Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#N.C[O-].[Na+].C(O)(=O)C>CO.CC(O)=O.[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]5[N:33]=[C:37]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=6)[NH:34][C:29]=5[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(N)c([N+](=O)[O-])c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4nc(-c5ccccn5)[nH]c4c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
The 4-[6-(4-Methyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-2-nitro-phenylamine (0.5 g, 0.99 mmol), was dissolved in 7:3 MeOH/HOAc (100 ml), and hydrogenated in the presence of 5% palladium on carbon (100 mg), overnight. The solution was then filtered through celite, washed with methanol (50 ml), and evaporated. The resulting diamine was dissolved in methanol (20 ml). To this was added a solution of 2-cyanopyridine (154 mg, 1.5 mmol) that had been treated (immediately before) with sodium methoxide (0.15 mmol) in methanol (2 mL) at 40° C. for 1.5 hour under nitrogen. To this mixture, acetic acid (0.21 ml, 3.8 mmol) was added. This mixture was heated at 80° C. overnight under nitrogen followed by cooling to room temperature, and removing the solvents under reduced pressure. Next the residue treated with a 5% aqueous ammonia solution, incubated at 5° C. over one day, decanted the aqueous layer, washed well with water. Resulting light tan solid was isolated and washed with ether to give the product 150 mg (15% yield). The material while not completely pure, could be taken to next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:42]=[CH:41][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[C:22]2[CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:30][C:21]=2[C:20]=4[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH:35]1([C:20]2[C:21]3[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][C:22]=3[N:23]3[C:19]=2[C:18]2[CH:41]=[CH:42][C:15]([O:14][CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[CH:16][C:17]=2[O:26][CH2:25][CH2:24]3)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1-3
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCNC2)ccc1-3
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
Methyl 3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g) was dissolved in trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 3 hr. Toluene was added to the reaction mixture and the solvent was evaporated under reduced pressure. 4N HCl-ethyl acetate solution (2.0 ml) was added to the obtained residue and the mixture was stirred, and the solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give methyl 12-cyclohexyl-3-(piperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.16 g, yield 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH:18](OC(C)(C)C)=O>>[N+:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)#[C-:18]
Reactant: CC(C)(C)OC=O
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Product: [C-]#[N+]c1ccc2cnn(C(=O)OC(C)(C)C)c2c1

Procedure:
Intermediate 8 was prepared in a similar manner as Intermediate 6 from tert-butyl 6-amino-1H-indazole-1-carboxylate. 1H NMR (400 MHz, CDCl3) δ 8.28 (1H, s), 8.20 (1H, s), 7.76 (1H, d, J=8.34 Hz), 7.28-7.40 (1H, m), 1.74 (9H, s) ppm. MS (ESI) m/z: 144 (M+H-Boc)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:26]=[CH:25][C:14]2[C:15]([CH2:18][CH2:19]OS(C)(=O)=O)=[CH:16][O:17][C:13]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[NH:33]1[CH2:43][CH2:42][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH2:34]1>CC#N>[CH2:40]([O:39][C:37]([CH:36]1[CH2:42][CH2:43][N:33]([CH2:19][CH2:18][C:15]2[C:14]3[CH:25]=[CH:26][C:11]([O:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][C:13]=3[O:17][CH:16]=2)[CH2:34][CH2:35]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCc2coc3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 70 °C
Yield: 47.9 %

Procedure:
