Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:32][CH2:33][CH2:34]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cn1cnc(-c2ccc(C#N)cc2)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1

Procedure:
4-(5-Chloro-1-methyl-1H-imidazol-4-yl)benzonitrile (1 g), 4-chlorobenzenethiol (797 mg), and 1.3 ml of triethylamine in 20 mL of DMF were heated in a microwave tube at 180° C. for 90 min. The reaction mixture was purified by reverse phase HPLC with MS detector to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.21 (d, 2H), 7.83 (s, 1H), 7.66 (d, 2H), 7.45 (d, 2H), 6.98 (d, 2H), 3.63 (s, 3H). LCMS: [M+1]=326.
Reaction SMILES: BrBr.[Br-:3].[Al+3].[Br-:5].[Br-].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:18](=[O:20])[CH3:19])[CH2:14]2.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:3][C:11]12[CH2:16][CH:7]3[CH2:14][C:13]([Br:5])([CH2:15][CH:9]([CH:8]3[NH:17][C:18](=[O:20])[CH3:19])[CH2:10]1)[CH2:12]2
Reactant: CC(=O)NC1C2CC3CC(C2)CC1C3
Reactant: [Br-]
Agent: BrBr
Agent: O=S([O-])O
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)NC1C2CC3(Br)CC1CC(Br)(C2)C3
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To bromine (20 mL, 40 mmol) and aluminum bromide (3.2 g, 20 mmol) was added N-(2-adamantyl)acetamide (4 g, 20 mmol) in portions. The reaction mixture was heated to 90° C. and stirred overnight. The mixture was cooled to rt and poured into ice/water. Satd aq sodium bisulfite was added slowly followed by dilution with CH2Cl2. The organic layer was separated, washed with brine, dried, filtered and concentrated. The crude product was purified by column chromatography to afford N-(5,7-dibromo-2-adamantyl)acetamide (1.98 g, 28%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([O:24][CH3:25])[N:15]3C3CCCCO3)=[C:11]([NH2:26])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>CO>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([O:24][CH3:25])[NH:15]3)=[C:11]([NH2:26])[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.7132 g, crude) was dissolved in methanol (5 mL). To this solution was added neat trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at ambient room temperature for 18 hours. The solvent was evaporated under reduced pressure and residue triturated with ethyl acetate (50 mL). The white resultant solid was filtered, washed using diethyl ether (10 mL) and then dried under suction. This gave clean title compound as a white solid (0.2799 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:20][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 88.8 %

Procedure:
4-Oxopiperidine-1-carboxylic acid tert-butyl ester (8.0 g; 40.2 mmol) was dissolved in toluene (80 mL). Carboethoxymethylene triphenylphosphorane (17.5 g; 50.2 mmol) was added and the reaction mixture was heated 12 hours at reflux. The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica (4.5×30 cm) using diethyl ether/heptane (1:1) as eluent to afford 9.5 g (35.7 mmol) of 4-Ethoxycarbonylmethylenepiperidine-1-carboxylic acid tert-butyl ester, which was dissolved in 1,4-dioxane and cooled to 0° C. Lithium hydroxide (2.73 g; 114 mmol) was dissolved in water (20 mL) and added. The reaction mixture was stirred for 12 hours at room temperature. Ethyl acetate (200 mL) and water (100 mL) was added. Sodium hydrogen sulfate (10%; aqueous solution) was added to pH 2. The organic phase was washed with water (100 mL), dried (magnesium sulfate) and evaporated in vacuo to afford 5.49 g of 4carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6]/[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12](/[C:5](=[CH:6]\[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])/[CH2:4][OH:3])=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C/C=C(/CO)c1ccc(S(C)(=O)=O)cc1
Yield: 57.6 %

Procedure:
Reduction of (E)-2-(4-methanesulfonyl-phenyl)-5,5-dimethyl-hex-2-enoic acid ethyl ester (710 mg, 2.15 mmol) with DIBAL in toluene (3.85 ml, 4.67 mmol) following the method of example 54e gives the title compound as an amorphous solid (350 mg). MS (m/e): 283 (M+H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])[CH:12]=2)=[O:7])CCC.C1CC2N(C3C=C(C=C(C4C=CC=CC=4)C4C=CC=CC=4)C=CC=3)C3C(C2C1)=C(/C=C1/C([N:43]([CH2:47][C:48]([OH:50])=[O:49])C(S/1)=S)=O)C=CC=3>>[C:21]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:43][CH2:47][C:48]([OH:50])=[O:49])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)c3ccccc3)ccc2c1O
Reactant: O=C(O)CN1C(=O)/C(=C/c2cccc3c2C2CCCC2N3c2cccc(C=C(c3ccccc3)c3ccccc3)c2)SC1=S
Product: O=C(O)CNC(=O)c1ncc2cc(S(=O)c3ccccc3)ccc2c1O

