Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][CH3:41])[CH2:38][CH2:39]2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CNC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CNC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-N-methylpiperidin-4-amine. MS (ESI): mass calcd. for C22H24FN5O2S, 441.16; m/z found, 442.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.21 (d, J=1.4, 1H), 8.12-8.09 (m, 1H), 7.96 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.32-7.30 (m, 1H), 7.28 (s, 1H), 3.49-3.42 (m, 2H), 3.10-3.01 (m, 1H), 2.63 (s, 3H), 2.54-2.42 (m, 2H), 2.00-1.92 (m, 2H), 1.47-1.35 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[CH2:17]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH2:33])[CH2:31]N)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C>[CH2:17]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][C@H:30]1[CH2:31][NH:16]/[C:13](=[N:12]\[C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])/[NH:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC[C@@H](N)CCCNC(=O)OCc1ccccc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCNC(=O)OCc3ccccc3)N2)nc1Cl
Temperature: 85 °C
Reaction time: 66 h

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (0.97 g, 3.72 mmol) is stirred in a three necked round bottom flask fitted with a bleach trap and condenser and ((S)-4,5-Diamino-pentyl)-carbamic acid benzyl ester (Intermediate S) (0.85 g, 3.38 mmol) in propan-2-ol (20 ml) is added. The reaction mixture is stirred at 85° C. for 66 hours. Purification by catch and release resin (SCX-2) followed by elution through a silica pad flushed with EtOAc, ethanol and MeOH yields the title compound as an orange foam; [M+H]+ 447.1
Reaction SMILES: [C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][C@@H:3]([CH2:4][CH3:5])[C@H:2]([C:1]([N:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][O:9][C:8]2=[O:18])=[O:6])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound from step 7b (490 mg, 2 mmol) was dissolved in methylene chloride (9 mL), and the solution was cooled to 0° C. and flushed with N2. N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (498 mg, 2.1 mmol) was added, the mixture was stirred for 20 minutes and trifluoroacetic acid (1M, 0.2 mL, 0.20 mmol) was added dropwise over 20 minutes with stirring at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 24 hours, then diluted with 50 mL of methylene chloride, washed with 10% aqueous K2CO3 and dried over Na2SO4. The solvent was removed and the residue was dried under vacuum (767 mg). The isomers were separated by medium pressure liquid chromatography on silica gel, eluting with 0.5% methanol/methylene chloride. The major isomer (3R,4R) (290 mg) was taken to the next step. MS m/z 379 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22]CC1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[F:1][C:2]([F:30])([F:31])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: FC(F)(F)COCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCOCCOCCOCCOCCOCCOCC(F)(F)F
Yield: 85.8 %

Procedure:
A stirred solution of the product of step (c) (16 g) and 10% palladium on carbon (1 g) in acetic acid:ethanol (1:1, 150 mL) was placed under an atmosphere of hydrogen at 20° C. for 24 hours. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to give the title compound (11 g). Mass spectrum m/z 382 [MNH4+]
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]([OH:17])=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[C:12]2=[O:18])=[C:7]1[C:28]([O:30][CH3:31])=[O:29].[CH3:32][NH2:33]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[CH2:19][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([OH:17])[C:15](=[O:16])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH3:32])[C:7]=2[C:28]([O:30][CH3:31])=[O:29])[C:12]1=[O:18]
Reactant: COC(=O)c1c2c(c(O)c(=O)n1CCCCCl)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CN
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CNCCCCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C

Procedure:
A mixture of methyl 2-(4-chlorobutyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.10 g, 0.21 mmol), methylamine in tetrahydrofuran (1 mL, 2M), and tetra-n-butylammonium iodide in tetrahydrofuran (5 mL) was heated at 60° C. for 3 days. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. This was used in the following step without further purification.
Reaction SMILES: BrC1C2C=NC=CC=2N(CCCS(C)(=O)=O)C=1C[N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:30][CH2:29]2)[C:20]1=[O:31].[Cl:32][C:33]1[CH:34]=[C:35]2[CH:41]=[C:40]([CH2:42]O)[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][F:48])[C:36]2=[CH:37][N:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]2[CH:41]=[C:40]([CH2:42][N:19]3[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]4[CH2:29][CH2:30]4)[C:20]3=[O:31])[N:39]([CH2:44][CH2:45][CH2:46][CH2:47][F:48])[C:36]2=[CH:37][N:38]=1
Reactant: OCc1cc2cc(Cl)ncc2n1CCCCF
Reactant: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Product: O=c1n(Cc2cc3cc(Cl)ncc3n2CCCCF)c2cnccc2n1C1CC1

