Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[CH2:31])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=[CH:12][C:7]=1/[CH:31]=[CH:30]/[C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1c(Br)c(/C=C/c2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 6.5 %

Procedure:
A mixture of 3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0023 mol), and 4-fluorostyrene (0.33 mL, 0.0028 mol) in degassed DMF (100 ml) containing diisopropyl ethyl amine (0.37 g, 0.0029 mol) was treated with PdCl2(PPh3)2 (0.32 g, 0.46 mmol) and heated at 65° C. under argon atmosphere for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford a yellow substance which was further purified by by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2SO4). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.06 g, 6%) as yellow powder: 1H NMR (CD3OD/400 MHz) δ 7.68 (m, 3H), 7.39 (m, 3H), 7.2-7.0 (m, 5H), 6.82 (d, 1H, J=7.2 Hz), and 5.22 (s, 2H); 19F NMR (CD3OD/400 MHz) δ−113.9 (m) and −115 (m); ES-HRMS m/z 402.0305 (M+HC20H15NOF2Br, requires 402.0300).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[C:28](=[O:39])[N:27]([CH3:40])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n1
Reaction time: 0.33 h
Yield: 15.4 %

Procedure:
At 0° C., to a suspension of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(2-methylpyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde 114c (130 mg, 0.24 mmol) in methanol (20 mL) was added sodium borohydride (27 mg, 0.72 mmol). The reaction mixture was stirred for 20 minutes and then quenched with water (10 mL). It was then concentrated under reduced pressure and the residue was extracted with dichloromethane (3×20 mL). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 114 (20 mg, 15%) as a white solid. MS-ESI: [M+H]+ 542.3. 1H NMR (500 MHz, CDCl3) 8.97 (d, J=2.5 Hz, 1H), 8.71 (d, J=5.0 Hz, 1H, 8.36 (d, J=2.0 Hz, 1H), 8.28 (d, J=5.5 Hz, 1H), 8.09-8.06 (m, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.60-7.56 (m, 3H), 6.61 (d, J=6.0 Hz, 1H), 4.54-4.43 (m, 2H), 4.16-4.13 (m, 1H), 3.75 (s, 3H), 2.62 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1)([O-])=O>CCOC(C)=O.CCO.O=[Pt]=O>[CH2:9]([N:7]1[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnn(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-nitro-1-phenethyl-1H-pyrazole (2.78 g, 12.87 mmol), in EtOAc (6 mL, degassed) and EtOH (18 mL, degassed), PtO2 (235 mg, 1.2 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound I-phenethyl-1H-pyrazol-4-ylamine as red solid. LC-MS conditions A: tR=0.54 min, [M+MeCN+H]+=229.04.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>C(OCC)(=O)C.[Pd]>[NH2:12][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(O)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
A suspension of methyl 3-hydroxy-2-nitrobenzoate (14 g, 71 mmol) and 10% Pd/C (1.4 g) in ethyl acetate (300 mL) was purged in 1 atm hydrogen and stirred at 25° C. for 4 hr. The mixture was filtered, and the filtrate was concentrated to give methyl 2-amino-3-hydroxybenzoate (11.5 g, yield 97%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.88 (s, 1H), 5.84 (s, br 3H), 6.50-6.54 (t, J=8.0 Hz, 1H), 6.84-6.86 (d, J=7.2 Hz, 1H), 7.47-7.49 (d, J=7.6 Hz, 1H); LC-MS (ESI) m/z 168 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=S)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=[N:30][CH2:29][CH2:28][CH2:27][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: Clc1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Yield: 34 %