Procedure:
Prepared in analogy to Example D-1 g) from 7-benzenesulfinyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (Compound D-102 A). MS-(+)-ion: M+1=371.1.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[O:41]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:46][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: OCC1CCOC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCOC1
Reaction time: 18 h
Yield: 30.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), tetrahydro-3-furanmethanol (90 mg, 0.88 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (12 ml) and the mixture stirred for 18 hours. The mixture was diluted with ether, and the resulting precipitate was removed by filtration. The solvent was removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (0.75 ml of a 1M solution, 0.75 mmol) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (a gradient from 50150/1 to 50/5012). The purified product was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(tetrahydrofuran-3-ylmethoxy)quinazoline (93 mg, 31%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4]>C1COCC1.O>[OH:4][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4ccccc4CO)cc3)CCCCN12
Reaction time: 0.5 h
Yield: 93438.5 %

Procedure:
NaBH4 (13.7 mg) was added to a solution of 6-[4-(2-formyl-phenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]-nonane-7,9-dione (0.178 mg) in THF (5 mL) at 0° C. After stirring for 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2, Chromatotron) afforded the titled compound (167 mg). MS (m/z) 477 (M+-OH).
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].C([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=O)C>C(O)(=O)C>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH2:34])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 82.8 %

Procedure:
A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqeous NaHCO3 (250 mL×2), brine (250 mL×2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuo at 60° C. to a constant weight, affording 19.4 g (75% yield) of S-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
Reaction SMILES: [ClH:1].Cl.Cl.O[N:5]([CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])[C:6]([NH2:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17].S(O)(O)(=O)=O.[NH2:34]N.C(=O)([O-])O.[K+]>CN(C)C=O>[ClH:1].[ClH:1].[ClH:1].[NH2:34][NH:18][C:6]([NH:5][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17]
Reactant: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CSCCN=C(NN)NCCSCc1[nH]cnc1C
Reaction time: 3 h

Procedure:
A mixture of the isothiourea trihydrochloride from Example 2 (ii) (5.1 g), hydrazine sulphate (1.6 g), potassium hydrogen carbonate (7.0 g) and anhydrous dimethyl formamide (60 ml) was stirred at 70° for 3 hours. Following cooling and filtration the filtrate containing the free base was treated with an excess of ethanolic hydrogen chloride to give the title compound.
Reaction SMILES: P(=O)(O)O.C[O:6][P:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]([CH3:37])=[C:18]2[CH2:38][C:39]([NH2:41])=[O:40])(=[O:10])[O:8]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:41][C:39](=[O:40])[CH2:38][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][P:7](=[O:6])([OH:10])[OH:8])[CH:16]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]=1[CH3:37]
Reactant: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1-c1ccccc1)OC
Agent: C[Si](C)(C)Br
Agent: O=[PH](O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1ccccc1-c1ccccc1
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
[3-[[3-(2-Amino)-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid. [3-[[3-(2-Amino-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (130 mg, 0.25 mmol) and 0.3 mL (3 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 41 mg (33% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 200-202° C.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH3:17])[CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(N)c(N)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a solution of ethyl 4-amino-2-methoxy-5-nitrobenzoate (248 mg, 1.03 mmol) in methanol (20 ml) was added 5% palladium on activated carbon (85 mg) and the mixture stirred vigorously at room temperature under a hydrogen atmosphere for 18 h. The reaction mixture was then filtered through celite, the catalyst/residue washed with methanol and the combined filtrate and washings concentrated to give crude ethyl 4,5-diamino-2-methoxybenzoate (220 mg, 100%) as a dark-brown material, which was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[NH:3][C:2]1=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH:23](I)[CH3:24].[OH-].[K+]>C(O)C>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:3]1[C:4]2[CH:13]=[CH:12][C:11]3[C:6]([C:5]=2[S:1][C:2]1=[O:14])=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: COCCOCCOC(C)I
Reactant: O=c1[nH]c2ccc3ccccc3c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCCOCCOCCn1c(=O)sc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.0 g of naphtho[2,1-d]thiazoline-2-on, 3.0 g of 2-methoxyethoxyethoxy-1-iodoethane (synthesized from methoxyethoxyethoxyethyl p-toluenesulfonate and sodium iodide), 0.6 g of potassium hydroxide and 20 ml of ethanol were fed into a 50 ml short-neck flask provided with a reflux condenser, and heated under reflux and under stirring for 4 hours. After cooling to room temperature followed by extraction with 300 ml of ethyl acetate and 150 ml of water, the thus-obtained ethyl acetate layer was dried over sodium sulfate, and ethyl acetate was distilled off under reduced pressure. The obtained compound was purified by column chromatography (hexane:ethyl acetate=1:1) to obtain the intended compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:12]1[N:13]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:14]=[CH:15][C:16]=1[C:17]([O:19]C(C)(C)C)=[O:18])[CH2:10][CH3:11])=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[NH2:8][C@@H:9]([C:12]1[N:13]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18])[CH2:10][CH3:11].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:8][C@@H:9]([C:12]1[N:13]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18])[CH2:10][CH3:11]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1c(C(=O)OC(C)(C)C)ccn1S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)c1c(C(=O)O)ccn1S(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C

