Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:29].O>C(O)C>[ClH:29].[C:21]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2-c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above ester (2.0 g, 5.7 mmol) was dissolved in ethanol (25 ml) and 4N sodium hydroxide (6.4 ml) was added. The mixture was stirred at ambient temperature for 3 h. Excess concentrated hydrochloric acid was added followed by a small portion of water. The mixture was concentrated in vacuo and dichloromethane (100 ml) and water (25 ml) were added. The phases were separated and the organic phase was dried (Na2S4). The solvent was evaporated in vacuo to give a solid residue which was recrystallised from acetone to give 1.2 g of title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C-:37]>CN(C)C=O.C(O)(=O)C.CCCCCC>[Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11]3[N:12]([CH:37]=[N:36][C:38]=3[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Br)c2C(=O)N2CC[C@@H]12
Reactant: [C-]#[N+]CC(=O)OCC
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
30 g (106.7 mmol) of (S)-5-bromo-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 50 ml of N,N-dimethylformamide, treated at -20° with 5.6 g (128 mmol) of sodium hydride dispersion (55% in oil) (washed with hexane) and deprotonized at -30° to -20° for 30 minutes. A solution of 43 g (160 mmol) of diphenyl chlorophosphate in 25 ml of N,N-dimethylformamide was added thereto at -60° and the mixture was stirred at max. -45° for 35 minutes. In the meanwhile and separately, 12 g (107 mmol) of potassium tert.-butylate were dissolved in 20 ml of N,N-dimethylformamide and treated at -60° with 12.1 g (107 mmol) of ethyl isocyanoacetate. The reaction mixture is added dropwise to the deprotonized ethyl isocyanoacetate at max. -65° within 11/4 hours. The mixture was stirred for 1 hour in an acetone/dry-ice bath, neutralized with 10 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.21), dried over magnesium sulfate and evaporated to dryness. By recrystallization of the residue from ethanol and ether there were obtained 23.7 g (49%) of ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]-benzodiazepine-1-carboxylate of m.p. 184°-185°.
Reaction SMILES: [Br-:1].C([O:6][C:7]([CH2:9][CH2:10][CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2)=[O:8])(C)(C)C.Br>C(Cl)Cl>[Br-:1].[C:7]([CH2:9][CH2:10][CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:13]2)([OH:8])=[O:6]
Reactant: CC(C)(C)OC(=O)CCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Agent: Br
Agent: [Br-]
Solvent: ClCCl
Product: O=C(O)CCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 163] (0.2 g, 0.41 mmol) in methylene chloride (1.5 ml) under an argon atmosphere at room temperature is added hydrobromic acid (33% in acetic acid, 0.36 ml). After stirring at room temperature for 30 minutes, concentration is followed by dissolution in water/acetonitrile and stirring for a further 30 minutes. Concentration then gives the title product.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[CH:4]([CH:8]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])[O:3]1.CCN(C(C)C)C(C)C.CN(C([O:40][N:41]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C[N:60]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NO>O1CCOCC1>[OH:40][NH:41][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([CH2:9][CH2:10][CH2:11][CH3:12])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH2:60])=[O:22])=[O:14]
Reactant: CCCCC(C(=O)N1CCC[C@H]1C(=O)O)C1OC(C)(C)OC1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(N)=O)[C@H](O)C(=O)NO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-carboxy-pyrrolidin-1-ylcarbonyl)pentane F-6 (50 mg) in dioxane (1 mL) was added an amine RNH2 (1 equivalent), DIEA (2.5 equivalents) and HATU or PyBOP (1 equivalent) and the solution stirred for 4 h. The reaction was then cooled to 0° C., 50% aqueous hydroxylamine was added (400 μL), and the solution stirred at 4° C. for 8 hours. The crude reaction mixture was then purified by preparative reverse-phase (C18) HPLC to afford N-hydroxy-3-(R)-n-butyl-3-[2-(S)-aminocarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-hydroxypropionamide F-7.
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][OH:24])=[O:17])=[C:14]([N+:29]([O-])=O)[C:13]=1[O:32][CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Ni]>[NH2:29][C:14]1[C:13]([O:32][CH3:33])=[C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:26]([O:27][CH3:28])=[CH:25][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][OH:24])=[O:17]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OCc1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Hydrazine hydrate (2.31 g, 72.2 mmol) was added dropwise to a solution of 125 (6.01 g, 14.4 mmol) in methanol (60 mL) gently refluxing over Raney nickel (1.1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the produc as a brown oil (3.97 g, 10.3 mmol, 73%): 1H NMR (270 MHz, CDCl3) δ 1.6-2.2 (m, 4H), 3.5-3.8 (m, 4H), 3.8 (s, 3H), 3.9 (s, 3H), 4.4 (br s, 1H), 5.1 (s, 2H), 6.6 (s, 1H), 7.3-7.6 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ 171.5, 144.9, 143.5, 141.9, 137.5, 134.6, 128.6, 128.5, 128.3, 128.2, 128.0, 115.1, 107.3, 75.1, 66.9, 61.0, 60.6, 60.4, 56.9, 50.9, 28.5, 24.9, 21.1, 14.2.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][C:16]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=C([N+]([O-])=O)C=1Cl)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][N:2]=2)[C:16]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:15][C:14]=1[CH3:29])=[O:12])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(C)nc(N2CCCCC2)c([N+](=O)[O-])c1Cl
Product: CCOC(=O)c1c(C)nc(N2CCCCC2)c2nccnc12