Procedure:
A mixture of 2.5 g of 1-p-chlorophenylmethylbenz[cd]indole-2(1H)-thione (Cp), 1.1 g of 1H-imidazole -1-propanamine, 200 ml of ethyl alcohol, and 2.6 g of mercuric acetate is reacted as described in Example 3, giving 1.1 g of the desired product, mp. 90°-91° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([C:13]#[C:14][CH2:15][OH:16])[CH:10]=[CH:11][CH:12]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].[NH4+].[Cl-]>C1COCC1>[C:19]([CH2:18][O:3][CH2:4][C:5]#[C:6][C:7]1[CH:8]=[C:9]([C:13]#[C:14][CH2:15][O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][CH:12]=1)([OH:21])=[O:20]
Reactant: COC(=O)CBr
Reactant: OCC#Cc1cccc(C#CCO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)COCC#Cc1cccc(C#CCOCC(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A 60% suspension of NaH (2.1 g, 53.7 mmol) is added to a solution of 3-[3-(3-hydroxyprop-1-ynyl)phenyl]prop-2-yn-1-ol (A5, 0.5 g, 2.68 mmol) in absolute THF (20 ml), and the mixture is stirred at 70° C. for 2 h. After cooling to RT, methyl bromoacetate (5.2 ml, 53.7 mmol) is added dropwise to the reaction solution, and the mixture is stirred at RT overnight. For work-up, the reaction solution is poured into an ice-cooled semisaturated aqueous NH4Cl solution (25 ml) and extracted (2×) with ethyl acetate. The combined organic phases are dried over MgSO4, filtered off and concentrated under reduced pressure. Further purification by chromatography [Tol/Ac (9:1)] over a silica gel column gives the title compound (0.85 g) as a colorless residue. TLC, silica gel, glass plates, [Tol/Ac (7:3)], Rf=0.80.
Reaction SMILES: [C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][O:29][P:30](=[O:47])([O:39]CC3C=CC=CC=3)[O:31]CC3C=CC=CC=3)[C:14]2=[O:48])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[N:15]([CH2:28][O:29][P:30](=[O:31])([OH:39])[OH:47])[C:14]2=[O:48])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: [H][H]
Reactant: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1COP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C(=O)N1COP(=O)(O)O

Procedure:
The phosphoric acid dibenzyl ester of (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-1-yl-methyl ester (0.160 g) in methanol (2 ml) and Pd/C (10%, 20 mg) was stirred at room temperature under 1 atmosphere of hydrogen for two hours. The mixture was filtered over Celite and the solvent removed to give (±)-phosphoric acid mono-[trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-1-ylmethyl]ester (0.110 g).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC2C=CC=CC=2)=[CH:10][CH:9]=1>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:26])=[O:25])=[CH:13][CH:12]=1
Reactant: CN(C)CCNC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(N)cc1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
Pd-C (1 g) was added to a methanol (140 ml) solution of benzyl 4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenylcarbamate (10 g), which was stirred under hydrogen atmosphere for 1 hour. Pd-C was removed, and the filtrate was concentrated. The residue was purified by alumina column chromatography (development solvent; ethyl acetate:hexane=1:1), to give the titled compound (6.63 g) as an oily substance.
Reaction SMILES: C1(C([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)/[C:27]([O-:29])=O)[N:25]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:88](=[O:89])[N:60]2[C:61]([C:72]([O:74]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:73])=[C:62]([CH2:65][CH:66]3[O:70][C:69](=[O:71])[CH:68]=[CH:67]3)[CH2:63][S:64][C@H:59]12>CN(C=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([NH:57][C@@H:58]2[C:88](=[O:89])[N:60]3[C:61]([C:72]([OH:74])=[O:73])=[C:62]([CH2:65][CH:66]4[O:70][C:69](=[O:71])[CH:68]=[CH:67]4)[CH2:63][S:64][C@H:59]23)=[O:29])[N:25]=1
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC3C=CC(=O)O3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CC4C=CC(=O)O4)CS[C@H]23)cs1
Yield: 82.8 %

Procedure:
Sodium 2-(2-triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyiminoacetate (1.33 g) in DMF (5 mls) was activated with methanesulphonyl chloride (0.148 mls) as described in example 7(a). Treatment with diphenylmethyl 7β-amino-3-[(5RS)-2,5-dihydro-2-oxofuran-5-ylmethyl]ceph-3-em-4-carboxylate (0.737 g) in DMF (5 mls), work up and purification by repeated flash, silica gel chromatography afforded major isomer of the title compound, (0.614 g, 35%), νmax 3380(w), 1785, 1770 (shoulder), 1755 (shoulder), 1725, 1685, 1510 and 1370cm-1 ; δH (CDCl3) 2.25 (1H, dd, J 9.9, 13.7Hz), 3.16 (1H, dd, J 2.9, 13.7Hz), 3.49 and 3.53 (2H, ABq, J 18.7Hz), 5.03 (1H, d, J 4.9Hz), 5.22 (1H, J 7.9Hz), 6.05 (1H, dd, J 1.9, 5.7Hz), 6.14 (1H, dd, J 4.9, 9.1Hz), 6.45 (1H, s), 6.76 (1H, broad s, exch.), 6.90 (1H, s), 7.07 (1H, d, J 9.1Hz, exch.), 7.19 (1H, dd, J 1.4, 5.7Hz) and 7.24 to 7.50 (40H, m); [mass spectrum: +ve ion (NOBA, Na+) MNa+ 1138]. The minor isomer was not progressed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12].[O-:13][CH2:14][CH3:15].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:13][CH2:14][CH3:15])[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:12]
Reactant: CC[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C)[n+]([O-])c(Br)c1
Yield: 83.7 %

