Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:20]4(OCC[O:23]4)[CH2:19][CH2:18]3)[C:8]2=[N:11]S(C(C)(C)C)=O)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC(=O)CC2
Reaction time: 8 h
Yield: 115.8 %

Procedure:
To N-(6″-bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-ylidene)-2-methylpropane-2-sulfinamide (Example 115, Step 1, 288 mg, 0.65 mmol) in 1,4-dioxane (2 mL) under N2 (g) was added HCl (4 M in 1,4-dioxane, 1.635 mL, 6.54 mmol). The mixture was stirred at r.t overnight and was then concentrated. The crude product was dissolved in DCM and was washed with NaHCO3 (sat. aq). The aqueous phase was extracted with DCM. The combined organics were dried using a phase separator and concentrated to give the title compound (220 mg, quantitative yield) that was used directly in the next step: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.24 (m, 2H) 1.25-1.35 (m, 2H) 1.66-1.75 (m, 2H) 1.83-1.93 (m, 2H) 2.86 (s, 2H) 5.83 (s, 1H) 7.40 (d, 1H) 7.64 (dd, 1H) 7.69 (d, 1H); MS (ES+) m/z 292 [M+H]+.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.C([O:30][C:31]1[CH:32]=[C:33]([CH:40]=[CH:41][CH:42]=1)[O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])C1C=CC=CC=1>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][O:34][C:33]1[CH:32]=[C:31]([OH:30])[CH:42]=[CH:41][CH:40]=1
Reactant: CN(C)CCOc1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1cccc(O)c1

Procedure:
Compound 113B was prepared in a similar manner to the synthesis of compound 31F by substituting compound 31E with compound 113A: 1H NMR (DMSO-d6): δ 9.34 (s, 1H), 7.03 (t, J=8.03 Hz, 1H), 6.30-6.36 (m, 3H), 3.96 (d, J=5.95 Hz, 2H), 2.58 (d, J=5.8 Hz, 2H), 2.20 (s, 2H) ESI (+)/MS: 182 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH3:11]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:11]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: N
Solvent: c1ccccc1
Product: NCc1c(F)cccc1Cl
Temperature: 100 °C

Procedure:
An autoclave was charged with 89.0 g. (0.5 mole) of 2-chloro-6-fluorobenzyl chloride, 170.0 g. (10 mole) ammonia and 50 ml. benzene. The reaction vessel was sealed and the contents heated at 100° C. for 15 hours. The excess ammonia was carefully evaporated off from the cooled contents of the autoclave with a stream of nitrogen. The residue was washed with water, and the organic phase after drying with anhydrous MgSO4, fractionated to afford 72.4 g. (90%) of product as a clear liquid; b.p. 99°-100° C./20 mm; NMR (CDCl3) δ 1.46 (s, 2H); 3.88 (d, 2H); 7.00 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>[Pd]>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1N1CCCCC1
Agent: [Pd]
Product: Nc1cccc(Cl)c1N1CCCCC1
Yield: 80 %

Procedure:
Using a procedure similar to Example 3, step (c), 1-(2-chloro-6-nitro-phenyl)-piperidine (79 mg, 0.32 mmol, as prepared in the previous step) was stirred with 44 mg of 5% Pd—C under H2 for 1 h 30 min to afford 54 mg (80%) of the title compound, contaminated with the des-chloro derivative, which was used immediately without further purification. Mass spectrum (ESI, m/z): Calcd. for C11H15ClN2, 211.0 (M+H), found 211.1.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[C:13]([OH:22])=[C:14]([CH2:19][CH:20]=O)[CH:15]=[C:16]([Cl:18])[CH:17]=1)([O:10][CH3:11])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>>[C:8]([C:12]1[C:13]2[O:22][CH:20]=[CH:19][C:14]=2[CH:15]=[C:16]([Cl:18])[CH:17]=1)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)cc(CC=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2ccoc12
Yield: 63.2 %