To a suspension of methanesulfonic acid 2-[6-(benzothiazol-2-yloxy)-benzofuran-3-yl]-ethyl ester (200 mg, 0.5 mmol) and K2CO3 (78 mg, 0.6 mmol) in MeCN (5.2 mL) was added ethyl isonipecotate (0.08 mL, 0.5 mmol) and the reaction mixture was heated (70° C., 48 h). The reaction mixture was filtered, concentrated in vacuo and the resulting residue was partitioned between EtOAc and brine (20 mL each). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (20-80%) to provide the title compound as a clear oil (108 mg, 47%). MS (ESI): mass calcd. for C25H26N2O4S, 450.6; m/z found, 451.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.43 (d, J=8.5, 1H), 7.65 (d, J=8.0, 1H), 7.58 (d, J=8.5, 1H), 7.54 (s, 1H), 7.51 (d, J=1.5, 1H), 7.39-7.36 (m, 1H), 7.27-7.24 (m, 2H), 4.14 (q, J=7.0, 2H), 2.98 (d, J=11.5, 2H), 2.89-2.85 (m, 2H), 2.69-2.66 (m, 2H), 2.34-2.29 (m, 1H), 2.14-2.10 (m, 2H), 1.96-2.94 (m, 2H), 1.85-1.77 (m, 2H), 1.26 (t, J=7.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1cccnc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Yield: 71.5 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.7 mmol) and pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) the title compound of Step A was obtained (2.9 g, 71.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H), 3.47-3.57 (m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1.[CH3:32][NH2:33]>>[CH3:30][C:28]1[NH:27][N:26]=[C:25]([NH:24][C:7]2[N:6]3[CH:31]=[C:3]([CH2:2][NH:33][CH3:32])[N:4]=[C:5]3[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:29]=1
Reactant: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CO)cn23)n[nH]1
Reactant: CN
Product: CNCc1cn2c(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)cc2n1

Procedure:
The title compound was synthesized using N-(4-(2-(hydroxymethyl)-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-7-ylthio)phenyl)cyclopropanecarboxamide and methyl amine using the procedure described in Example 283. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=5.56 Hz, 4H) 1.82 (dt, J=12.06, 5.97 Hz, 1H) 2.11 (s, 3H) 3.28 (s, 3H) 4.03 (s, 2H) 5.84 (s, 1H) 6.49 (s, 1H) 7.53 (d, J=8.08 Hz, 2H) 7.75 (d, J=8.08 Hz, 2H) 8.27 (s, 1H) 10.48 (s, 1H) 12.12 (s, 1H); ESI-MS: m/z calc'd for C22H24N8OS 448.54; found 449.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:16](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]3[C:16]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[NH:4][C:5]=3[S:9][C:8]=2[CH:10]=1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(OC)ccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c3c(sc2c1)Nc1ccccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-aminoanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:25]1([CH2:24][NH:23][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[N:15][CH:16]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Product: O=C(NCC1CC1)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 97 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using aminomethylcyclopropane instead of 4-aminotetrahydropyran to the title compound (80 mg, 97%) which was obtained as a white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([OH:28])=[C:4]([C:29]([O:31][CH3:32])=[O:30])[C:3]=1[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.CC(C)=O>[C:44]1([CH2:43][O:28][C:5]2[C:6]3[C:11](=[C:10]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=[CH:8][C:7]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:2]([O:1][CH2:33][C:3]3[CH:4]=[CH:5][CH:6]=[CH:11][CH:2]=3)=[C:3]([C:33]([O:35][CH3:36])=[O:34])[C:4]=2[C:29]([O:31][CH3:32])=[O:30])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)c1c(C(=O)OC)c(O)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(OCc2ccccc2)c2c(OCc3ccccc3)ccc(OCc3ccccc3)c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.00 g of dimethyl 1,4-dihydroxy-5,8-bis(phenylmethoxyl)-2,3-naphthalene dicarboxylate prepared in Step 2A-b above, 12.00 g of potassium carbonate and 8.0 mL of benzyl bromide in 100 mL of dimethyl formamide and 200 mL of acetone was stirred at room temperature for 2 days. The reaction was filtered. The filtrate was then concentrated and the solid was washed with mixed solvent of ethyl acetate and petroleum ether to give 12.50 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][C:21]([O:28][CH3:29])=[C:22]([O:26][CH3:27])[CH:23]=4)[C:18]3=[O:30])[CH2:11]2)=[CH:6][CH:7]=1)[C:38]([CH3:39])=[O:40]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(N)cc3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(NC(C)=O)cc3)C1)C2
Temperature: 25 °C

Procedure:
819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)-piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30° C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is crystallised from acetone.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][O:14][CH:15]1[CH2:31][CH:30]2[C:18]([CH3:43])([CH:19]3[CH:27]([CH:28]([OH:32])[CH2:29]2)[CH:26]2[C:22]([CH3:41])([CH:23]([CH:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24][CH2:25]2)[CH:21]([OH:42])[CH2:20]3)[CH2:17][CH2:16]1.O.NN.Cl>CO>[NH2:3][CH2:12][CH2:13][O:14][CH:15]1[CH2:31][CH:30]2[C:18]([CH3:43])([CH:19]3[CH:27]([CH:28]([OH:32])[CH2:29]2)[CH:26]2[C:22]([CH3:41])([CH:23]([CH:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24][CH2:25]2)[CH:21]([OH:42])[CH2:20]3)[CH2:17][CH2:16]1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN5C(=O)c6ccccc6C5=O)CCC4(C)C3CC(O)C12C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCN)CCC4(C)C3CC(O)C12C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
1.7 g of methyl 4-{3-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethoxy]-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl}pentanoate and 0.52 ml of hydrazine hydrate (80%) are dissolved in 14 ml of methanol and the solution is refluxed for 3 hours. It is then cooled to 40° C. and the reaction mixture is treated with 8.7 ml of a 2N aqueous HCl solution. It is stirred at 40° C. for 30 minutes, then the volatile constituents are removed in vacuo. Chromatography on silica gel using acetone/water 10:1 yields 540 mg of resinous solid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Br:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1>O1CCOCC1>[Br:21][C:22]1[C:23]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2Br)C1
Reaction time: 20 h
Yield: 66.7 %

Procedure:
(S)-(−)-1-Boc-3-aminopyrrolidine (0.817 g, 4.39 mmol) and triethylamine (1.22 mL, 8.78 mmol) were added to a solution of 5-bromo-2,4-dichloropyrimidine (1.00 g, 4.39 mmol) in dioxane (22 mL) at 10° C. After 20 hours at room temperature, the solution was concentrated, dissolved in CH2Cl2 (50 mL) and washed with 2 M aqueous K2CO3 (50 mL). The aqueous layer was further extracted with CH2Cl2 (50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the title compound as an oil (1.106 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Br
Yield: 57 %

Procedure:
This reaction was carried out similarly to Example 1, with 2-bromo-5-nitrobenzaldehyde and malonic acid in pyridine and with piperidine. The product of melting point 185° C, was obtained in 57% yield.
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH:17]=1)[OH:16])([CH3:10])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]1=O)(=O)[CH3:20]>>[OH:18][C:13]1[C:14]2[CH:19]([CH3:20])[C:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]=3[O:16][C:15]=2[CH:17]=[C:11]([C:2]([CH3:1])([CH3:10])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]=1
Reactant: CCCCCC(C)C(C)(C)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCC(C)C(C)(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Reaction of 5-(1,1,2-trimethylheptyl)resorcinol with 2-acetyl-5-methylcyclohexanone as described in Example 1 gives the title compound.
Reaction SMILES: [Na+].[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][S:8]([O-])(=[O:10])=[O:9])#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH2:7][S:8]([Cl:16])(=[O:10])=[O:9])#[N:3]
Reactant: N#Cc1cccc(CS(=O)(=O)[O-])c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(CS(=O)(=O)Cl)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
5 g (22.83 mmol) of 3-cyanobenzylsulfonic acid sodium salt were moistened with approx. 20 ml of phosphoryl chloride, after which 5.2 g (25.11 mmol) of PCl5 were added and the mixture was stirred for 15 min while being cooled with ice. The mixture was then heated at 80° C. for 4 h. After that, the mixture was poured onto ice and stirred vigorously for 30 min in connection with which the product sedimented as a white solid on the ice. After the ice had been partially thawed, the mixture was filtered through a frit and the product/ice mixture which remained was washed several times with water. The crystals which remained were dried in vacuo and used directly for the next step in the synthesis.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15](OC)=[CH:14][C:13]=1[N+:20]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:24]([OH:26])C>>[CH2:9]([O:8][C:6]([CH:5]1[C:4](=[O:23])[NH:20][C:13]2[CH:14]=[CH:15][C:16]([O:26][CH3:24])=[CH:17][C:12]=2[O:11]1)=[O:7])[CH3:10]