Procedure:
2-Bromo-6-methyl-4-nitro-pyridine 1-oxide (1 g, 4.3 mmol) was dissolved in ethanol (anhydrous, 50 ml), and sodium ethoxide (21% in ethanol, 1.4 ml, 4.3 mmol) was added dropwise with stirring. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, the residue was taken up in DCM (50 ml), the mixture was washed with water (50 ml), dried (sodium sulfate) and concentrated under reduced pressure to yield 0.84 g of brown yellow crystals (3.6 mmol, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19]CC)=O)=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([NH:23][NH2:24])=[O:19])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Solvent: O
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(O)cc2C(=O)NN)c1
Temperature: 95 °C
Reaction time: 46 h

Procedure:
To a solution of ethyl 2′-fluoro-4-hydroxy-5′-methoxy-[1,1′-biphenyl]-2-carboxylate (1.37 g) in ethanol (15 mL) was added hydrazine monohydrate (4.47 mL), and the mixture was stirred at 95° C. for 46 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (1.05 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][NH:33][C:34]([NH:36][OH:37])=[NH:35].[ClH:38]>C(O)C>[ClH:38].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:32][NH:33][C:34](=[NH:35])[NH:36][OH:37])[CH2:10]1
Reactant: N=C(NN)NO
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)ccnc3C2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2CC(=NNC(=N)NO)c3c(C)ccnc3C2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2,5-dimethylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (100 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (131 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (2 ml) was stirred at 85° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (20 ml), tetrahydrofuran (12 ml) and 0.2 N sodium hydroxide (10 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (5 ml) and water (5 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.5 ml), and the mixture was concentrated under reduced pressure. The residue was washed with a mixture of ether (4 ml) and ethanol (2 ml), and dried to give 7-(2,5-dimethylphenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 94) (121 mg) as yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])C.[OH-].[K+].Cl>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:15])=[O:3])=[C:6]([O:12][CH2:13][CH3:14])[CH:7]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(Cl)ccc1C(=O)O

Procedure:
4-Chloro-2-ethoxybenzoic acid ethyl ester (˜18 g) was suspended in ethanol (500 mL). This was treated with potassium hydroxide (200 mL, 2 M solution) and refluxed for 1 h. The reaction was cooled and poured into cold aqueous hydrochloric acid (300 mL, 3 M solution) and extracted into dichloromethane (3×500 mL). The dichloromethane was washed with water (500 mL) and dried over magnesium sulfate and evaporated to dryness to give 4-chloro-2-ethoxy-benzoic acid as a solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[CH:22]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:13]([CH3:17])[CH:12]=1)=[O:23]
Reactant: COc1ccc2c(ccn2C)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(C=O)cn2C
Temperature: 110 °C

Procedure:
While cooling in order to maintain the temperature of the reaction medium below 15° C., phosphorus oxychloride (9 ml) is added dropwise to 35 ml of dimethylformamide (DMF), and 5-methoxy-1-methylindole (14.1 g), dissolved in DMF (25 ml) is added in a single portion. The resulting heterogeneous mixture is heated to 110° C. for 1 minute, and then maintained at 65° C. for 30 minutes while being stirred mechanically. After the mixture has been allowed to cool, it is decomposed by adding 200 ml of ice-cold water, and then treated with 5N sodium hydroxide solution (100 ml). The precipitate formed is filtered off and recrystallized in ethanol, to give 14.53 g (87.7%) of colorless scales, m.p.=134° C.
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11]COC)[CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.C1CCCCC1.CN(C)[CH:28]=[O:29].Cl>O1CCCC1>[CH:1]1([C:5]2[C:6]([OH:11])=[C:7]([CH:8]=[CH:9][CH:10]=2)[CH:28]=[O:29])[CH2:2][CH2:3][CH2:4]1
Reactant: CN(C)C=O
Reactant: COCOc1ccccc1C1CCC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1cccc(C2CCC2)c1O
Reaction time: 2 h