Procedure:
By substituting piperidine for N-methylpiperazine in Example 1 b and the resulting 4-chloro-2-methyl-6-(1-piperidinyl)-5-nitropyridine-3-carboxylic acid ethyl ester is processed according to the procedure in Example 1 c-e, 7-methyl-5-(1-piperidinyl)pyrido[3,4-b]pyrazine-8-carboxylic acid ethyl ester is obtained, m.p. 73°-74° (petroleum ether).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](#[N:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22]>CC(O)C>[C:19]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:27]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1ccccc1C#N
Yield: 64.6 %

Procedure:
The reaction mixture of 102.0 mg (0.37 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 53.0 mg (0.44 mmol) of anthranilonitrile in 2.0 mL of 2-propanol was refluxed for 2 h and cooled down. The yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 40° C. overnight to give 84.5 mg (65%) of the title compound.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43](Cl)=O>C1(C)C=CC=CC=1>[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43]1[O:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C(Cl)CCC(F)(F)F
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(CCC(F)(F)F)cc2c1
Reaction time: 2 h

Procedure:
A suspension of 4.0 g (8.1 mmol) of (2-hydroxy-5-nitrophenyl) methyltriphenylphosphonium bromide in 50 ml of toluene is heated to reflux, then 5.1 ml (36 mmol) of triethylamine and 1.9 g (12 mmol) of 4,4,4-trifluorobutyryl chloride are added. The mixture is stirred for 2 hours, then it is filtered and the filtrate is concentrated under reduced pressure. By chromatography of the residue on a silica column using a 0-30% mixture of dichloromethane in cyclohexane, 1.1 g of product are obtained. Melting point: 70-71° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:40]=[CH:41][CH:42]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[F:39][C:36]1[CH:35]=[CH:34][C:33]([N:14]2[C:15]3([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:16](=[O:17])[N:12]([CH2:11][C:10]3[CH:9]=[C:8]([CH:42]=[CH:41][CH:40]=3)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.82 g, 1.43 mmol) in methanol (10 mL), was added 10 wt % palladium on carbon (0.2 g). After stirring under hydrogen at room temperature and atmospheric pressure for 4 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.62 g, 99%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[O:15][N:14]=[C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]=12.C([O:24][C:25](=O)[C:26](=[O:33])[CH2:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[O:29])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:17]4[CH:18]=[CH:19][C:12]5=[N:11][O:15][N:14]=[C:13]5[CH:16]=4)[C:27]([C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[C:26]([OH:33])[C:25]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc2nonc2c1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: CCO
Product: O=C(C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2nonc2c1)C1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:38][CH2:39][C@@H:40]([N:50]=[N+]=[N-])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH2:20]([O:38][CH2:39][C@@H:40]([NH2:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@H](CCCCCCCCC)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC[C@@H](N)CCCCCCCCC