Procedure:
A trifluoroacetic acid (25 ml) solution of 3-carbomethoxy-5-chloro-2-hydroxyphenylacetaldehyde (5c) (5.20 g, 22.7 mmol) was refluxed for 2 hours under argon, and then poured into saturated Na2CO3. The resulting precipitate was collected by filtration, and then purified by column chromatography (100% CH2Cl2) to give 6c as a cream colored solid (3.02 g, 63.2% yield). Analytical sample was prepared by recrystallization from ethyl ether, mp 144°-145° C. IR (nujol) 1710 (ester) cm-1NMR (CDCl3) δ 7.87-6.70 (m, 4H, aromatic protons) and 4.0 (s, 3H, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:30]1[CH2:32][C@H:31]1[CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=1>>[OH:30][C@@H:31]([CH2:32][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1)[CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)sc2ccccc12
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4cccc(NC(C)=O)c4)cc3)CC2)sc2ccccc12
Yield: 23.4 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methoxy-1-benzothiophen-2-yl)methanone (0.170 g, 0.415 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.086 g, 0.415 mmol) according to Procedure G to give the title compound (0.06 g, 0.097 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[N:6][C:5]=1[CH:12]1[CH2:14][CH2:13]1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[C:7]([CH3:11])=[N:6][C:5]=1[CH:12]1[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(O)c(C)nc1C1CC1
Reactant: N#Cc1cccc(CBr)c1
Product: COC(=O)c1cc(OCc2cccc(C#N)c2)c(C)nc1C1CC1
Yield: 72.7 %

Procedure:
The coupling of 2-cyclopropyl-5-hydroxy-6-methyl-nicotinic acid methyl ester (183) (605 mg, 2.9 mmol) and α-bromo-m-tolunitrile (629 mg, 3.2 mmol), as described in Example 1, gave 5-(3-cyano-benzyloxy)-2-cyclopropyl-6-methyl-nicotinic acid methyl ester (184) (680 mg, 72% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([O:23][CH3:24])[CH:9]=1)(=[O:7])[CH3:6]>O>[C:5]([C:8]1[C:22]([N+:1]([O-:4])=[O:2])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([O:23][CH3:24])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CCCOc1ccc(C(C)=O)cc1OC
Solvent: O
Product: CCOC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
70% Nitric acid (60 mL) was cooled in an ice bath. Ethyl 4-(4-ethanoyl-2-methoxylphenoxy)butanoate (21 g, 0.075 mol) was added in portions over 20 minutes. The solution was stirred for 1.5 h while monitoring the temperature, which did not rise above 22° C. The solution was cautiously poured into water (800 mL), which was then cooled to 4° C. for several hours. The product was collected via filtration and recrystallized from ethanol (250 mL) to yield ethyl 4-(4-ethanoyl-2-methoxy-5-nitrophenoxy)butanoate (11.04 g, 45.3%) as a yellow flocculent powder. 1H NMR (δ, ppm): 1.31 (t, CO2CH2CH3), 2.21 (p, ArOCH2CH2CH2), 2.52 (s, ArCOCH3), 2.56 (t, ArOCH2CH2CH2), 3.98 (s, ArOCH3), 4.19 (m, ArOCH2 and CO2CH2), 6.76 (d, aromatic H ortho to ArOCH2), 7.65 (s, aromatic H ortho to ArOCH3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=O)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:6]2.[NH4+:34]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH2:34])=[O:29])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)=[N:6]2
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)c1
Solvent: CO
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(N)=O)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To methyl 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (Example 12) (0.020 g, 0.044 mmol) was added 7N ammonium in methanol (5 mL). The solution was heated in a sealed tube for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure to give 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzamide (0.015 g) as a yellow solid. 1H NMR (CDCl3): δ9.41 (s, 1H), 9.16 (s, 1H), 8.73 (d, J=7.3 Hz, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.23-8.17 (m, 1H), 7.75-7.59 (m, 3H) 7.26 (s, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.72 (s, 3H), 2.71 (s, 3H). MS m/z 435 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:14][C@H:15]1[CH2:20][CH2:19][O:18][C@@H:17]([C:21](OCC)=[O:22])[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([NH:14][C@H:15]1[CH2:20][CH2:19][O:18][C@@H:17]([CH2:21][OH:22])[CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@H]1C[C@@H](NCc2ccccc2)CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1C[C@@H](NCc2ccccc2)CCO1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
LiAlH4 (1.0 g, 26 mol) was added at 0° C. to a stirred solution of cis-ethyl 4-(benzylamino)-tetrahydro-2H-pyran-2-carboxylate (1.3 g, 5.0 mol) in anhydrous THF (50 mL). After stirring for 1 hour, the reaction was quenched by slow, sequential addition of water (1 mL), 15% NaOH (1 mL), and water (3 mL). The inorganic salt was filtered off, and the filtrated was diluted with EtOAc (50 mL), dried and concentrated to give cis-4-(benzylamino)-(tetrahydro-2H-pyran-2-yl)methanol (1.1 g, 100% yield). LCMS (ESI) m/z: 222.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(CCC(=O)OCc2ccccc2)cc1