Procedure:
3-((5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P11 was synthesized following the procedure reported for the synthesis of 3-((3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one P17, using (5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol 10 instead of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12. 1H NMR (360 MHz, DMSO-d6) δ ppm 0.87-0.97 (m, 2H), 1.02-1.13 (m, 2H), 1.57-1.78 (m, 4H), 2.99 (tt, J=6.9, 3.6 Hz, 1H), 4.30-4.43 (m, 3H), 4.49 (m, J=5.7, 5.7 Hz, 1H), 5.35 (s, 2H), 6.53 (s, 1H), 7.29 (d, J=5.5 Hz, 1H), 7.56 (s, 1H), 8.26 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 8.70 (s, 1H); m/z=414 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:9]1[CH2:14][CH2:13][CH:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Oc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A mixture of 2-aminophenol (1 g, 9.164 mmol), tetrahydropyran-4-one (1.099 ml, 11.913 mmol), and sodium triacetoxy-borohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred at r.t. for 16 h. The crude was filtered over diatomaceous earth, washed with DCM and the filtrate was evaporated in vacuo to yield D7 (0.69 g) that was used as such in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)Cl>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][N:41]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:40]
Reactant: CNCC(O)CO
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN(C)CC(O)CO)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 3-methylamino-1,2-propanediol hydrochloride (49 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 537 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]C(CC)C.C([N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O)(OC(C)(C)C)=O>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([S:2](/[CH:1]=[C:35]3/[NH:34][CH2:38][CH2:37][CH2:36]/3)(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[C:13]([O:20][CH3:21])[CH:14]=1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CCc1ccc(Oc2ccc(S(C)(=O)=O)cc2)c(OC)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)/C=C3\CCCN3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (0.44 mmol; 136 mg), in anhydrous THF (1 mL), under argon, cooled to 0° C., was added sBuLi (1.2M in cyclohexane; 0.89 mmol; 0.74 mL). After stirring for 30 min, a solution of 1-BOC-2-Pyrrolidinone (0.44 mmol; 0.08 mL) in anhydrous THF (1 mL) was slowly added. The reaction was stirred at 0° C. for 30 min. then slowly warmed up to room temperature overnight. The mixture was quenched with water and NH4Cl sat. (3 mL), extracted with ethyl acetate (2*3 mL), to yield a light yellow oil (164 mg), used without further purification.
Reaction SMILES: Cl.CCOCC.[CH2:7]([N:14]1[CH2:18][CH2:17][C:16]2([CH2:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][O:34]C4CCCCO4)=[O:32])[CH:24]=3)[O:19]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[CH2:18][CH2:17][C:16]2([CH2:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][OH:34])=[O:32])[CH:24]=3)[O:19]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NO
Reaction time: 1 h
Yield: 59.3 %

Procedure:
1 M HCl in Et2O (5 ml, 5 mmol) was added dropwise to a solution of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (172 mg, 0.37 mmol) in DCM (3 ml). After 1 h stirring a white solid precipitated, which was then filtered off, washed with DCM, dried under vacuum and collected to give 83 mg of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide as its hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:21]([C:26]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30](Cl)=[O:31])([CH2:24][CH3:25])([CH3:23])[CH3:22].O>C(O)(=O)C>[C:21]([C:26]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:31])([CH2:24][CH3:25])([CH3:23])[CH3:22]
Reactant: Nc1ccc(Nc2cccc(O)c2)cc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2ccc(Nc3cccc(O)c3)cc2)c(C(C)(C)CC)c1