Procedure:
An orange solution of (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)propyl)-1-tosyl-1H-pyrrole-3-carboxylate (505c, 6.19 g, 12.93 mmol) in DCM (15 mL) was treated with TFA (15 mL, 202 mmol) and heated at 40° C. for 4 h. The TFA and DCM was removed in vacuo affording (R)-2-(1-aminopropyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with TFA (1:1) as a viscous orange oil (505d) which was used the next step without further purification. m/z (ESI, +ve) 323.1 (M+1)′.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH:32]([CH3:33])[CH3:34])[C:25]=5[F:24])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)Oc1cccc(B(O)O)c1F
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(OC(C)C)c4F)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-fluoro-3-isopropoxyphenylboronic acid (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.91 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.11-8.07 (m, 2H), 7.77-7.73 (m, 1H), 7.56-7.54 (m, 1H), 7.22-7.15 (m, 2H), 6.99-6.92 (m, 1H), 4.64 (hp, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H), 1.33-1.28 (m, 6H))
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:32]1([O:41][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.Cl.NO.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([NH:4][C:5](=[O:24])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:32][OH:41])=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccc(C(=Cc2ccc(C(=O)O)cc2)C(=O)NC2CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=Cc2ccc(C(=O)NO)cc2)C(=O)NC2CC2)cc1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a suspension of 4-(3-(cyclopropylamino)-2-(p-tolyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.1 g, 0.3 mmol) in DMF (3 mL), benzotriazol-1-yloxy-tris(dimethyl amino)phosphonium hexafluorophosphate (BOP reagent, 0.23 g, 0.55 mmol), HOBt (0.04 g, 0.3 mmol), hydroxylamine hydrochloride (0.03 g, 0.35 mmol), were added followed by DIPEA (0.16 mL, 0.9 mmol). The reaction mixture was stirred for 1 hour, after which the mixture was added to cold water (100 mL) and kept it for 1 hour at 0° C. the white solid formed. The obtained solid was filtered and washed with water (50 mL), dried under vacuum to afford the title compound as white solid (0.080 g, 77% yield). 1H NMR (DMSO-d6) δ (ppm): 0.46-0.51 (2H, m, —CH2), 0.58-0.60 (2H, m, —CH2), 2.29 (3H, s, CH3), 2.69-2.70 (1H, m, —CH), 6.81 (4H, m, Ar—H), 6.97-7.03 (3H, m, Ar—H), 7.36-7.38 (I+1H, d, Ar—H and ═CH), 7.70 (1H, d, NH), 8.99 (1H, s, OH), 11.10 (1H, s, NH), MS m/z: 337.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][F:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH2:20][CH2:21][CH2:22][F:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCF)Cc1ccc(Br)cc1
Reaction time: 24 h
Yield: 45.6 %

Procedure:
To a solution of compound 138 (286 mg, 1.0 mmol) in anhydrous DMF (3.0 mL) was added sodium hydride (NaH, 60% oil dispersion, 48.0 mg, 1.2 mmol, 1.2 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before 1-bromo-3-fluoropropane 139 (170 mg, 1.2 mmol, 1.2 equiv) was added. The reaction mixture was subsequently warmed to 50–60° C. and stirred for 24 hours. The reaction mixture was then quenched with H2O (10 mL), and the resulting aqueous solution was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H2O (10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (10–15% EtOAc/hexane gradient elution) to afford bromide 136 (158 mg, 46% yield) as a colorless oil.