Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:33]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(S)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
Triphenylmethanol (39.7 g, 149.4 mmol) was dissolved in the solution of crude 4-fluoro-2-trifluoromethyl-benzenethiol in dichloromethane (ca. 260 mL) of the preceding step and a solution of trifluoroacetic acid (21.2 g, 186 mmol) in dichloromethane (20 mL) was added at room temperature. After stirring for 15 h, the mixture was basified by subsequent addition of water (20 mL), concentrated aqueous sodium hydroxide solution (32% m/m, 26.9 g, 215 mmol) and water again (240 mL). Phases were separated, the aqueous layer was extracted with dichloromethane (100 mL) and the combined organic extracts concentrated in vacuo at 50° C. to a volume of ca. 330 mL. Ethanol (400 mL) was continuously added to the distillation, while the overall volume was kept constant (solvent exchange). The solution (ca. 300 mL) was allowed to cool to room temperature, crystallization started at 42° C. The suspension was stirred for 18 h at room temperature and for 1 h at 0° C. After filtration, the precipitate was washed with cold ethanol (100 mL) and dried in vacuo at 40° C. to give rise to the title compound as a white crystalline solid (52.5 g, 79%). MS (EI): m/z=243 [CPh3]+. 1H NMR (CDCl3, 600 MHz): δ 6.73 (ddd, J=2.8 Hz, 8.3 Hz, 8.3 Hz, 1H), 7.04 (dd, J=5.4 Hz, 8.8 Hz, 1H), 7.18-7.25 (m, 10H), 7.35-7.37 (m, 6H). Anal. Calcd for C26H18F4S: C, 71.22; H, 4.14; S, 7.31; F, 17.33. Found: C, 71.16; H, 4.26; S, 7.15; F, 17.09.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
Methyl 4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (Intermediate #5) (104 mg, 0.26 mmol) was dissolved in methanol (5 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (0.65 mL, 1.29 mmol). The mixture was stirred at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the product as a white solid (89 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[N:11]([O-])=O.[Na+]>O.C(O)(=O)C.O>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[N:11]1
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)c(N)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 mmol of 3,4-Diamino-benzonitrile were suspended in water/acetic acid (4:1) and cooled to 0° C. 1.05 eq of NaNO2 were dissolved in water and added inert 30 min. The reaction was stirred at room temperature overnight. The precipitate was filtered off, washed with ether and dried under vacuum. The intermediate was not further characterized.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N([CH2:20][CH3:21])CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[C:2]1([C:20]#[C:21][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-bromo-5-nitrobenzoate (10 g) phenyl acetylene (4.2 ml), triethylamine (100 ml), cuprous iodide(0.4 g),dimethylformamide (200 ml) and bis-(triphenylphosphine)-palladium(II)chloride (1.35 g) was stirred at ambient temperature for 1 hour under an argon atmosphere. The solvents were removed under reduced pressure and the residue treated with 1N, hydrochloric acid (2 L) and then extracted with ethyl acetate (2×300 ml). The combined organic extracts were washed with saturated aequeous sodium bicarbonate solution (100 ml), water (3×100 ml) and brine (100 ml) filtered through phase separating paper and evaporated to dryness. The residue was purified by flash column chromatography on silica using ethyl acetate/hexane(gradient: 0 to 10%) as eluant to give methyl 2-(2-phenylethynyl)-5-nitrobenzoate (compound 76) as a yellow solid (9.98 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)(C)C.Cl[CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][Cl:20].[OH-].[Na+]>O>[Cl:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(OCC(O)CCCl)ccc1Cl
Temperature: 40 °C
Reaction time: 10 h
Yield: 22.3 %

Procedure:
To a mixture of 286 g (2 mole) of 3-methyl-4-chlorophenol, 700 ml of tertiary butanol, 700 ml of water and 3.0 mole of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g in 700 ml of water) was added with stirring at 40° C. to maintain a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr; the reaction was stirred at 40° C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium hydroxide at 25° C. The chloroform extract was washed with sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give 110.9 g of the product which distilled at 135°-143° C./0.007 mm and melted at 87°-89° C. after recrystallization with isopropanol and petroleum ether (30°-60° C.).
Reaction SMILES: [Cl-].C([Al+]CC)C.[N-:7]=[N+:8]=[N-:9].[Na+].[OH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[Na+].[Cl-]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]1[NH:15][N:9]=[N:8][N:7]=1
Reactant: N#Cc1ccccc1O
Reactant: [N-]=[N+]=[N-]
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccccc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Into the flask, 100 mL of anhydrous toluene and diethyl aluminum chloride (40 mmol, 1.8 M toluene solution) were put and cooled to 0° C. Sodium azide (2.6 g, 40 mmol) was put into the mixture, and the mixture was agitated at room temperature for 4 hours. After the agitated solution was cooled to 0° C. again, 2-hydroxybenzonitrile (20 mmol, 2.38 g) was added thereto. The reaction mixture was refluxed at 80 for 1 day. After the reaction was finished, the mixture was cooled to 0° C., 70 mL of 6 M HCL, 50 mL of distilled water, 100 mL of ethyl acetate, and 80 mL of saturated NaCl were dropped thereon, treated, and extracted. The organic phase was reextracted by using 200 mL of water twice. The combined water layers were extracted with 200 mL of ethyl acetate twice. The combined organic layers were dried through Na2SO4. The solvent was removed to obtain the product. The product was recrystallized from ethyl acetate to obtain a pure product (yield 80%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:22]>CS(C)=O>[OH:21][C@@H:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][N:1]([CH2:20][C@@H:19]([OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: O
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCCN(C[C@@H](O)c2ccccc2)C[C@@H](O)c2ccccc2)s1

