Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH:10]([NH:12][C:13]1[NH:17][N:16]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[N:14]=1)=[O:11].S(Cl)(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([C:15]2[N:14]=[C:13]([NH:12][CH:10]=[O:11])[NH:17][N:16]=2)(=[O:19])=[O:20])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=CNc1nc(S(=O)(=O)Cl)n[nH]1
Solvent: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(NS(=O)(=O)c2n[nH]c(NC=O)n2)ccc1Br

Procedure:
A mixture of 4-bromo-3-methylaniline (3.72 g, 20 mmol) and 5-formamido-1,2,4-triazole-3-sulfonyl chloride (2.10 g, 10 mmol) in 50 mL of acetonitrile was refluxed under nitrogen until all of the sulfonyl chloride has been consumed (approximately 1 hr). The mixture was cooled and filtered. The precipitate was dispersed in 200 mL of 1% aqueous HCl solution and filtered again to yield the title compound as a white solid, 3.0 g (84%) m.p. 282°-284° C., M+ -Br at 280.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([F:28])[C:22]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:29])C1C=CC=CC=1>[Pd]>[F:28][C:21]1[C:22]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:29]
Reactant: O=C1c2cccc3c(N4CCCC4)c(F)cc(c23)C(=O)N1OCc1ccccc1
Agent: [Pd]
Product: O=C1c2cccc3c(N4CCCC4)c(F)cc(c23)C(=O)N1O
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A solution of 28 mg (0.72 mmol) of 2-benzyloxy-5-fluoro-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (from Example Z3) was hydrogenated over 15 mg of 10% Pd/C at room temperature and atmospheric pressure for 2 hours. Pd/C was removed by filtration, and the filtrate was evaporated to yield 10 mg of the title compound, mp 224-226° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si]([N-:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(C)C.[Na+].C1(=O)C2C=CC3C(=CC=CC=3)C=2C=CC1=O.C1(=N)C2C=CC3C(=CC=CC=3)C=2C=CC1=N.[Cl-]>>[CH3:23][Si:22]([N:21]=[C:13]1[C:12](=[N:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:25])[CH3:24]
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N=C1C=Cc2c(ccc3ccccc23)C1=N
Agent: O=C1C=Cc2c(ccc3ccccc23)C1=O
Agent: [Cl-]
Product: C[Si](C)(C)N=C1C(=N[Si](C)(C)C)c2ccccc2-c2ccccc21
Yield: 37 %

Procedure:
Ligand Synthesis. 9,10-Phenanthrenequinone bis((trimethylsilyl)-imine) (silylphi) was synthesized from 9,10-phenanthrenequinone (Aldrich) and sodium bis(trimethylsilyl)amide (Fluka) as described by Tuchtenhagan and Ruhlmann. (11) Important modifications to this synthesis include a reaction temperature of no greater than 65° C. and a final phenanthrenequinone concentration of 0.08 M. Under these conditions, orange crystalline silylphi was obtained in 37% yield and stored under nitrogen. The phenanthrenequinone diimine ligand (phi) was generated and chelated in situ by combining the silylated imine ligand with an ethanolic solution of metal chloride by using a modificaiton of Schlosser's method. (12)
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:36])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:35])[CH2:9][CH2:10][C@@:11]3([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:38])[CH3:37].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:35][C@:8]12[C@@:7]3([CH3:36])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:37])([CH3:38])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the resulting tert-butyl ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate in dichloromethane (100 mL) was added pyridinium chlorochromate (4.69 g, 21.74 mmol). The mixture was stirred at rt for 5 h then an additional 1.0 g of PCC was added and the mixture was stirred at rt for 1 h. The mixture was filtered through a plug of silica gel and celite which was washed with a solution of 25% ethyl acetate in hexanes. The filtrate was concentrated under reduced pressure to give tert-butyl ((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)carbamate as a light-yellow foam. 1H NMR (500 MHz, CHLOROFORM-d) δ=4.74 (d, J=1.7 Hz, 1H), 4.63 (t, J=1.7 Hz, 1H), 4.34 (br. s., 1H), 2.65-2.34 (m, 5H), 2.05-1.88 (m, 2H), 1.71 (s, 3H), 1.47 (s, 9H), 1.10 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 1.76-0.93 (m, 18H).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: COc1cncc(-c2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cncc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 4-({cyclohexyl[5-(5-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoic acid (210 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (226 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22]([C:24]1[S:28][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[NH:35][CH2:36][CH2:37][N:38]=2)=[N:26][N:25]=1)=[O:23])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][NH:21][C:22]([C:24]1[S:28][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[NH:35][CH2:36][CH2:37][N:38]=2)=[N:26][N:25]=1)=[O:23])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1nnc(CCCCNC2=NCCN2)s1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CNC(=O)c1nnc(CCCCNC2=NCCN2)s1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
t-Butyl 2(S)-benzyloxycarbonylamino-3-[[2-[4-[(N-imidazolin-2-yl)amino]butyl]-1,3,4-thiadiazol-5-yl]carbonyl]aminopropionate (100 mg, 0.18 mmol) was dissolved in CH2Cl2 containg 0.25 mL of TFA. The solution was stirred at rt for 24 hrs. Concentration gave the product(80 mg, 89% yield). 1H NMR(300 MHz, DMSO-d6)δ1.56(m, 2H), 1.86(m, 2H), 3.18(m, 4H), 3.54(m, 1H), 3.58(s, 4H), 3.66(m, 1H), 4.10(m, 1H), 5.00(s, 2H), 7.30(m, 5H), 7.76(d, 1H), 8.16(t, 1H), 9.10(t, 1H); MS(ESI) Calc. for (M+1)+ : 491. Found: 491.
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(OC([NH:39][C@@H:40]([CH2:44][C:45]1[S:46][CH:47]=[CH:48][CH:49]=1)[C:41](O)=[O:42])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:19]=3)[CH2:17][CH2:16][N:15]([C:41](=[O:42])[C@@H:40]([NH2:39])[CH2:44][C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(NCC1CCCCC1)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(C(=O)NCC2CCCCC2)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide hydrochloride (0.169 mmol; 0.08 g) in DMF (3 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.203 mmol; 55.1 mg), N,N-diisopropyl-N-ethylamine (0.338 mmol; 0.059 mL) and HBTU (0.203 mmol; 77 mg), and the resulting mixture was stirred at room temperature for 20 min. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in 1,4-dioxane (3 mL) and a 4N HCl solution in 1,4-dioxane (3 mL) was added. The resulting solution was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[N:23]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:23]1([CH2:29][CH2:30][CH2:31][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:12]=[C:11]([O:21][CH2:31][CH2:30][CH2:29][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:10]=4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(ccc(OCCCN4CCCCC4)c3c1)-c1cc(OCCCN3CCCCC3)ccc1-2

