Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:5]1[C@@H:10]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][C@H:8]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:6]12[CH3:7])[C@:25]1([CH3:26])[C@H](CCC(=O)[CH2:24]1)CC3)(=O)C.[OH2:31]>N1CCCCC1.C(O)=O>[N:11]1([C@H:10]2[CH2:24][C@@:25]3([CH3:26])[C@@H:6]([CH2:29][CH2:28][C@@H:17]4[C@@H:27]3[CH2:28][CH2:29][C@@:6]3([CH3:7])[C@H:8]4[CH2:9][C@H:10]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C@@H:5]3[OH:31])[CH2:8][CH2:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CCC(=O)C[C@]4(C)[C@H]3CC[C@@]21C
Reactant: O
Solvent: O=CO
Solvent: C1CCNCC1
Product: C[C@]12C[C@H](N3CCCCC3)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Temperature: 25 °C

Procedure:
A solution of 17β-acetyloxy-16β-(1-piperidinyl)-5α-androstan-2-one (8.24 g) in piperidine (36 ml) and formic acid (12 ml) was heated at reflux temperature under a nitrogen (oxygen-free) atmosphere for 4.5 h. When the solution had cooled to room temperature, water (50 ml) was added to precipitate the product, which was filtered off and washed well with water (300 ml). A solution of the crude product in diethyl ether (60 ml) was washed with water (2×100 ml), dried (MgSO4) and evaporated to dryness. Crytsllisation of the residue from acetone afforded 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol (4.17 g), m.p. 176°-181° C.; [α]D +41.3° (c 0.59 in CHCl3).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>O1CCCC1>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: COCCCCCCCO
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCOCCCCCCCOC
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.2 %

Procedure:
Sodium hydride (665 mg, 17 mmol, washed three times with hexane) was treated with the title product of Example 3 (2.0 g, 14 mmol) in 90 mL of tetrahydrofuran at reflux for one hour. A solution of 5-bromopentene (2.0 g, 14 mmol) in 50 mL of tetrahydrofuran was added dropwise and refluxing continued for 20 hours. After cooling to room temperature, 50 mL of water was added, the layers separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude residue on silica gel using 50--50 ethyl acetate-heptane as eluant gave the title compound (485 mg) as a yellow oil and the structure verified by NMR.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]([CH2:15][CH3:16])=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1.[OH-].[Na+]>O.O[PH2]=O.C([O-])(O)=O.[Na+]>[CH2:15]([C:8]1[S:7][CH:6]=[N:10][C:9]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:16]
Reactant: CCc1sc(N)nc1C(=O)OC
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CCc1scnc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The following diazotization step was adapted from Barton, A.; Breukelman, S. P.; Kaye, P. T.; Meakins, G. D.; Morgan, D. J. J. C. S. Perkin Trans I 1982, 159-164: A solution of NaNO2 (150 mg, 2.17 mmol) in water (1.0 mL) was added dropwise to a stirred, cold (0° C.) solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg, 1.0 mmol) in 50% H3PO2 (3.2 mL). The mixture was stirred at 0° C. for 1 h and allowed to warm up to room temperature where it stirred further for 2 h. After recooling to 0° C., the mixture was treated slowly with a solution of NaOH (85 mg) in water (10 mL). The mixture was then diluted with saturated NaHCO3 solution and extracted twice with ether. The organic layers were combined, dried over MgSO4 and concentrated to give methyl 5-ethylthiazole-4-carboxylate (i.e. Cap-173, step a) (134 mg, 78%) as an orange oil (85% pure) which was used directly in the next reaction. Rt=1.58 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C7H10NO2S: 172.05; found: 172.05.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:21]=[C:20]1[NH2:31])=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCCl.ClCCl>[C:12]([O:16][C:17]([N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:21]=[C:20]1[NH2:31])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)O)nc1N
Temperature: 60 °C

Procedure:
General Aminolysis Procedure: To a stirring 0° C. solution of amine (0.704 mmol) in anhydrous 1,2-dichloroethane (1 mL) was added drop-wise a 2M solution of AlMe3 in PhCH3 (0.351 mL, 0.704 mmol). The solution was stirred for 10 min before the addition of 2-amino-4-(3-methoxycarbonyl-propyl)-imidazole-1-carboxylic acid tert-butyl ester 18 (100 mg, 0.352 mmol) in several portions. Once dissolution was complete, the reaction was warmed to 60° C. and stirred until completion as evident by TLC analysis. The reaction was then cooled back down to 0° C. before being diluted with dichloromethane (5 mL) and quenched with water (1 mL). The resulting viscous solution was warmed to ambient temperature and Celite® diatomite was added. After stirring for 5 min, the mixture was filtered and the filtrate washed with brine (2×3 mL), dried (Na2SO4), and evaporated to dryness. The crude product was purified via flash column chromatography (2-10% MeOH/CH2Cl2) to afford pure product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>>[F:27][C:28]([F:34])([F:33])[S:29]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCN(S(=O)(=O)C(F)(F)F)CC2)c(F)c1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was treated with trifluoromethanesulfonyl chloride essentially as in Example 76. Crude material was purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (444 mg). MS (ESP): 476 (MH+) for C18H17F4N5O4S
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C@H:19]2[CH2:23][C@@H:22]([C:24](O)=[O:25])[C@H:21]([C:27](=[O:32])[NH:28][CH2:29][C:30]#[N:31])[CH2:20]2)(=[O:18])=[O:17])=[C:12]([CH3:33])[CH:11]=1>>[C:30]([CH2:29][NH:28][C:27]([C@@H:21]1[CH2:20][C@@H:19]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[CH3:33])(=[O:17])=[O:18])[CH2:23][C@H:22]1[C:24]([N:4]1[CH2:5][C@@H:6]([CH3:8])[O:7][C@@H:2]([CH3:1])[CH2:3]1)=[O:25])=[O:32])#[N:31]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1cc(Cl)ccc1S(=O)(=O)[C@H]1C[C@@H](C(=O)O)[C@H](C(=O)NCC#N)C1
Product: Cc1cc(Cl)ccc1S(=O)(=O)[C@@H]1C[C@@H](C(=O)NCC#N)[C@H](C(=O)N2C[C@@H](C)O[C@@H](C)C2)C1

Procedure:
The title compound was prepared in analogy to example 11 using cis-2,6-dimethymorpholine instead of 2-oxa-6-aza-spiro[3.3]heptan and (1R,2R,4R)-4-(4-chloro-2-methyl-benzenesulfonyl)-2-(cyanomethyl-carbamoyl)-cyclopentanecarboxylic acid instead of (1R,2R,4R)-4-benzenesulfonyl-2-(1-cyano-cyclopropylcarbamoyl)-cyclopentanecarboxylic acid. Colorless oil. MS: 480.0 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:27][CH:28]1[CH2:30][CH2:29]1)(=[O:25])[NH2:26]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=409.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]([CH:12]([OH:14])[CH3:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].C(OC=C)(=O)CCCCCCCCCCC>>[CH2:1]([CH:4]([C@@H:12]([OH:14])[CH3:13])[C:5]([O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC(C)(C)C)C(C)O
Agent: C=COC(=O)CCCCCCCCCCC
Product: C=CCC(C(=O)OC(C)(C)C)[C@H](C)O
Temperature: 35 °C
Reaction time: 216 h
Yield: 45.3 %

Procedure:
A mixture of 15.0 g of t-butyl 2-allyl-3-hydroxybutanoate as racemate, 13.7 g of vinyl laurate, and 8.0 g of Lipase P (trade name, supplied by Amano Pharmaceutical Co., Ltd.) was stirred at 35° C. for 9 days. After stopping the reaction, the enzyme was removed by filtration and the enzyme was washed with n-heptane on a filter paper. The filtrate was distilled away and the residue was subjected to vacuum distillation to give 6.8 g of t-butyl (3S)-2-allyl-3-hydroxybutanoate of the following formula, b.p. 79°-85° C. (5.0 mm Hg), [α]D30 =+5.0° (C=1.35, CHCl3). ##STR79## The NMR chart is shown in FIG. 9.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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.CN(C)C(=O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1F
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: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1F
Temperature: 110 °C
Reaction time: 6 h
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-4-fluoronitrobenzene (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylacetamide (50 mL), and 2.0 M aqueous potassium carbonate (10 mL) under argon was added tetrakis(triphenylphosphine)palladium (0) (0.394 g, 0.3 mmol). The mixture was stirred at 110° C. for 6 hrs. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100 mL) and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% methylene chloride/hexanes) to afford a light yellow oil (1.5 g, 94%). 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, 1H, J=9.0, 5.1 Hz), 7.44 (m, 1H), 7.34 (td, 1H, J=7.5, 2.1 Hz), 7.31-7.10 (m, 4H).
