Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15](O)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:23])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 96.7 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10-(1H,9H)-dione (1 g, 3.44 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (0.64 mg, 3.95 mmol) in N,N-dimethylformamide (25 mL) was stirred for 64.5 hours. In one portion, ammonium acetate (0.796 mg, 10.33 mmol) was added, followed by additional N,N-dimethylformamide (15 mL). The solution was stirred for 3.75 hours at room temperature and concentrated in vacuo for 45 minutes. The residue was washed with water (3×20 mL). The insoluble material was filtered and dried to give the title compound (967 mg, 97% yield, m.p. 224-225° C.).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccccc2OCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 2-benzyloxybenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.49-7.20 (m, 11H), 7.05-6.92 (m, 3H), 6.41 (s, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.51-3.45 (m, 4H), 2.55-2.49 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[CH2:29]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][CH2:48][CH3:49])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([N:39]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][CH2:48][CH3:49])=[CH:44][CH:45]=3)[C:36]3[CH:35]=[CH:34][C:33]([CH2:29][CH2:30][CH2:31][CH3:32])=[CH:38][CH:37]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Brc1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Reactant: CCCCc1ccc(Nc2ccc(CCCC)cc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N(c2ccc(CCCC)cc2)c2ccc(N(c3ccc(Br)cc3)c3ccc(Br)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
Under an inert atmosphere, in a 300 mL three-necked flask, 0.24 g (0.27 mmol) of tris(dibenzylideneacetone)dipalladium, 0.22 g (0.4 mmol) of diphenylphosphinoferrocene, 2.56 g (26.7 mmol) of sodium tertiary butoxide and 125 mL of toluene were charged, followed by stirring at room temperature for 10 minutes. Subsequently, 12.9 g (26.7 mmol) of tris-(4-bromophenyl)amine was charged, followed by stirring at room temperature for 10 minutes. Thereafter, 5 g (17.8 mmol) of bis(4-butylphenyl) amine was charged, and the mixture was heated to 125° C. and refluxed for 9 hours. After the completion of the reaction, the reaction solution was filtered to remove insolubles, passed through a short column of silica gel and then purified by a silica gel column using cyclohexane as an eluent to obtain N,N-bis(4-bromophenyl)-N′,N′-bis(4-butylphenyl)-1,4-phenylenediamine (aromatic amine A) (2.96 g, yield: 24%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[O:21]=[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=2)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11]1
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccc2c(c1)C(=O)CCN2C(=O)CC
Reaction time: 0.17 h
Yield: 110.3 %

Procedure:
A solution of propionyl chloride (1.018 g) in chloroform (5 ml) was added dropwise to a solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.09 g), N,N-dimethylaniline (1.513 g), and 4-dimethylaminopyridine (0.061 g) in chloroform (20 ml) with stirring and ice cooling over a period of 10 minutes. After being stirred overnight at ambient temperature, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% hydrochloric acid, water, aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated in vacuo to give an oil of 4-oxo-1-propionyl-6-propionyloxy-1,2,3,4-tetrahydroquinoline (1.51 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]([NH2:36])(=[O:35])[CH:33]=[CH2:34]>CN(C=O)C.O.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>[OH:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2](/[CH:34]=[CH:33]/[C:32]([NH2:36])=[O:35])=[CH:7][CH:6]=1)[N:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][CH2:11]2
Reactant: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(I)cc1
Reactant: C=CC(N)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)/C=C/c1ccc(C2c3ccc(O)cc3CCN2c2ccccc2)cc1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a stirred solution of 1-(4-iodo-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.234 mmol), triethylamine (0.163 ml, 1.17 mmol), and acrylamide (0.082 g, 0.351 mmol) in DMF (2 ml), under an atmosphere of N2, was added Pd(PPh3)4 (0.014 g, 0.012 mmol). The solution was heated to 100° C. overnight, then cooled to RT and diluted with water (20 ml). The aqueous mixture was extracted with EtOAc (3×10 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 5% MeOH/CH2Cl2) to give the desired product (0.030 g, 0.089 mmol, 35% yield).
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=O)=[O:6].[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[NH2:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N:49]1[CH:54]=[CH:53][CH:52]=[N:51][C:50]=1[NH:55][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=[O:4])=[O:6]
Reactant: Nc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ncccn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
A roundbottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 48.52 mg, 0.069 mmol), pyrimidin-2-amine (7.84 mg, 0.082 mmol), and THF (343 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (144 μl, 0.144 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the cooling bath was removed. After 20 min, the mixture was diluted with TFA (0.5 mL), then concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL) and stirred for 20 min. The mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500-mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g, eluting with 5 to 10% MeOH/DCM, then with 20 to 40% of 2N ammonia in methanol solution dissolved in DCM). The fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered through cotton. The filtrate was concentrated, and the residue was taken up in 10% MeOH/DCM and filtered through cotton. The filtrate was concentrated to give N-(pyrimidin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.66 mg, 0.026 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=4.7 Hz, 2 H), 7.69 (d, J=8.5 Hz, 1 H), 7.59-7.48 (m, 2 H), 7.33 (s, 1 H), 7.25 (dd, J=1.8, 8.6 Hz, 1 H), 6.83 (t, J=4.6 Hz, 1 H), 6.41 (d, J=8.6 Hz, 1 H), 5.83 (br. s., 1 H), 4.25 (br. s., 2H), 3.59 (br. s., 2 H), 3.38 (br. s., 2 H), 2.87 (br. s., 2 H), 2.33 (br. s., 1 H), 2.23 (br. s., 1 H). m/z (ESI) 518.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=2)[O:35]1>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[CH2:43][CH:42]([OH:44])[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:40]=2)[O:35]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2F)O3)nc1