Procedure:
To a solution of 11 g (0.055 mol) of 3-(4-aminoanilino)phenol in glacial acetic acid was added 4.6 g of anhydrous sodium acetate. During agitation at room temperature, the mixture was charged with 17.1 g (0.055 mol) of 2,4-di-tert-amylphenoxyacetyl chloride at a temperature below 30° C. After continuing the agitation for an additional 30 minutes at that temperature, the mixture was poured into iced water, and the deposited crystals were filtered, followed by recrystallization with methanol. The yield was 20 g and the melting point was 150°-152° C.
Reaction SMILES: [CH3:1][C:2]1([C:5]2O[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1.[OH-].[NH4+:13]>>[CH3:1][C:2]1([C:5]2[NH:13][CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: CC1(c2cc(=O)cco2)CC1
Agent: [OH-]
Product: CC1(c2cc(=O)cc[nH]2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-(1-methyl-cyclopropyl)-pyran-4-one (Step 1.6) (66.6 mmol) and a 28-30% aqueous solution of ammonium hydroxide (182 mL) was stirred for 1 h at 65° C. After cooling to rt, the reaction mixture was decanted to remove a dark brown solid and then concentrated. The residue was diluted with MeOH and re-concentrated (3×) to afford the title compound as a brown-orange solid. HPLC: tR=3.56 min (method B); LC-MS: tR=0.87 min, [M+H]+ 151; TLC: Rf=0.18 (9:1 CH2Cl2/MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 35 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 91%) as a white foam: [α]30589=−79.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C22H28N3O5SCl (M+H)+ 482.1511, observed 482.1511; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.79-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH22), 3.96 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=1.7 Hz, 1H, Ar), 7.51 (d, J=1.7 Hz, 1H, Ar), 7.62 (d, Jo=8.0 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.0 Hz, 1H, Ar), 10.85 (s, 1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][N:19]([CH3:21])[CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Yield: 97.3 %

Procedure:
To a stirred solution of 5.0 g of ethyl 2-chlorobenzoylacetate in 50 cc of benzene was added dropwise 5 cc of dimethylformamide dimethylacetal in 15 cc of benzene at room temperature. The resulting mixture was heated under reflux for 6 hours. After cooling, the solvent was distilled off to obtain 6.2 g of compound D. Yield: 97.3%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCCC(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (300 mg, 1.2 mmol) and triethylamine (260 μL, 1.8 mmol) in methylene chloride (50 mL) was added dropwise butyryl chloride (140 μL, 1.3 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 1 h and then washed with a dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 330 mg (86%) of the title compound as white crystals: mp 131-132° C.; [α]21D +24° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 315 (39, M+).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)ONC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl hydroxycarbamate (1 g, 5.98 mmol) in DCM (20 ml) is added triethylamine (0.6 g, 5.98 mmol) and 2,2-dimethylpropanoyl chloride (0.74 ml, 5.98 mmol). After 2 hours the reaction mixture is quenched by the addition of water (10 ml) and the organics are extracted into DCM (2×20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil which is used without any further purification. (1.6 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (1H, br. s.), 7.29-7.43 (5H, m), 5.22 (2H, s), 1.30 (9H, s).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH:17]([OH:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:18]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1C(O)CCC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1C(=O)CCC2
Yield: 97.1 %

Procedure:
To a solution of 5.49 g (19.4 mmol) of material prepared in Example 11 in 250 mL of methylene chloride was added 8.35 g (39 mmol) of pyridiniumchlorochromate. After 3 hours the reaction mixture was diluted with ether and passed through a plug of fluorosil to give 5.3 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][C:60]=1[CH3:66]>O1CCCC1>[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:22])=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:61][C:60]=1[CH3:66]
Reactant: CN(C)CC#Cc1ccc(/C(=C/CO)c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (407 mg, 1.397 mmol) in dry tetrahydrofuran (40 mL) was added tributylphosphine (0.50 ml, 2.79 mmol). To the mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (703 mg, 2.79 mmol) and after 10 min. (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (301 mg, 1.536 mmol) was added. After stirring for 1.5 hr at 0° C. the mixture was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methylphenoxy)-acetic acid methyl ester as an oil.