Procedure:
3-(4-tert-Butoxycarbonylmethoxy-phenyl)-propionic acid benzyl ester (step 1) (10 g, 27 mmol) in DCM (100 ml) was treated with TFA (20 ml) and heated at reflux for 4 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo a further four times until a viscous oil of the title compound was obtained.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[S:26][CH2:27][CH3:28])[N:6]=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]([NH:3][CH2:1][CH3:2])[C:14]3[C:9](=[CH:10][C:11]([C:15]([F:17])([F:16])[F:18])=[CH:12][CH:13]=3)[N:8]=2)=[C:20]([S:26][CH2:27][CH3:28])[CH:21]=1
Reactant: CCN
Reactant: CCSc1cc(Cl)ccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(Cl)cc2SCC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 ml of ethylamine (a 70% aqueous solution) was added to a mixture of 600 mg of 4-chloro-2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 10 ml of THF, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 606 mg of 2-(4-chloro-2-ethylsulfanylphenyl)-4-ethylamino-7-trifluoromethylquinazoline (Compound of Present Invention 15).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:4].C(N(CC)CC)C.C1C[O:34][CH2:33][CH2:32]1.C(Cl)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:33](=[O:34])[CH3:32])[CH2:20][CH2:19]1)=[O:4]
Reactant: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCNCC1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a room temperature solution of 3-piperidin-4-yl-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (4.37 g, 12.7 mmol), triethylamine (2.70 mL.19.4 mmol), and anhydrous THF (80 mL) under nitrogen was added acetyl chloride (1.10 mL, 15.5 mmol) in one portion and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate (300 mL) and washed with water (150 mL) and brine (150 mL) successively. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed. The residue was chromatographed on silica, eluting with 10% methanol/ethyl acetate, to afford 4.28 g (88%) of the desired product as a white solid, mp: 155.2° C.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@@H]2O[C@@H](CN)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N.[NH2:34][C@H:35]([C:43](N)=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>>[NH2:34][C@H:35]([C:43]([OH:44])=[O:8])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41]
Reactant: NC[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@@H](O)[C@H](O)[C@H]1O
Reactant: N=C(N)NCCC[C@H](N)C(N)=O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
R4K was characterized as a free base and consisted, according to HPLC, of essentially one product, the kanamycin A derivative. The 1H NMR (400 MHz, D2O) spectrum revealed the presence of the characteristic groups of the protons of arginine amide moieties at chemical shifts of (δ) 3.38 (Hα), 3.21 (Hβ) and 1.64 ppm (Hγ,δ) All the characteristic kanamycin proton signals, in particular the anomeric hydrogens (as doublets at 4.99 and 5.15 ppm), were observed. Integration afforded 1:4 ratio of antibiotic to arginine components. A 13C NMR (100,609 MHz 10% D2O) spectrum of R4K revealed carbon resonances of the C-arginine amide moieties and the kanamycin moiety. The presence of antibiotic anomeric carbon signals at δ 101.77 and 101.07 ppm, the amide carbons at 181.13, 180.81, 180.38, 179.76 ppm and the guanidino carbons at 159.47 ppm 5 confirmed the structure of the aminoglycoside-arginine conjugate. FABHRMS of R4K revealed a mass peak of 1109.7 Da (calculated molecular weight of R4K: 1109.25 Da). A second peak of 1067.4 Da (−42.3 from mass peak) was attributed to a loss of aminoamino carbon fragment during ionization.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Part A: To a cooled (ice bath) solution of 2,4-dichlorobenzoyl chloride (5 mL, 35.66 mmol) in 50 mL CH2Cl2 was added phenol (3.13 mL, 35.66 mmol), followed by triethylamine (4.97 mL, 35.66 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The mixture was then partitioned between CH2Cl2 and water. The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo to yield 9.5 g of phenyl 2,4-dichlorobenzoate. MS (NH3-CI) 284 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:19])[C:3]=1OB(O)O.FC1C=C(C=C(F)C=1)C=O.[I-].C(OC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)C.C=CC1C=CC=CC=1.Br[C:73]1[CH:78]=[CH:77][C:76]([CH2:79][CH2:80][CH3:81])=[CH:75][CH:74]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:73]3[CH:78]=[CH:77][C:76]([CH2:79][CH2:80][CH3:81])=[CH:75][CH:74]=3)=[C:4]([F:19])[CH:5]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCCc1ccc(Br)cc1
Reactant: CCOc1ccc(CCc2cc(F)c(OB(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2c(F)cc(CCc3ccc(OCC)cc3)cc2F)cc1