Procedure:
5 g of 5-(3-aminopropyl)-2-thiophenecarboxamide and 3.4 ml of (S)-phenylethylene oxide were stirred at 95° for 26 hours in 68 ml of dimethyl sulphoxide. The mixture was poured into 200 ml of water and extracted three times with 150 ml of methylene chloride. The methylene chloride solutions were washed with water, dried and evaporated in vacuo. Chromatography of the residue on silica gel with ether/methanol gave 2.85 g of 5-[3-[bis-[(S)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide; [α]D =+76° (c=0.1% in dioxan); UV: ε277 =10390.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH3:25])=[CH:20][CH2:19][CH2:18]2.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[CH2:20][CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0592 g (0.099 mmol) (S,S)-ethylene-1,2-bis(η5 -4,5,6,7-tetrahydro- 1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2 x ~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.122 mL, 1.58M in hexanes, 0.193 mmol, 1.95 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.03 1 mL, 0.243 mmol, 2.5 equiv) and 0.378 g (2.19 mmol, 22 equiv ) 6-methoxy-1-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 1800 psig with hydrogen and placed in an oil bath at 68° C. The reaction mixture was allowed to stir for 132 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether hexane (1/4) and water and separating the layers. The organic extract was concentrated and chromatographed on 50 mL silica gel to yield 0.268 g (1.54 mmol, 70%) of 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene with an ee of 94.7%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11](=[O:24])[C:12]2[S:13][C:14]([CH3:23])=[C:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=23)[CH:6]=[C:5]([CH3:25])[C:4]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCc1cc(C=CC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1CCC(=O)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propenyl]-phenyl}-acrylic acid (Intermediate 3; 340 mg, 0.805 mmol) and DIPEA (182 mg, 1.41 mmol) in ethanol, Pd/C (340 mg, 10% Pd, moistened with 50% water) is added and the resulting slurry is stirred at 50° C. for 72 h under 10 bar of H2. Another portion of Pd/C is added and stirring is continued for 16 h at 50° C. under 10 bar of H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenyl}-propionic acid (154 mg) as a colourless foam; LC-MS: tR=1.15 min, [M+1]=427.30.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Temperature: 85 °C
Yield: 48.4 %

Procedure:
A 100-mL round-bottomed flask was charged with 118a (800 mg, 2.83 mmol), bromoethane (216 mg, 1.98 mmol), K2CO3 (780 mg, 5.66 mmol), and DMF (20 mL). The mixture was heated at 85° C. overnight. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 118b as a red solid (298 mg, 37%). MS-ESI: [M+H]+ 311.0. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 5.85 (s, 1H), 3.98-3.94 (m, 2H), 3.48 (s, 3H), 2.19 (s, 3H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1[OH:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([O:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1[O:23][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CCC(=O)C=C1[C@H](O)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1[C@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
In a manner similar to that described in Example 1C, treat 6β,7α-dihydroxy-4-androstene-3,17-dione (150 mg.) in pyridine (5 ml.) with methanesulfonyl chloride (1 ml.) for two hours at room temperature. Isolate the resultant product in a manner similar to that described in Example 1C to obtain 180 mg. of 6β,7α-dimethanesulfonyloxy-4-androstene-3,17-dione which is used without further purification in the following step 31C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][P:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH2:18]1N2CCN(CC2)C1.[CH3:26][C:27]12[O:36][C:31]3([CH3:37])[O:32][CH:33]([CH2:35][C:29]([CH3:38])([O:30]3)[PH:28]1)[CH2:34]2>C1(C)C=CC=CC=1.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>[C:6]([P:5]([CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[P:28]1[C:29]2([CH3:35])[CH2:38][C:31]3([CH3:37])[O:32][C:33]([CH3:18])([CH2:34][C:27]1([CH3:26])[O:36]3)[O:30]2)[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC12OC3CC(C)(O1)PC(C)(C3)O2
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)P(Cc1ccccc1Br)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1CP(C(C)(C)C)C(C)(C)C)O2
Temperature: 140 °C
Reaction time: 12 h

