Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:24][CH2:22][CH3:23])=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and ethylamine hydrochloride in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][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.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=[N+]([O-])c1cccc(F)c1Br
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(F)c1-c1ccccc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-bromo-3-fluoronitrobenzene (1.500 g, 6.8 mmol), 2-fluorophenylboronic acid (1.145 g, 8.2 mmol), N,N-dimethylformamide (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 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and 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 pale yellow solid (0.780 g, 49%). 1H NMR (300 MHz, CDCl3) δ 7.86 (dt, 1H, J=7.8, 1.2 Hz), 7.56 (td, 1H, J=8.1, 5.7 Hz), 7.52-7.40 (m, 2H), 7.35-7.15 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCOc1ccc(OCc2ccccc2)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(OCc2ccccc2)c(CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
A mixture of (2-benzyloxy-5-methoxymethoxyphenyl)methanol (8.0 g), triphenylphosphine (7.66 g), carbon tetrabromide (9.68 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1.5 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.49 g, 46%) of 1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 55-57° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:6]([CH:29]=1)[CH:7]([NH:14][C:15]([CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[CH3:38]I>CN(C)C=O>[CH3:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[C:6]([CH:29]=1)[CH:7]([NH:14][C:15]([CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2cc(O)ccc2N2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2cc(OC)ccc2N2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
Four hundred seventy-two milligrams (1 m mol) of ethyl 4-[N-(5-hydroxy-α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate were dissolved in 25 ml of absolute dimethylformamide. After addition of 50 g of 50% sodium hydride, the mixture was stirred for 30 minutes. Then, 0.5 gm of methyl iodide were added dropwise, and the resulting mixture was stirred overnight. To work the mixture up, it was poured onto ice-water and extracted with methylene chloride. The concentrated extracts were purified by column chromatography on silica gel by use of toluene/ethyl acetate (4:1) as eluant.
Reaction SMILES: [C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([O:18]C)=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:4][CH2:3][CH2:2]2.[Li+].[OH-].Cl>C1COCC1.O>[C:1]12([O:8][C:7]3[CH:9]=[CH:10][C:11]([C:13]4([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]4)=[CH:12][C:6]=3[O:5]1)[CH2:2][CH2:3][CH2:4]2
Reactant: COC(=O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a mixture of methyl 1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylate (0.60 g, 2.3 mmol) in THF/H2O (4:1, 10 mL) was added LiOH (0.30 g, 6.9 mmol). The mixture was stirred at 60° C. for 24 h. HCl (0.5 N) was added slowly to the mixture at 0° C. until pH 2-3. The mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and washed with petroleum ether to give 1-(spiro[benzo[d][1,3]-dioxole-2,1′-cyclobutane]-5-yl)cyclopropane carboxylic acid (330 mg, 59%). 1HNMR (400 MHz, CDCl3) δ 6.78-6.65 (m, 3H), 2.65-2.58 (m, 4H), 1.86-1.78 (m, 2H), 1.63-1.60 (m, 2H), 1.26-1.19 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[CH2:22]([NH:21][C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)C1
Reaction time: 5 h
Yield: 63.5 %