Procedure:
1-cyclobutyl-2-methoxymethoxybenzene (1.18 g) was dissolved in tetrahydrofuran (11 mL), and a 1.01M s-butyllithium-cyclohexane solution (8.7 mL) was added to the solution at −60° C. over 15 minutes under an argon gas flow, and then the mixture was stirred for 2 hours. N,N-dimethylformamide (0.90 mL) was added and the mixture was stirred at the same temperature for 2 hours. 4N hydrochloric acid (15 mL) was added at room temperature, and then the mixture was stirred at 60° C. for 20 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to obtain the title compound (0.95 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.NC(N)=O.[C:13](=[O:18])([O:15][CH2:16][CH3:17])N.C(O)C>ClC1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CCOC(N)=O
Reactant: Nc1ccc(Cl)cc1
Agent: NC(N)=O
Solvent: Clc1ccccc1
Solvent: CCO
Product: CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Following the procedure described in Example 1, 638 g of 4-chloroaniline, 240 g of urea, 89 g of ethyl carbamate, 625 g of ethanol (approximately 96%) and 1400 g of chlorobenzene were reacted for 6.5 hours at 200° C. in the pressure apparatus described in Example 1. After the apparatus had been cooled and vented, the reaction mixture was removed. Excess ethanol was removed by fractional distillation at atmospheric pressure. The mixture (while being stirred) was then exposed to hydrogen chloride gas at room temperature, filtered and subjected to fractional distillation in vacuo. Chlorobenzene was separated off at 15 mbar. Subsequent distillation at 0.2 mbar yielded 785 g (78.6% of the theoretical yield) of N-(4-chlorophenyl)-carbamic acid ethyl ester melting at from 68° to 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH:20]([S:23]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][N:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:24])=[O:25])=[N:27]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CC(C)S(=O)(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole (72 mg, 0.22 mmol), 3-(isopropylsulfonyl)-1H-indazole (50 mg, 0.22 mmol), K2CO3 (61 mg, 0.44 mmol) and DMF (1.5 mL) was stirred at RT overnight. The resultant mixture was purified by pre-HPLC to give 1-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-3-(propan-2-ylsulfonyl)-1H-indazole as white solid (31.0 mg, yield: 27.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:34]=CC)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:37]1CCCC1>O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:34]=[O:37])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL) was added OsO4 (1.65 mL, 0.270 mmole). Then a solution of NalO4 (9.45 g, 44.2 mmole) in water (100 mL) was added dropwise. The reaction was stirred at room temperature under nitrogen overnight. Water (250 mL) was added to the mixture and it was then extracted with ethyl acetate. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of the title compound as a yellow solid. 1H (CDCl3) broad singlet 10.8 δ (1H); singlet 10.1 δ (1H); doublet 7.9 δ (1H); doublet 7.8 δ (2H); multiplet 7.4 δ (7H); doublet 7.0 δ (1H); singlet 5.2 δ(2H); multiplet 4.5 δ (1H); multiplet 4.2 δ (3H); multiplet 4.1 6 δ (1H); singlet 2.4 δ (3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN1C(=O)CCC1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCBr
Reactant: c1ccc(-c2cc3c(nc2-c2ccccc2)NCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCCCN1CCCc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A solution of 6,7-diphenyl-1,2,3,4-tetrahydro-[1,8]naphthyridine (Intermediate B) (200 mg, 0.698 mmol) in dry NMP (1 ml) under N2 was treated with cesium carbonate (910 mg, 2.79 mmol) and ethyl 7-bromoheptanoate (0.544 ml, 2.79 mmol). The reaction mixture was stirred at 120° C. for 1 h and a further 3 h at 140° C. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 4:1 iso-hexane/EtOAc afforded a pink oil residue.