Procedure:
Triphenyl phosphine (4.54 g, 17.3 mmol) and the azide (8 g, 17.3 mmol) were dissolved in THF. The reaction mixture was split into 3 μw tubes and irradiated at 120° C. for 1 hour each. Considerable pressure built in each tube so care should be noted. LC indicated 100% conversion to phosphoimine intermediate. To each tube was added ˜3 mL of water and the reaction irradiated for 10 min at 120° C. The reaction mixtures were combined and concentrated to remove organic solvent. Hexane was added to precipitate phosphine oxides which were filtered through cintered glass funnel. The solvent was then removed in vacuo. The crude product was purified using HPLC with 30 min run and 60-100% water/acetonitrile gradient. The combined HPLC fractions were neutralized with sodium bicarbonate evaoporated in vacuo. The pure product was partitioned between water/hexanes. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to afford (2S)-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]undecan-2-amine (2). 1H NMR (CDCl3, 300 mHz) δ 0.88-0.87 (m, 6H), 1.25-1.29 (s, 32H), 1.54-1.54 (m, 2H), 2.03-2.05 (m, 4H), 2.23 (s, 2H), 2.75-2.76 (m, 2H), 2.96 (m, 1H), 3.13-3.18 (m, 1H), 3.38-3.45 (m, 3H), 5.31-5.38 (m, 4H); LC/MS (m+1) 436.7.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([N:19]([C:28](=[O:35])[CH2:29][C:30]([O:32][CH2:33]C)=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=O)C.C[O-].[Na+].CO>>[CH3:33][O:32][C:30]([C:29]1[C:28](=[O:35])[N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:7]2[C:6](=[CH:14][C:13]3[C:8]2=[CH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:12]=3)[C:4]=1[OH:3])=[O:31]
Reactant: CCOC(=O)CC(=O)N(Cc1ccc(F)cc1)n1c(C(=O)OCC)cc2ccc(C(F)(F)F)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)c2cc3ccc(C(F)(F)F)cc3n2n(Cc2ccc(F)cc2)c1=O
Yield: 22.3 %

Procedure:
A mixture of 1-[(2-ethoxycarbonyl-acetyl)-(4-fluoro-benzyl)-amino]-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.32 mmol) in 0.5 N NaOMe/MeOH solution (2.5 mL, 1.25 mmol) was refluxed overnight. After cooled, the mixture was concentrated, and the residue was dissolved in water (80 mL), acidified to pH=3-4 using 1 N HCl solution, extracted with EtOAc (2 times). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography (50%-100% EtOAc/DCM then 2%-10% MeOH/DCM) to provide the title compound 31 mg. ESI (m/z): 435.14 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]([O:12][CH3:13])([O:10][CH3:11])[CH3:9].[BH4-].[Li+]>C1COCC1>[CH3:13][O:12][C:8]([O:10][CH3:11])([CH3:9])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:14])[CH2:3][OH:2]
Reactant: COC(=O)[C@@H](C)CCCC(C)(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(CCC[C@H](C)CO)OC
Temperature: 55 °C