Procedure:
2.5 g (7.9 mmol) of the thus obtained 2-bromobenzyl(di-tert-butyl)phosphine, 2.24 g DABCO (20 mmol), 1.94 g 1,3,5-trimethyl-4,6,9-trioxa-2-phosphatricyclo[3.3.1.1{3,7}]decane (9 mmol) and 0.23 g Pd(PPh3)4 (0.2 mmol) in 10 ml toluene were added into a 250 ml glass vessel under inert atmosphere, and the content of the vessel was heated to 140° C. under stirring for 12 hours. The mixture was than allowed to cool to 100° C., and was then filtered. The filtrate was cooled to room temperature, then 30 ml of methanol added were added and the mixture cooled for a period for 12 hours to −35+ C., 8-(2-{[di(tert-butyl)-phosphino]-methyl}phenyl)-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1{3,7}]decane was isolated as yellow crystals (2.2 g, 4.9 mmol, 62%), and could be characterized by showing two distinct resonance signals in 31P NMR at +38.08 and −38.96 ppm.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1(C)C=CC=CC=1>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:22](=[O:23])[CH2:21][C:19]#[N:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CCOC(=O)CC#N
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 105.5 %

Procedure:
To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 100° C. and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@@H:30]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C@@H:31]([OH:40])[CH2:32][S:33][CH2:34][C:35]([O:37]CC)=O)=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CN(C)CCN>[C:1]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@@H:30]([CH2:41][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1)[C@@H:31]([OH:40])[CH2:32][S:33][CH2:34][C:35]([N:8]([CH3:1])[CH2:9][CH2:17][NH:19][CH3:20])=[O:37])=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCOC(=O)CSC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)CCN
Product: CNCCN(C)C(=O)CSC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 74 mg (0.11 mmole) of ethyl 2-[[(2R,3S)-3-(Boc-L-phenylalanyl-L-histidylamino)-4-cyclohexyl-2-hydroxy-1-butyl]thio]acetate was added 100 μl of N,N-dimethylethylenediamine. The mixture, which was stirred at room temperature in a stoppered flask, became homogeneous within a few minutes. After 18 hours, the mixture, which had gelled, was triturated thoroughly with hot ether. The resulting solid was collected on a filter and washed several times with ether, triturating thoroughly each time. This yielded 68 mg (86%) of white powder, mp 160°-164° (preliminary softening), virtually homogeneous by TLC (90:10:1 CHCl3 --MeOH-cond. NH4OH). Mass spectrum and 200 MHz NMR (DMSO d6) were in accord with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH3:2].C(#N)C1C=CC=CC=1.C(=O)(O)[O-:40].[Na+].OO>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:29])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][C:11]=3[N+:10]([O-:40])=[CH:9][C:8]=2[N:23]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: N#Cc1ccccc1
Product: CCOCc1nc2c[n+]([O-])c3cc(N4CCOCC4)ccc3c2n1CCCOC(C)C
Reaction time: 8 h

Procedure:
2-Ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline (1.0 g), benzonitrile (0.44 mL) and sodium bicarbonate (0.15 g) were slurried in methanol. Hydrogen peroxide (55% by weight in water, 0.395 mL) was added dropwise over 1 hour. The reaction was stirred overnight. The methanol was removed under reduced pressure and the residue was purified by column chromatography on a Biotage Horizon™ High Performance Flash Chromatography instrument. The purification was carried out eluting with chloroform:CMA in a gradient from 98:2 to 75:25. 2-Ethoxymethyl-1-(3-isopropoxypropyl)-7-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline 5-oxide was isolated as a yellow oil (0.166 g).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][C:17]=1[Cl:23].O[C@H:25]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[ClH:23].[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Oc1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccccc1O[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Diisopropyl azodicarboxylate (21 mL, 107 mmol) and 4-hydroxy-3-chlorophenol (11.1 mL, 107 mmol) were added portionwise to an ice-cold solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (20 g, 107 mmol) and triphenylphosphine (28.1 g, 107 mmol) in tetrahydrofuran (320 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (400 mL) and water (400 mL). The organic layer was separated and washed with water (100 mL), and the combined aqueous solution was washed with ethyl acetate (2×300 mL), basified to pH9 with solid potassium carbonate and extracted with ethyl acetate (2×400 mL). The combined organic solution was then washed with water (3×300 mL), dried over magnesium sulfate and concentrated in vacuo. The residual oil was dissolved in diethyl ether (60 mL), treated dropwise with hydrochloric acid (4M in dioxane, 25 mL) and the resulting precipitate was filtered off, washing through with diethyl ether, and dried to afford the title compound as a white solid in 55% yield, 13.69 g. LRMS APCI m/z 198 [M+H]+.