Procedure:
2-(2-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 315 mg of 2-(2-fluorophenyl)chroman-4,6-diol (Example 19(b)). The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.61 (m, 1H), 7.43 (m, 1H), 7.31-7.24 (m, 3H), 7.23 (d, 1H, J 9.1 Hz), 7.02 (dd, 1H, J 8.7, 3.1 Hz), 6.89 (d, 1H, J 8.7 Hz), 5.69 (d, 1H, J 6.3 Hz), 5.55 (d, 1H, J 11.9 Hz), 5.00 (m, 1H), 2.33 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[N:27]([CH3:28])[C:26]3[CH:29]=[CH:30][C:31]([C@@:33]([NH:42][CH2:43][C:44]([O:46]CC)=[O:45])([C:35]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH3:34])=[CH:32][C:25]=3[N:24]=2)=[CH:17][CH:16]=1)(=[NH:14])[NH2:13].[OH-].[K+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:12]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:22][C:23]2[N:27]([CH3:28])[C:26]3[CH:29]=[CH:30][C:31]([C@@:33]([NH:42][CH2:43][C:44]([OH:46])=[O:45])([C:35]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH3:34])=[CH:32][C:25]=3[N:24]=2)=[CH:19][CH:20]=1)(=[NH:13])[NH2:14]
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc([C@@](C)(NCC(=O)O)C(=O)N3CCCC3)ccc21
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
3.7 kg (5.49 mol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazol-p-toluenesulphonic acid salt are dissolved in 7.4 L of methanol at 40° C. To this solution is added a solution of 0.795 kg (12.8 mol) of potassium hydroxide powder in 5.6 L of methanol und this is then rinsed with 1.8 L of methanol. The mixture is stirred for 2.5 hours at 40° C. The potassium salt of the p-toluenesulphonic acid crystallises out. A solution of 1.37 kg (7.2 mol) of p-toluenesulphonic acid monohydrate in 2.8 L of methanol is added to the suspension, this is rinsed with 1.8 litres of methanol and cooled to 22° C. The precipitated potassium salt of p-toluenesulphonic acid is separated off using a pressure filter and the filter cake is washed with 7.4 litres of methanol. The filtrate is inoculated with the title compound and stirred overnight. The precipitated product is suction filtered under argon, washed with 3.7 L of methanol and recycled into the reactor while still damp. 18.5 L of methanol are added and the suspension is refluxed for one hour and cooled to 22° C. The product is suction filtered under argon, washed with 3.7 L of methanol and dried at 30° C. in a circulating air drier. 2.22 kg (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC1CC1
Reaction time: 2 h

Procedure:
To a stirred 0° C. solution of 683 mg (6.0 mmol) of 4-cyclopropylbutanol and 1.25 mL (9.0 mmol) of triethylamine in 10 mL of CH2Cl2 was added 697 μL (9.0 mmol) of methanesulfonyl chloride dropwise under Ar. The cold bath was allowed to expire over a 2 h period at which time the reaction mixture was diluted with CH2Cl2, washed with cold 1M HCl, water, sat. NaHCO3, brine, dried over MgSO4 and the solvents removed to give the title compound as a yellow oil:
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH:27]C(C)=O)[N:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[CH:19]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)C.S(=O)(=O)(O)O>C([O-])([O-])=O.[Na+].[Na+]>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH2:27])[N:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[CH:19]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)cn1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cc3c(s2)-c2ncccc2OCC3)cn1-c1ccccc1Cl

Procedure:
From Example 37, 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-(2-chlorophenyl)-2-amino-1H-imidazole 127 (27 mg, 0.062 mmol) was added to ethanol (2 mL, 30 mmol) containing 1 ml of 10% aqueous sulfuric acid. The reaction was microwaved on 300 watts at 100° C. for 15 minutes. The reaction mixture was mixed with 10 ml of 1 M aq Na2CO3 and extracted with ethyl acetate twice. The organic layer was washed with brine and dried over K2CO3. The solvent was evaporated to afford 128. (18 mg, 74%). MS (ESI+) 395.1
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1nccs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1C
Temperature: 25 °C
Yield: 22.4 %