Reaction SMILES: [BH4-].[Li+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21](OC)=[O:22])[CH2:17][CH2:16]3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[OH-].[Na+]>O1CCCC1>[OH:22][CH2:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:3][N:4]=[CH:5]3)=[O:13])[CH2:16][CH2:17]1
Reactant: COC(=O)C1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1CCC(CO)CC1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Lithium borohydride (10.0 mg, 0.459 mmol) was added to a solution of the methyl 4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexanecarboxylate (30.0 mg, 0.0951 mmol) obtained in Example 186 in tetrahydrofuran (3.0 ml) at room temperature, and the resulting mixture was stirred for 2 hours with heating under reflux while maintaining the temperature. A 1N aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and then was concentrated to dryness. The resulting crude product residue was stirred in methanol (3.0 ml) for another 1 hour with heating under reflux while maintaining the temperature. The resulting mixture was concentrated to dryness and purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-(4-hydroxymethylcyclohexyl)-1H-indazole-5-carboxamide (23.5 mg, 91%).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC(O)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and Cul (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[C:7]#[N:8])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO.Cl>C1COCC1.O>[C:1]([C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[CH2:7][NH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1CN
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 2-tert-butyl-5-nitrobenzonitrile (612 mg, 3.0 mmol) in THF (10 mL) was added a solution of BH3.THF (12 mL, 1M in THF, 12.0 mmol) under nitrogen. The reaction mixture was stirred at 70° C. overnight and cooled to 0° C. Methanol (2 mL) was added followed by the addition of 1N HCl (2 mL). After refluxing for 30 min, the solution was diluted with water and extracted with EtOAc. The aqueous layer was basified with 1N NaOH and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over Mg2SO4. After removal of solvent, the residue was purified by column chromatography (0-10% MeOH—CH2Cl2) to give (2-tert-butyl-5-nitrophenyl)methanamine (268 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=2.7 Hz, 1H), 7.99 (dd, J=8.8, 2.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 4.03 (s, 2H), 2.00 (t, J=2.1 Hz, 2H), 1.40 (s, 9H); HPLC ret. time 2.05 min, 10-100% CH3CN, 5 min gradient; ESI-MS 209.3 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22](OC)=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[C:3]([CH:22]=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution (20 mL) of methyl 4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (920 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (6.3 mL) of diisobutylaluminum hydride was added dropwise, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (20 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (110 mg), N-methylmorpholine N-oxide (554 mg) and molecular sieves 4A powder (2.0 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give 4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde as a brown oil (yield 461 mg, 55%). 4-Methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (460 mg) was dissolved in methanol (25 mL), and methylammonium chloride (952 mg) and sodium cyanoborohydride (266 mg) were added. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→ethyl acetate). The obtained oil was dissolved in ethyl acetate (5 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. The precipitated crystal was collected by filtration, and vacuum-dried to give the title compound as a colorless solid (yield 196 mg, 37%).