Procedure:
A mixture of 9.2 g of 2,6-difluoro-4-[2-(p-ethoxyphenyl)ethyl]phenylboric acid (prepared by reacting 3,5-difluorobenzaldehyde with p-ethoxybenzyltriphenylphosphonium iodide by the Wittig method and subsequently hydrogenating the resulting styrene derivative on Pd/C), 6.0 g of 1-bromo-4-n-propylbenzene, 38 ml of 2 ml [sic] aqueous Na2CO3 solution, 0.6 g of tetrakis(triphenylphosphine)palladium(0) and 75 ml of toluene is refluxed for two hours. The aqueous phase is extracted twice with toluene and combined with the organic phase. Conventional aqueous work-up and chromatographic purification of the residue give 4-[2-(p-ethoxyphenyl)ethyl]-2,6-difluoro-4′-n-propylbiphenyl.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][C@@H:8]([NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][N:10]=[N+]=[N-])C(C)C.[ClH:25]>>[ClH:25].[S:14]([NH:13][C@@H:8]([CH2:9][NH2:10])[CH2:7][C:6]([OH:24])=[O:5])([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CN=[N+]=[N-])CC(=O)OCC(C)C)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN)CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
A solution of 1.1 g of 9 (3.0 mmol) in 143 ml of HCl 2N was hydrogenated in H2 atmosphere overnight at 60 psi. After this time the residue was filtered and the acqueous phase was left under magnetic stirring for additional 48 hours at 40° C. Then the water was evaporated under vacuum and the residue was taken up twice with CH3CN (evaporating under vacuum every time) until a solid residue, insoluble in CH3CN, was obtained. The pale yellow wax was filtered and dried to give 0.300 g of final product with a yield of 32% which was used without further purification;
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])([NH:21][C:22]([C:24]3[N:25]=[CH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[C:11]2=[O:40])=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:34][CH2:35][C:36]([O-:38])=[O:37])([NH:21][C:22]([C:24]3[N:25]=[CH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[C:11]2=[O:40])=[CH:6][CH:5]=1.[Na+:2]
Reactant: COC(=O)CCC1(NC(=O)c2cc3ccccc3cn2)C(=O)N(c2ccc(F)cc2)c2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2(CCC(=O)[O-])NC(=O)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.21 ml of 1N sodium hydroxide, 1.80 g of (+)-methyl 3-{1-(4-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinyl)carbonylamino]-6-methoxy-2-oxo-1H-indol-3-yl}propionate, and ethanol (20 ml) was stirred at room temperature overnight. After removal of solvent, the residue was purified by a nonionic adsorption resin (trade name: HP-20, produced by Mitsubishi Kasei Corporation) to afford 1.64 g of (+)-sodium 3-{1-(4-fluorophenyl)-2,3-dihydro-3-[(3-isoquinolinyl)carbonylamino]-6-methoxy-2-oxo-1H-indol-3-yl}propionate as a colorless powder. [α]D25 : +72.94° (c=0.414, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cccc2cnccc12
Product: O=C(NCc1ccccc1)Nc1cccc2cnccc12

Procedure:
Prepared from 5-aminoisoquinoline and benzyl isocyanate according to the procedure of Description 61. m/z (ES+) 278 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:3])[CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Reactant: CC(C)=CCCC(C)CCOC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)CCOC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
11.0 Grams (0.05 moles) of citronellyl chloroformate is added over a period of 1/2 hour to a stirred suspension of 10 grams (0.05 moles) of 2-(4-thiazolyl)benzimidazole and 75 ml. of pyridine at room temperature. The reaction mixture is stirred overnight at room temperature protected from moisture. The solid material is filtered, washed with pryidine and the filtrate and washings evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and the solution washed successively with dilute cold hydrochloric acid, cold water, cold dilute sodium bicarbonate solution and water. The methylene chloride is dried, evaporated to dryness in vacuo affording 16.6 grams of a viscous oil. The oil is chromatographed on a column of silica gel eluting with hexane affording 14.6 grams (76%) of an oil which thin layer chromatography reveals to be pure material and which analyzes as 1-citronellyloxycarbonyl-2-(4-thiazolyl)benzimidazole.