Procedure:
MeOH (60 mL) was added to a flask containing 4-{1-[(thiazol-2-ylmethyl)-amino]-ethylidene}-pent-2-enedioic acid dimethyl ester (2.12 g, 7.16 mmol). NaOMe solution (1.64 mL, 7.16 mmol, 4.375 M in MeOH) and N-bromosuccinimide (1.53 g, 8.59 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-80% EtOAc/hexanes) to give 551 mg of the title compound as a yellow solid. MS: (+) m/z 343.11, 345.12 (M+1, 79/81Br).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:18]2[CH:53]=[CH:52][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][CH2:31][CH:32]([S:41][C:42]3[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=3)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([C:18]2[CH:53]=[CH:52][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][CH2:31][CH:32]([S:41]([C:42]3[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=3)=[O:9])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)Sc1ccc(C(=O)OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)S(=O)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 47 mg (0.19 mmol) of metachloroperbenzoic acid were added to a solution of 113 mg (0.19 mmol) of methyl 4-{[1-(2-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-ethyl)-6-methoxy-6-oxohexyl]sulfanyl}benzoate 187 in 25 ml of CH2Cl2. The mixture was stirred at 0° C. for 30 min, and the cooling bath was then removed and stirring, was continued at room temperature for 16 h. After the reaction had ended, the mixture was washed successively with saturated Na2SO3 solution, saturated Na2CO3 solution, saturated NaCl solution and water. The organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/ethyl acetate 2:1)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl.[OH-].[Na+]>[Fe].C(O)C.O>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([NH2:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Br)cc1C=O
Yield: 78 %

Procedure:
To a solution of Example 115A (1.0 g, 4.0 mmol) in 1: 1 ethanol-water (50 mL), was added iron-powder (0.6 g) then 6 N hydrochloric acid (1 mL). The reaction mixture was heated to reflux overnight, cooled, neutralized with I N sodium hydroxide, filtered, and the filtrate extracted with ethyl acetate (3x). The organic extracts were dried over magnesium sulfate, filtered and solvent evaporated to provide 0.68 g of 5-bromo-4-fluoro-2-aminobenzaldehyde. To a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (0.68 g, 3.1 mmol) in water (10 mL) at 0 ° C. was added sulfuric acid (2 mL) then slowly a solution of sodium nitrite (0.23 g, 3.4 mmol) in water (10 mL) keeping the temperature below 10 ° C.. After stirring at this temperature for 1 hour this suspension was added to a solution of potassium iodide (0.50 g, 3.1 mmol) in water (20 mL), the reaction mixture stirred at room temperature overnight, extracted with ethyl acetate (3x). The organic extracts were washed with aqueous sodium thiosulfate, 5% sodium bicarbonate solution and water, then dried over magnesium sulfate, filtered and solvent evaporated. The crude residue was purified by flash chromatography over silica gel eluting with ethyl acetate:hexane (1:9) to provide 0.16 g of the title compound as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12](=[O:13])[NH:14][CH2:15][C:16]([O:18][N:20]2[C:24](=[O:25])[CH2:23][CH2:22][C:21]2=[O:26])=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2.83 g of product from Example 255 in 43 ml of dioxane is added 1.28 g of N-hydroxysuccinimide and 2.30 g of 1,3-dicyclohexylcarbodiimide, hereinafter called DCC, in 13 ml of dioxane.The formed suspension is stirred at room temperature overnight. The urea by-product is collected and the filtrate is concentrated in vacuo to give an oil. The oil is dissolved in methylene chloride, washed with water, thelayers are separated and the organic phase is cooled. The formed crystals are collected and dried to give 1.87 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C.[ClH:55]>CO.C(OCC)(=O)C>[ClH:55].[ClH:55].[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: NN1CCOCC1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCNN2CCOCC2)C[C@H]1Cc1c[nH]c2ccccc12

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (150 mg), 4-aminomorpholine (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) to afford an oily product, which was treated with 4N hydrogen chloride in ethyl acetate solution (0.5 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(morpholinoamino)propyl]piperazine dihydrochloride (58 mg).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[N:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[C:17]=4[NH:16][C:15]3=[O:27])[CH2:10][CH2:9]2)C=CC=CC=1>[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[NH:16][C:15]2=[O:27])[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Yield: 98.5 %

Procedure:
Prepared analogously to Example A3f) from 1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone by hydrogenolysis in the presence of palladium/charcoal in a yield of 98.5% of theory. Colourless crystals, Rf=0.63 (FM1).