Reactant: CCO
Reactant: CCOC(=O)C(Oc1ccc(OC)cc1[N+](=O)[O-])C(=O)OCC
Product: CCOC(=O)C1Oc2cc(OC)ccc2NC1=O
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2-nitro-phenoxy)-malonic acid diethyl ester (2.3 g, 7.0 mmol) in ethanol containing 10% Pd/C was hydrogenated at 35 psi for 18 hours. The catalyst was filtered through celite and the solvents were removed under vacuum to afford a solid which was washed with ether to afford 1.25 g of a white solid. The mother liquor was concentrated and the solid again washed with ether to afford another 100 mg of product. Yield: (1.35 g, 76%): mp 138.5-139.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:27]=[CH:26][C:19]([O:20][CH:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1.Cl[CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].O>CN(C)C=O>[Cl:7][C:8]1[CH:29]=[CH:28][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:27]=[CH:26][C:19]([O:20][CH:21]([CH3:25])[C:22]([O:24][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:23])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1
Reactant: C[Si](C)(C)CCl
Reactant: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)OC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
2.9 g of potassium carbonate are added to a solution of 6.2 g (0.179 mole) of the R-enantiomer of 2-{4-[(6-chloro-2-benzothiazolyl)-oxy]-phenoxy}-propionic acid in 20 ml of dimethylformamide. After the mixture has been stirred at 50° C. for 15 minutes, 2.7 g (0.021 mole) of chloromethyltrimethylsilane are added dropwise at this temperature. The mixture is then subsequently stirred at 80° C. for 2 hours. It is then worked up by stripping off the solvent under reduced pressure, adding water to the residue and extracting the resulting oily product with 100 ml of toluene. The organic phase is washed successively with aqueous sodium carbonate solution and with water, dried and concentrated under reduced pressure. 7 g (89% of theory) of the R-enantiomer of trimethylsilyl-methyl 2-{4-[(6-chloro-2-benzothiazolyl)-oxy]-phenoxy}-propionate are obtained in this manner in the form of a viscous oil.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[N:9]=[C:8]([OH:10])[C:7]([F:11])=[CH:6][CH:5]=1>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:1])[C:7]([F:11])=[CH:6][CH:5]=1
Reactant: Oc1nc(Cl)ccc1F
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(Cl)ccc1F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Methyl iodide (262 ul) and silver carbonate (1.12 g) were added to a chloroform (3 ml) solution of the compound 325-1 (300 mg), and the obtained mixture was stirred at 40° C. for 5 hours. The temperature of the reaction solution was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:0 to 1:1), so as to obtain the title compound (86 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:18]=3)[C:13](=[O:27])[C:12]([C:28]([OH:30])=[O:29])=[CH:11]2)=[C:6]([F:31])[CH:5]=1)([O-:3])=[O:2].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:26])=[C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:33][C:34]([C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[O:35])[CH2:22][CH2:21]4)[CH:18]=3)[C:13](=[O:27])[C:12]([C:28]([OH:30])=[O:29])=[CH:11]2)=[C:6]([F:31])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cn(-c2ccc([N+](=O)[O-])cc2F)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of the 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.43 g, 1 mmol) in DMF (15 ml) was added 2-bromo-4′-methoxyacetophenone (0.29 g, 1.28 mmol) and sodium bicarbonate (0.08 g, 1 mmol). The reaction mixture was stirred for 24 hr at room temperature. After removing the solvent, the residue was taken up by CH2Cl2, solution, and after washed with water and dried with Na2SO4, was evaporated to dryness. Crystallization of the solid residue from CH2Cl2/methanol (10:1) afforded the desired 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.37 g, 86%). Mp: 136° C. (dec). 1H NMR (DMSO-d6) δ 2.63 and 3.10 (two m, 8),3.81-3.83 (m, 5H) 6.40 (d, 1H, J=6.8), 7.01 (d, 2H, J=9.0), 7.94-8.03 (m, 3H), 8.17-8.56 (m, 3H), 8.93 (s, 1H), 14.88 (br s, 1H). Anal. Calcd. for C29H24F2N4O7•H2O: C, 58.39; H, 4.39; N, 9.39. Found: C, 58.75; H, 4.42; N, 9.20.