:
The title compound was prepared according to the procedure described in step-3 of Intermediate-1 by using 2-chloro-6-fluoro-N-(4-iodophenyl)benzenecarbohydrazonoyl chloride (1.00 g, 2.44 mmol), aq. ammonia (2.0 mL) and dry THF (10 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.28 (br s, 2H), 6.70 (d, J=8.4 Hz, 2H), 7.27 (t, J=8.7 Hz, 1H), 7.36-7.42 (m, 3H), 7.45-7.51 (m, 1H), 8.33 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([CH3:21])=[CH:19][N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt-]=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:19]=[C:20]([CH3:21])[C:13]=12
Reactant: Cc1cn(COCC[Si](C)(C)C)c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Agent: O=[Pt-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc(Nc3ccc(N)cc3F)c12
Reaction time: 8 h

Procedure:
20 mg (50 μmol) of N-(2-fluoro-4-nitrophenyl)-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 8 ml of a mixture of ethanol/THF (1:1). 11 mg (50 μmol) of platinum(I) oxide are added, and the mixture is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The suspension is then filtered through Celite, the Celite is washed with a little ethanol and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2>CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]2[CH3:1])=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(C)n(Cc2ccc(N)cc2)c2ccccc12
Yield: 95.1 %

Procedure:
Into a dry reaction vessel, methyl 2-[2-methyl-1-(4-nitrobenzyl)-1H-indol-3-yl]acetate (300 mg, 0.887 mmol) was added, and dissolved in 10 mL methanol. 10% Pd/C 20 mg was added, and reacted under hydrogen for 3 hours. After completion of the reaction, it was filtered. The filter cake was washed with methanol, and the filtrate was rotate evaporated to dryness to obtain a solid 260 mg, at a yield of 95.0%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) and tert-butyl piperazine-1-carboxylate (726 mg, 3.9 mmol) in dimethylformamide was treated with potassium carbonate (735 mg, 5.32 mmol) and the suspension was heated at 55° C. for 4 hours and then stirred overnight at room temperature. The reaction was poured into water and the suspension was filtered with water washes to provide the title compound after vacuum drying.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.O.[CH3:14][CH2:15]O>>[CH:1]1([C:5]([O:7][CH2:14][CH3:15])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: O=C(O)C1CCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C1CCC1
Yield: 69 %

Procedure:
To a solution of cyclobutanecarboxylic acid (50 g, 500 mmol) in EtOH (1.2 L) was slowly added H2SO4 (20 mL) at room temperature. The solution was stirred at reflux overnight, and then cooled and poured into H2O. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give ethyl cyclobutanecarboxylate as a colorless oil (44 g, 69%). 1H NMR (400 MHz, CDCl3-d3) δ 4.04 (q, 2H), 3.04 (m, 1H), 2.12 (m, 4H), 1.88 (m, 2H), 1.18 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]=[C:10]=[O:11])=[O:8])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)C.C(#N)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([NH:9][C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:11])=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(NC(=O)c1ccc(C(F)(F)F)cc1)Nc1ccc(Cl)cc1

Procedure:
To a stirred solution of 1.08 g of 4-trifluoromethylbenzoylisocyanate in 5 ml of dry diethylether is added a solution of 0.64 g of 4-chloroaniline in 50 ml of acetonitrile. A precipitate is immediately formed. The precipitate is sucked off and washed with acetonitrile. The title compound is obtained a yield of 1.1 g; melting point 260° C.
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]([OH:10])[CH2:3]2.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH2:19][OH:20]>C(O)C>[OH:20][CH2:19][CH2:18][N:9]1[CH:6]2[CH2:7][CH2:8][CH:2]1[CH2:3][CH:4]([OH:10])[CH2:5]2
Reactant: OCCBr
Reactant: OC1CC2CCC(C1)N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCN1C2CCC1CC(O)C2
Temperature: 25 °C