Procedure:
To stirred solution of ethyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-3-carboxylate (1 g, 3.1 mmol) in 10 ml THF: H2O (3:1) was added lithium hydroxide (0.35 g, 15.4 mmol) at room temperature. The resulting mixture was stirred for 5 h, solvent was evaporated and residue was dissolved in water washed with dichloromethane. The aqueous layer was then neutralised with 2M HCl to get yellow solid 1-(3-(benzylamino)-4-nitrophenyl)piperidine-3-carboxylic acid (0.7 g), 86% yield: 1H NMR (500 MHz, DMSO): δ 1.55 (m, 1H), 1.87 (m, 2H), 2.10 (m, 1H), 2.62 (m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.60 (m, 1H), 3.82 (dd, J=3.6, 5.6 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 5.92 (d, J=2.5 Hz, 1H), 6.28 (dd, J=2.6 Hz, 1H), 7.32 (m, 2H), 7.41 (m, 3H), 8.12 (d, J=9.6 Hz, 1H), 8.8 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[S:19][N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[C:12]([C:15]([NH2:16])=[O:33])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-((1R,2S)-2-aminocyclohexylamino)-3-(isothiazolo[3,4-b]pyridin-3-ylamino)pyrazine-2-carbonitrile (36 mg) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (30%, 1 mL) were added. The mixture was stirred at room temperature for 20 h. After being neutralized with HOAc (0.3 mL), the mixture was purified by HPLC to give the titled compound (7 mg). MS found for C17H20N8OS as (M+H)+ MS 385.3. UV: λ=UV 207.4, 245.8, 298.6, 343.2 nm. 1H NMR: (CD3OD) δ 8.50 (dd, 1H), 8.22 (dd, 1H), 7.73 (s, 1H), 7.05 (dd, 1H), 4.70-4.62 (m, 1H), 4.12-4.05 (m, 1H), 2.14-1.60 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:13](=[O:22])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccccc2)c2cnc3ccc(Br)cc3c2n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.13 mmol) of 8-bromo-1-(2-chloro-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one [see under B)], 48.8 mg (0.40 mmol) of phenylboronic acid (Fluka, Buchs, Switzerland), 53 mg (0.27 mmol) of cupric acetate anhydrous (Fluka, Buchs, Switzerland) and 56 μl (0.4 mmol) of triethylamine are dissolved in 1 ml of anhydrous dichloromethane and the suspension is stirred for 16 h at room temperature. After this time, additional phenylboronic acid (24 mg), cupric acetate anhydrous (27 mg) and triethylamine (28 μl) are added and the suspension is stirred at room temperature for 24 h. The suspension is evaporated to dryness and the crude compound is purified by clash chromatography (dichloromethan with 0.5% of methanol) to obtain the title compound: Analytical HPLC: tret=8.22 min (Grad. 2); ES-MS: m/e0=449.9. 451.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25](=[S:26])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: S=C=NCc1ccccc1
Product: CN1CCC(C(=O)c2cccc(NC(=S)NCc3ccccc3)c2)CC1
Yield: 89 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and benzyl isothiocyanate (92 μL, 0.688 mmol), 37.6 mg (89%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][N:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1.[OH2:12]>>[Cl:1][C:2]1[C:7]([OH:12])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cn1
Reactant: O
Product: O=C(O)c1cc(Cl)c(O)cn1