Reaction SMILES: C(OC(=O)[CH2:5][N:6]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7](=[O:28])[CH:8]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)C>C(Cl)Cl.Cl.O1CCOCC1.ClC(Cl)C>[CH2:29]([N:6]1[CH2:5][C:21](=[O:22])[NH:20][C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:7]1=[O:28])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)C(Cc1ccc(C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(C(F)(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred solution of [benzyl-[2-tert-butoxycarbonylamino-3-(4-trifluoromethyl-phenyl)-propionyl]-amino]-acetic acid ethyl ester (1.5 g, 2.95 mmol) in dry CH2Cl2 (50 mL), 4N HCl in dioxane (25 mL, Aldrich) was added and stirred at room temperature for 2 h and then conc in vacuo. The r×n product was partitioned between CH2Cl2 (100 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, dried over MgSO4 and conc in vacuo to give a clear oil. The oil was diluted in dichloroethane (50 mL) and stirred in 60° C. bath for 2 h to yield 1.02 g (95%) of the product as a off white solid. MS (ESI) 363 (M+H).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[C:8]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:19][CH:20]([CH3:22])[CH3:21])[CH:17]=3)[CH2:12][CH2:11][N:10]2[C:25]=1[C:26]([OH:28])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN1C(=O)CCC1.O>[C:1]([N:5]1[C:26](=[O:28])[C:25]2[N:10]3[CH2:11][CH2:12][C:13]4[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][C:18]=4[C:9]3=[C:8]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:7]=2[CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CNC(C)(C)C)c(C(=O)O)n1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)C3
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A mixture of 55 mg of 15e and 100 μl of DiPEA in 0.5 ml of THF and 0.1 ml of NMP was treated with 50 mg of HATU. The mixture was stirred overnight and then diluted with 5 ml of water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and the crude material was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate, to provide 27 mg of 15f. MS-ESI:
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][C:5](=O)[C:4](Cl)([CH2:9][C:10]#[C:11][CH2:12][CH3:13])[C:3]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:5][C:6]1[CH2:7][CH2:2][C:3](=[O:15])[C:4]=1[CH2:9][C:10]#[C:11][CH2:12][CH3:13]
Reactant: CCC#CCC1(Cl)C(=O)CCC(C)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCC#CCC1=C(C)CCC1=O

Procedure:
4-Methyl-2-chloro-2-(pent-2-ynyl)-cyclohexane-1,3-dione (3 g; 0.015 Mole) in dry xylene (15 ml) was allowed to reflux in the presence of anhydrous sodium carbonate (1.6 g; 0.015 Mole) until gas evolution ceased (3 h.). The reaction mixture was then washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. Distillation afforded 3-methyl-2-(pent-2-ynyl)-cyclopent-2-enone (dehydrojasmone); b.p. 80°-90°/0.001 Torr; 850 mg (35 %).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[CH2:28][CH2:27][C:26](=O)[NH:25][C:24]=3[N:23]=[C:22]([CH:31]([CH3:33])[CH3:32])[C:21]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[N:23]=[C:22]([CH:31]([CH3:32])[CH3:33])[C:21]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCC(=O)N2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCN2
Temperature: 5 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of Red-Al (185 mL, 0.613 mol, 65 weight % in toluene) in anhydrous toluene (250 mL) was cooled to 5° C. A solution of Part B methyl 4-(4-fluorophenyl)-2-isopropyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate (100. g, 0.292 mol) in anhydrous THF (500 mL) was added over 30 min. The reaction mixture was stirred at 5° C. for 3 h. The reaction was quenched by adding a solution of potassium sodium tartrate (10%, 200 mL) slowly. After toluene (100 mL) was added, the two phases were separated. The organic phase was washed with NaH2PO4 (5%, 200 mL), followed by H2O (200 m]L), and brine (200 m]L), dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the obtained solid dried at 40° C. under vacuum to provide 88.27 g (92% yield) of methyl 4-(4-fluorophenyl)-2-isopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate as an off-white solid: mp 168-170° C.; 1H NMR (400 MHz, CDCl3) δ 1.23 (d, J=7.0 Hz, 6H), 1.79 (m, 2H), 2.37 (t, J=6.4 Hz, 2H), 2.99 (m, 1H), 3.39 (m, 2H), 3.40 (s, 3H), 5.07 (s, 1H), 7.03-7.16 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 169.5, 162.9, 160.4, 155.7, 146.1, 133.8, 129.9, 117.9, 115.1, 114.9, 110.6, 52.0, 41.9, 33.4, 25.3, 23.0, 22.0; HRMS calcd for C19H22FN2O2 (M+1) 329.1665, found 329.1666.