Procedure:
8-Aza-bicyclo[3.2.1]octan-3-ol hydrochloride (5.1 g, 31.45 mmol)) and sodium carbonate (13.3 g, 125.8 mmol) are suspended in 150 ml of ethanol at room temperature. 2-Bromo-ethanol (4.4 ml, 62.9 mmol) is added dropwise within 20 minutes and the reaction mixture is refluxed for 15 hours. After cooling to room temperature the reaction mixture is evaporated under reduced pressure. The mixture is stirred with 200 ml of DCM and filtered. The clear filtrate is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and dried at high vacuum.
Reaction SMILES: [S-2].[Na+].[Na+].[C:4]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([S:27](C)(=O)=O)[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]3=[CH:12][C:11]=2[Cl:31])=[CH:6][CH:5]=1.O>CN(C=O)C>[C:4]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([SH:27])[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]3=[CH:12][C:11]=2[Cl:31])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(S)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium sulfide (65.6 mg, 0.840 mmol) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridine (144 mg, 0.280 mmol) in DMF (2 ml) and the mixture was stirred at room temperature for 3 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel Biotage™ 25S, eluting with 0-30% EtOAc/hexane to give title compound. LC-MS: calculated for C24H26ClN3OSSi 467.13 observed m/e: 468.12 (M+H)+ (Rt 1.38/2 min).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]([O:18]C)=O)[CH:15]=2)[N:9]=1)[NH2:3].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.C[O-].[Na+]>CO>[CH:20]1([NH:25][C:16]([C:14]2[CH:15]=[C:10]([C:8]3[N:9]=[C:5]([N:4]=[C:2]([NH2:1])[NH2:3])[S:6][CH:7]=3)[CH:11]=[N:12][CH:13]=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Reactant: NC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(N)=Nc1nc(-c2cncc(C(=O)NC3CCCC3)c2)cs1
Yield: 8.4 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3-yl)thiazole (2.0 g), cyclopentylamine (3.7 g) and 28% sodium methoxide methanolic solution (5 ml) in methanol (50 ml) was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (50 ml). The mixture was extracted with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The extract was dried over magnesium sulfate and then was evaporated. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(5-cyclopentylaminocarbonylpyridin-3-yl)-2-(diaminomethyleneamino)thiazole (0.2 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:19]
Reactant: O=CC1CCCCC1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(C1CCCCC1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of cyclohexanal (112 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[CH:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])C>C1COCC1>[CH2:12]([O:11][C:9]([NH:8][CH:7]([C:6]([OH:31])=[O:5])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cc1cccc(NS(C)(=O)=O)c1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(CC(NC(=O)OCc2ccccc2)C(=O)O)c1
Reaction time: 8 h

Procedure:
Add 1N NaOH (107 mL) to the product of Step A (14.80 g) in THF (100 mL) and stir overnight. Concentrate the THF solution in vacuo and partition between EtOAc (700 mL)/2N HCl (200 mL). Concentrate the dried (MgSO4) EtOAc solution in vacuo to a residue. Add CH2Cl2 (50 mL) and concentrate in vacuo (3 times) to give N-benzyloxycarbonyl-3-methanesulfonamido-D,L-phenylalanine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([N:23]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25][CH2:24]3)=[N:20][C:19]=2[CH:32]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([N:23]4[CH:29]5[CH2:28][CH2:27][N:26]([CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[N:20][C:19]=3[CH:32]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Product: FC(F)(F)c1ccc(-c2ccc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Yield: 54 %

Procedure:
The title compound was prepared according to the procedure in Example 44 using 4-trifluoromethyl-phenylboronic acid and 4-(5-bromo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane in 54% yield: MS (Cl) m/z 388.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2ccc(Cl)cc2C1=O
Yield: 39 %

Procedure:
A solution of 20.2 g of 6-chloro-1-indanone, 25 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 25 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 16 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 10.3 g (39%) of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [CH3:1][N+:2]#[C-:3].C([Li])CCC.[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13](OCC)=[O:14])[CH3:10].CC(O)=O>C1COCC1.CCOC(C)=O.CCCCCC>[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]1[O:14][CH:1]=[N:2][CH:3]=1)[CH3:10]
Reactant: [C-]#[N+]C
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(OCC)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
Prepared according to the procedure of Schollkopf (J. Am. Chem. Soc. 112 (10) 4070 (1990)). To a solution of methyl isocyanide (2.88 g, 0.0702 mol) in THF (50 mL) under argon at -78° C. was added dropwise n-butyllithium solution (1.6M in hexanes, 44 mL) over 15 mins. After stirring for an additional 20 mins at -78° C., a solution of ethyl diethoxyacetate (12.62 g, 0.0702 mol) in THF (15 mL) was added dropwise over 20 mins. The bath was allowed to warm to -30° C. over the next 2 hrs and the reaction was then stirred at 0° C. for 30 mins. The reaction was quenched at 0° C. with glacial HOAc (4.22 g, 0.0702 mol) and the solvent was removed by rotary evaporation in vacuo. The golden solid was partitioned with H2O (45 mL) and EtOAc (200 mL), and the aqueous extracted with EtOAc (2×200 mL). The combined organic was washed with said aq NaCl, dried over Na2SO4, and concentrated in vacuo to a brown oil. Chromatography on a 300 g SiO2 flash column with a gradient of EtOAc/hexane (10%, 15%, 20%) afforded the desired compound as a colorless liquid (7.46 g, 0.0436 mol, 62%): 1H NMR (CDCl3)δ1.25 (t, J=6.9 Hz, 6H), 3.56-3.70 (m, 4H), 5.62 (s, 1H), 7.26 (s, 1H), 7.86 (s, 1H). Mass spectrum: (M+H)+ =172.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3,3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:6][C:4]1([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])[O:13][CH2:12][CH2:11][O:5]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C)OCCO1
Yield: 91.5 %

Procedure:
A mixture of ethyl levulinate (58.35 g, 400.0 mmol), ethylene glycol (75.36 g, 1.21 mol), pyridinium p-toluenesulfonate (100 mg) and toluene (200 mL) was heated at reflux under a Dean Stark trap. The trap was emptied every 15 minutes during the reaction until approximately 200 mL of reaction volatiles had been removed. The remaining toluene was removed under reduced pressure, and the resulting oil was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was separated and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL); dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 68.9 g of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a light yellow oil.