Procedure:
By applying the reaction sequence of either esterification, Suzuki reaction, hydrogenation, saponification or esterification, Negishi reaction and saponification, a commercially available compound of Structure 32 may be transformed into a compound of Structure 33. The compounds of Structure 32 may be prepared, for instance, by reacting 4,5-dichloro-picolinic acid with water in their presence of an acid (Lit.: e.g. J. Prakt. Chem.; 27 (1883), 293) to give 4-chloro-5-hydroxy-picolinic acid. This compound may then be alkylated in analogy to literature procedures (T. Vermonden; D. Branowska; A. T. M. Marcelis; E. J. R. Sudholter; Tetrahedron 59 (2003), 5039-5045) to give 4-chloro-5-methoxy picolinic acid methyl ester which can be hydrolysed under acidic or basic conditions to the desired compound of Structure 32.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:14][CH2:13]1.[H][H]>[Ni].C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[NH2:26])[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
20 g of 1-[(benzo-1,4-dioxan-2-yl)-methyl]-4-(5-chloro-2-nitroanilino)-piperidine were hydrogenated under normal pressure and at room temperature, using 4 g of Raney nickel as a catalyst in 200 ml of ethanol. When the uptake of hydrogen had ended, the mixture was filtered, the material on the filter was rinsed with ethanol and the filtrate was concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
To a solution of 6 (0.50 g, 1.07 mmol), in CH2Cl2 (5 mL) at room temperature, trifluoroacetic acid (1.0 mL) was added and the reaction mixture was stirred for 6 h. Et3SiH (0.34 mL, 2.14 mmol) was added to the reaction mixture and the resulting pink solution was stirred overnight at room temperature. Solvent was evaporated under reduced pressure and the residue was neutralized with aqueous NaHCO3 solution and extracted with CH2Cl2 (2×10 mL). The combined organic layer was washed with H2O (5 mL), brine (5 mL) and then dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure and the residual light yellow syrup was purified by column chromatography using 20% acetone/hexane as the eluent to afford the title compound 8 (0.39 g, 81%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]1[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[C:18]1=[O:29].O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH:21]1[CH2:22][C:23]2[C:28]3=[C:27]([CH2:17][C:18](=[O:29])[N:19]3[CH2:20]1)[CH:26]=[CH:25][CH:24]=2)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCC(=O)Cl
Reactant: O=C1Cc2cccc3c2N1CCC3
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCCCC(=O)C1Cc2cccc3c2N(C1)C(=O)C3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in absolute CH2Cl2 (50 ml) is added in drops at 0° C. within 10 minutes to a suspension of anhydrous aluminum chloride (61.5 g, 461.6 mmol) in absolute CH2Cl2 (500 ml), and it is stirred for 15 minutes at this temperature. 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g (57.7 mmol) in absolute CH2Cl2 (100 ml) is added in drops within 15 minutes at 0° C., then it is heated to boiling temperature and stirred for 30 minutes. It is cooled to 0° C., hydrolyzed with ice and dispersed between water (300 ml) and CH2Cl2 (100 ml). The aqueous phase is extracted with CH2Cl2 (2×100 ml), the combined organic phases are washed with 2N hydrochloric acid (2×250 ml), water (2×250 ml), semi-concentrated aqueous Na2CO3 solution (2×250 ml), concentrated aqueous Na2CO3 solution (2×250 ml) and concentrated common salt solution (1×250 ml), dried (sodium sulfate/activated carbon), and the solvent is removed in a rotary evaporator.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[N:8]([C:15](=[O:18])[NH:16][N:17]=2)[C:9]=1[CH:10]=[CH:11][CH:12]([CH3:14])[CH3:13])([CH3:3])[CH3:2]>CCO.[Pd]>[CH:1]([C:4]1[N:5]=[C:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[N:8]([C:15](=[O:18])[NH:16][N:17]=2)[C:9]=1[CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])([CH3:2])[CH3:3]
Reactant: CC(C)C=Cc1c(C(C)C)nc(NC(C)C)c2n[nH]c(=O)n12
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCc1c(C(C)C)nc(NC(C)C)c2n[nH]c(=O)n12

Procedure:
A solution of 30 mg of 6-isopropyl-8-isopropylamino-5-(3-methyl-but-1-enyl)-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one in EtOH (10 mL) was treated with 50 mg of 10% Pd/C. The mixture was hydrogenated at 35 psi for one h and the solids were removed by filtration through diatomaceous earth. The filtrate was concentrated to provide the title compound as a white solid. MS (M+H+)=304.4.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:10]([CH2:12]O)[N:11]=1>C(Cl)(Cl)Cl>[CH3:5][NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:10]([CH2:12][Cl:3])[N:11]=1
Reactant: CNc1nc(CO)c(-c2ccncc2)s1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNc1nc(CCl)c(-c2ccncc2)s1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A solution of thionylchloride (1.06 g) in chloroform (5 ml) was dropwise added to a solution of 2-methylamino-4-hydroxymethyl-5-(4-pyridyl)thiazole (1.0 g) in chloroform (20 ml) at ambient temperature for a period of 5 minutes with stirring, which was continued under the same condition for 90 minutes and at 50° C. for 30 minutes. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (50 ml) and ethyl acetate (30 ml). The solution was adjusted to pH 6.5 with 30% aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give yellow powder of 2-methylamino-4-chloromethyl-5-(4-pyridyl)thiazole (0.9 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.3 mmol) and N,N-diethylethanamine (1.5 g, 8.2 mmol) in CH2Cl2 (30 ml) was added methanesulfonyl chloride (869 mg, 7.6 mmol). The mixture was stirred for 6 hours at ambient temperature. After dilution with CHCl3 and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to give ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.2 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:10][CH:9]([CH3:11])[CH:8]2C[CH:4]1[C:5](C)=[CH:6][CH2:7]2.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:11])[CH3:10]
Reactant: COC1CC(C)C2CC=C(C)C1C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC(C)OC
Reaction time: 6 h
Yield: 107.2 %