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 29.8 (0.15 mole) of 3-piperidinopropyl chloride hydrochloride and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-piperidinopropoxy)fluoranthene, M.P. 92°-93°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH3:19]C[O-].[Na+].CCO.ClC1C2C(=CC=CC=2)C(C=O)=C2C=1C=CC=C2>C(Cl)Cl.CCCCCC>[CH2:1]([O:2][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:17]=[O:18])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH3:19]
Reactant: COc1c2ccccc2c(C=O)c2ccccc12
Reactant: CC[O-]
Agent: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCO
Product: CCOc1c2ccccc2c(C=O)c2ccccc12

Procedure:
Using the procedure outlined in 13A, except that NaOEt (Aldrich)/EtOH was used instead of NaOCH3 /CH3OH, 10-chloro-9-anthraldehyde (Aldrich) gave 10-ethoxy-9-anthracenecarbaldehyde mp 88°-90°, (CH2Cl2 /hexane) (C, H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O1CC[CH2:11][CH2:10]1.Cl.[OH-].[Na+]>C(OCC)C.C([Mg]Br)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1([NH2:2])[CH2:11][CH2:10]1
Reactant: N#Cc1ccccn1
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Solvent: CCOCC
Product: NC1(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
In a nitrogen-atmosphere, to a solution of 1.0 g of 2-cyanopyridine and 3.0 g of titanium tetraisopropoxide in 14 mL of diethyl ether, 20 mL of ethyl magnesium bromide (in a 0.96 M tetrahydrofuran solution) was dropped while stirring the solution at −78° C. After the completion of the dropping, the resultant mixture was stirred at room temperature for 1 hour. Next, to the reaction mixture, 2.7 g of a trifluoroboron diethyl ether complex was added and the stirring of the reaction mixture was continued for another 18 hours in a nitrogen-atmosphere at room temperature. After the completion of the reaction, to the reaction mixture, 20 mL of a 1N hydrochloric acid aqueous solution was added and the resultant mixture was stirred for 10 minutes. Next, 30 mL of a 1N sodium hydroxide aqueous solution was added to the reaction mixture while ice-cooling the mixture to convert the mixture to basic and thereafter, the reaction mixture was extracted with diethyl ether (50 mL×2). The organic phase was dehydrated and dried with saturated brine and over anhydrous sodium sulfate, respectively, in this order, and the solvent was distilled off under reduced pressure to obtain 1.0 g of crude 1-(2-pyridyl)cyclopropylamine as a yellow oily substance. This substance was used in the reaction as it is without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2]>Cl.O1CCOCC1.CN1CCCC1=O>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(C#N)c4)n3)cccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: N#Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)ccc1OCC1CC1
Reaction time: 4.5 h
Yield: 33.1 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-cyano-4-[(cyclopropylmethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D48; 36 mg, 0.072 mmol) was dissolved in 4N HCl in 1,4-dioxane (4 ml) and the mixture was allowed to stand at room temperature for 4.5 h. The solvent was evaporated in vacuo and the residue triturated with dry ether to give a white solid which was dissolved in N-methyl-2-pyrrolidinone (1 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was dried under a stream of nitrogen to give the title compound as a white solid (10.5 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH:29]=C)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:31]1CCOCC1>O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:16]([CH3:28])[C:15]([CH2:29][OH:31])=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1c(CO)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 56.7 %