Procedure:
A solution prepared by dissolving 5.13 g (content 96.2%, 22.6 mmol) of (S)-6,6-dimethoxy-2-methylheptanoic acid methyl ester in 10 g of THF was dropped at room temperature into a suspension prepared by adding 15 g of THF to 0.65 g (content 90%, 26.6 mmol) of lithium borohydride. Next, the reaction mixture was heated up to 55° C., and reacted at the same temperature for 9 hours, to give (S)-6,6-dimethoxy-2-methylheptanol. Next, into this reaction mixture, 7.32 g of methanol was dropped at room temperature over a period of about 1 hour, then, the mixture was stirred at the same temperature for 4 hours. Next, into this reaction mixture, 25.08 g of 5% hydrochloric acid was dropped at room temperature, and the mixture was further stirred at the same temperature for 30 minutes. This solution was extracted twice with 15 g and 12.5 g of methyl isobutyl ketone, then, the resultant organic layers were combined, and washed twice with 10 g of 15% sodium carbonate aqueous solution, to obtain 51.7 g of a MIBK solution containing 2.95 g (yield 89.5%) of (S)-7-hydroxy-6-methylheptan-2-one. The solvent was distilled off under reduced pressure to obtain 3.68 g of a coarse product of (S)-7-hydroxy-6-methylheptan-2-one as a pale yellow oil. This may be used in the subsequent reaction without purification, or if necessary, may be purified by distillation under reduced pressure. A part of the resultant coarse product of (S)-7-hydroxy-6-methylheptan-2-one was purified by distillation, to obtain (S)-7-hydroxy-6-methylheptan-2-one in the form of colorless oil. [α]D27=−13.9° (5.03% in EtOH)
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(N(CC)CC)C.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: C=Cc1ccccc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12
Yield: 74.4 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were placed in a screw capped sealable tube with a stir bar. The mixture was warmed to 60° and then 200 mg of styrene was added and the vessel was flushed with argon. The vessel was then capped and heated at 120° for 24 h. The reaction mixture was cooled, diluted with ethyl acetate and filtered and the filtrate was concentrated under vacuum. The residue was dissolved in chloroform and washed twice with water. The organic layer was dried, filtered and evaporated under vacuum to obtain 400 mg of residue, which was recrystallized from ethyl acetate to obtain the desired product. m.p. 173°-175°. FDMS m/e=331.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:3][C:4]([OH:6])=[O:5].Cl.O1CCOC[CH2:19]1>CO>[NH2:1][CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH3:19])=[O:5]
Reactant: Cc1ccc(SCCC(N)CC(=O)O)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)CC(N)CCSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-5-[(4-methylphenyl)thio]pentanoic acid (1.0 g) [prepared according to U.S. Pat. No. 5,409,939] in methanol (50 ml) was treated with 4N HCl/dioxane (10 ml). The reaction was stirred overnight at room temperature. The excess solvent was removed under reduced pressure. Methyl 3-amino-5-[(4-methylphenyl)thio]pentanoate (1.1 g) as a white solid was obtained. MS and 1H-NMR were consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH2:3][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:5][OH:6].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:6][CH2:5][C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:3][C:2]([Cl:14])([Cl:15])[Cl:1])(=[O:26])=[O:25]
Reactant: OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(O)(CC(Cl)(Cl)Cl)c1ccccc1

Procedure:
4,4,4-Trichloro-2-phenyl-2-hydroxybutanol (160 grams; 0.60 mole) was mixed with about 2000 milliliters (ml.) of methylene chloride and triethylamine (63.6 grams; 0.63 mole) was added thereto. The resulting mixture was cooled in an ice-methanol bath to a temperature of about -6 to about -8° C. Methanesulfonyl chloride (69 grams; 0.60 mole) in about 250 ml. of methylene chloride was added dropwise to the stirred reaction mixture over a period of about 45 minutes. The reaction mixture temperature was maintained below about 0° C. during the addition and, following the completion of the methanesulfonyl chloride solution; the reaction mixture temperature was allowed to come to room temperature. Thereafter, the reaction mixture was washed with water (four - 700 ml. portions), then with 700 ml. of a 10% sodium carbonate solution, and finally with another 700 ml. portion of water. An additional 600 ml. of methylene chloride was added to the organic product layer which was then dried over sodium sulfate. The volume of the organic product mixture was reduced to about 400 ml. by evaporation of the carrier medium in vacuo. The resulting white product precipitate was obtained by filtration. As a result of such operations, the desired 4,4,4-trichloro-2-phenyl-2-hydroxybutyl 1-methanesulfonate product was obtained as a white crystalline solid having a melting point of 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)CCCCCCCCCCC.C(N(CC)CC)C.CCOCC>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])[C:15](=[N+:41]=[N-:42])[C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)C(=[N+]=[N-])C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 0.51 g (1.8 mmol) of 1-(tert-butoxycarbonyl)-4-(1,3-dioxo-but-1-yl)piperidine (from Step B) and 0.65 g (1.8 mmol) of para-dodecylbenzenesulfonyl azide (Syn. Comm. 1981, 11, 947–956) in CH3CN at 0° C. was treated with 0.26 mL (1.8 mmol) of triethylamine. The reaction was warmed to rt and stirred for 4.5 hours. The reaction was poured into 100 mL of Et2O and washed with 100 mL of H2O, 100 mL of 2 N HCl and 100 mL of brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 9:1 v/v of hexanes/acetone to afford the title compound as a light yellow oil: RF: 0.33 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.46 (s, 9H), 1.57–1.76 (m, 4H), 2.42 (s, 3H), 2.82 (m, 2H), 3.24 (m, 1H), 4.14 (m, 2H).