Procedure:
To a solution of 1 g (5.6 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-yl methyl ether [IB] in 10 ml of ethanol was added 0.1 g of 5% of Pd/C and the resulting mixture was heated with stirring at a hydrogen pressure of 20 atm and a reaction temperature of 70° C. for 6 hours. After cooling, the Pd/C was filtered off and the ethanol was distilled off under reduced pressure. The residue was subjected to column chromatography and eluate with toluene gave 0.95 g of the title compound, which had a camphor-like smell.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[C:8]([Cl:15])[N:7]=1>O1CCCC1>[Cl:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[CH:9]=[C:8]([Cl:15])[N:7]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)c1

Procedure:
To a tetrahydrofuran solution containing methanol (0.37 g, 0.0104×1.1 mol), sodium hydride (0.44 g (ca. 60% in mineral oil), 0.0104×1.05 mol) was added, then 2,6-dichloro-4-nitropyridine (2.00. g, 0.0104 mol) was added thereto and the resultant solution was stirred for about 2 hours at room temperature. After it was confirmed that there was no bubbling with the addition of methanol (1.0 g, 0.0355×0.9 mol), the resultant solution was stirred for about another 1 hour. After the reaction solution was partitioned between ethyl acetate and water, the obtained organic layer was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter concentrated to obtain the substantially pure end product.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[C:8](Cl)[S:7][N:6]=1)[CH:2]=[CH2:3].NC(N)=[S:13].O1CCCC1>O>[CH2:1]([S:4][C:5]1[N:9]=[C:8]([SH:13])[S:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCSc1nsc(Cl)n1
Reactant: NC(N)=S
Solvent: O
Solvent: C1CCOC1
Product: C=CCSc1nsc(S)n1
Reaction time: 8.5 h
Yield: 57.4 %

Procedure:
A mixture of 3-allylthio-5-chloro-1,2,4-thiadiazole (15.0 g), thiourea (5.95 g), tetrahydrofuran (45 ml) and water (15 ml) was gently boiled for 8.5 hours at 65° C. The reaction mixture was post-treated according to conventional manner to give powder of 3-allylthio-1,2,4-thiadiazole-5-thiol (8.5 g), mp. 107° to 108° C.
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCNC(=N)N[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1>C(O)(C(F)(F)F)=O>[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:68]2[C:73](=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]2[C:79]1=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][C:52]=1[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c(S(=O)(=O)c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Temperature: 30 °C

Procedure:
Fmoc-Arg(Pmc)-OH (0.5 g, 0.75 mmol) and Fmoc-Trp-OH (0.43 g, 0.1 mmol) was dissolved in 10 ml 100% TFA and heated at 30° C. for 1.5 hours. After evaporation of TFA, Fmoc-Arg-OH was removed by column chromatography on silica gel with heptane/ethyl acetate 2:1 as mobile phase. Fmoc-Trp(2Pmc)-OH was isolated by preparative HPLC (Cl8, 70-100% B in 15 min., tR 14.8 min, (A: H2O+0.1% TFA; B: CH3CN+0.1% TFA)). Isolated yield 130 mg (0.19 mmol, 25%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1F.[F:15]C1C(OC)=C([N+]([O-])=O)C=CC=1CO>>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([O:9][CH3:10])[C:8]=1[F:15]
Reactant: COc1cc(CCl)c(F)cc1[N+](=O)[O-]
Reactant: COc1c([N+](=O)[O-])ccc(CO)c1F
Product: COc1c([N+](=O)[O-])ccc(CCl)c1F

Procedure:
The title compound was prepared using the procedure from Compound 130C (1-(chloromethyl)-2-fluoro-5-methoxy-4-nitrobenzene) with (2-fluoro-3-methoxy-4-nitrophenyl)methanol (Compound 147D). 1H NMR (CDCl3, 400 MHz): δ=4.10 (d, J=1.77 Hz, 3 H), 4.64 (d, J=1.52 Hz, 2 H), 7.62 (dd, J=8.59, 1.77 Hz, 1 H). MS (ES+): m/z 220.00 [MH+] (TOF, polar).