Procedure:
A solution of Example 173B (127 mg, 0.3 mmol) in dioxane (6 mL) and water (2 mL) was treated with OSO4 (2.5% wt in t-butanol, 0.5 mL), stirred for 8 minutes at ambient temperature, treated with NaIO4 (128 mg, 0.6 mmol), stirred for 30 minutes, diluted with brine, and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered, and concentrated. This concentrate was dissolved in absolute ethanol (5 mL) and THF (5 mL), treated with NaBH4 (7 mg), stirred for 30 minutes, treated with brine (10 mL), and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography with 45% ethyl acetate/hexanes to provide the desired product (71 mg, 56.7%). 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 4.42 (d, 2H), 5.12 (t, 1H), 5.24 (s, 2H), 6.84 (d, 1H), 7.35-7.46 (m, 8H), 7.70-7.75 (m, 2H), 9.81 (s, 1H); MS (ESI(−)) m/e 428 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][CH:13]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:17][CH:16]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CCC=CCCc1ccc(CCC=CCCC(=O)OCC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCCc1ccc(CCCCCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
First, 707 mg of 1,4-bis(6-ethoxycarbonyl-3-hexenyl)benzene was dissolved in 14 ml of ethanol, and after adding 70 mg of 5% palladium/carbon, the mixture was stirred under hydrogen flow at a room temperature for 2 hours, filtered to remove the catalyst, and concentrated under a reduced pressure to obtain 601 mg of 1,4-bis(6-ethoxycarbonylhexyl)benzene as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(NC(C)C)(C)C.CS(Cl)(=O)=O.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:13][S:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 0° C. solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (30 g, 137 mmol) and diisopropylamine (58 mL, 330 mmol) in dichloromethane (250 mL) was treated with methanesulfonyl chloride (11.65 mL, 151 mmol), stirred for 20 minutes, treated with thiophenol (15.5 mL, 151 mmol), warmed to room temperature, stirred for 30 minutes, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 310 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][N:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34].[H-].[Na+]>CCN(CC)CC>[CH3:31][N:32]1[CH2:38][C:36](=[O:37])[N:35]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:34]
Reactant: CN1CC(=O)NC1=O
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CN(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 42.6 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 1-methyl-hydantoin, and 63 mg of NaH, 22.0 mg of the product was obtained.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:18]=[CH:19][C:20](=[S:23])[NH:21][N:22]=1>>[CH2:1]([S:23][C:20]1[N:21]=[N:22][C:17]([C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(=S)[nH]n2)c(C)c1
Reactant: BrCc1ccccc1
Product: Cc1ccc(-c2ccc(SCc3ccccc3)nn2)c(C)c1

Procedure:
Prepared in a similar manner to example 13 using benzyl bromide and 6-(2,4-dimethylphenyl)pyridazine-3(2H)-thione (Example 13a). Yield 53.5 mg (38%). 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.34 (s, 3H), 4.60 (s, 2H), 7.16-7.17 (m, 2H), 7.30-7.34 (m, 4H), 7.47-7.49 (d, 2H), 7.64-7.72 (m, 2H); MS (M+H, 307).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:28](O)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCc5ccccc54)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 16.2 mg (0.10 mMol) 1,2,3,4-tetrahydro-1-naphthoic acid at 70° C., 16.2 mg (84%) of the title compound were recovered.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2.[OH-].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.S(=O)(=O)(O)O>[C:18]1([S:24][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: c1ccc(Sc2ccc3ncccc3c2)cc1

Procedure:
A solution of sodium nitrite (1 g, 14 mmol) in water (6 mL) was slowly added to a stirred solution of 6-amino-quinoline (1.44 g, 10 mmol) in sulfuric acid (50%) (8 mL). The temperature was kept below 5° C. during the addition. The reaction mixture was poured into a solution of potassium hydroxide (9 g, 16 mmol) and thiophenol (1 mL, 9 mmol) in water (30 mL). The reaction mixture was refluxed for 3 h, cooled and extracted with diethyl ether. The insoluble material was eliminated by filtration. During filtration most of the material was trapped in the solid phase. The filtrate was evaporated and the residue was purified by column chromatography (SiO2, ethyl acetate:hexane, 1:2) to yield a colorless oil (100 mg, 4% PS: the low yield is due to the loss of the material during the filtration procedure). MS m/z: 238 [M+H+]. 1H NMR (270 MHz, CD3Cl) δ ppm 7.34 (m, 4H) 7.42 (m, 2H) 7.57 (dd, J=8.97, 2.11 Hz, 1H) 7.67 (d, J=2.11 Hz, 1H) 7.99 (m, 2H) 8.84 (dd, J=4.22, 1.58 Hz, 1H).