Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(Cl)[C:10](=[CH:14][C:15](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[N+:16]([O-:18])=[O:17])[N+:11]([O-:13])=[O:12]>[Cu]>[N+:21]([C:20]1[CH:19]=[C:15]([N+:16]([O-:18])=[O:17])[CH:14]=[C:10]([N+:11]([O-:13])=[O:12])[C:9]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Product: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1). C 7 ⁢ H 7 ⁢ I + C 6 ⁢ H 2 ⁢ Cl ⁢ N 3 ⁢   ⁢ O 6 ⁢ → Δ Cu ⁢ C 13 ⁢ H 9 ⁢ I 3 ⁢ N 3 ⁢   ⁢ O 6 2′,4′,6′-trinitro-4-methylbiphenyl (1) is reacted with stannous chloride and hydrochloric acid to yield 2′,4′,6′-triamino-4-methylbiphenyl (2). C 13 ⁢ H 9 ⁢ N 3 ⁢   ⁢ O 6 ⁢ → H ⁢   ⁢ Cl Sn ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 15 ⁢ N 3 2′,4′,6′-triamino-4-methylbiphenyl (2) is reacted with sodium nitrite and hydrochloric acid to convert the amino groups to diazonium groups. The diazonium groups react with potassium iodide to yield 2′,4′,6′-triiodo-4-methylbiphenyl (3). C 13 ⁢ H 15 ⁢ N 3 ⁢ → H ⁢   ⁢ Cl Na ⁢   ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ I ⁢   ⁢ C 13 ⁢ H 9 ⁢ I 3 Aromatic nitration of 2′,4′,6′-triiodo-4-methylbiphenyl (3) is performed with nitric acid and sulfuric acid to yield a mixture of 2′,4′,6′-triiodo-2-nitro-4-methylbiphenyl (4) and 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5). The products are separated using column chromatography. C 13 ⁢ H 9 ⁢ I 3 ⁢ → H 2 ⁢   ⁢ S ⁢   ⁢ O 4 H ⁢   ⁢ N ⁢   ⁢ O 3 ⁢ C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 The methyl group of 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5) is oxidized by potassium permanganate to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6). C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ Mn ⁢   ⁢ O 4 ⁢ C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 5 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 The hydroxyl groups of D-Glucosamine (8) are protected by reaction with acetic anhydride in the presence of pyridine to yield 1,3,4,6-tetra-O-acetyl-D-glucosamine (9). C 6 ⁢ H 13 ⁢ N ⁢   ⁢ O 5 ⁢ → C 5 ⁢   ⁢ H 5 ⁢ N C 4 ⁢   ⁢ H 6 ⁢   ⁢ O 3 ⁢ C 14 ⁢ H 21 ⁢ N ⁢   ⁢ O 9 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7) to yield 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10). C14H21NO9+C13H5ClI3NO3→C27H25I3N2O12 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10) is treated with stannous chloride in the presence of hydrochloric acid to yield 2-amino-4-(2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (11). C 27 ⁢ H 25 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 19 ⁢ H 19 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1.O[Li:34].O>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[CH3:22])=[O:19])[CH2:3]1.[Li+:34]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H](O)CN2Cc2cccc(C(F)(F)F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E19) (9 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((2R,4R)-4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D36) (10.3 mg). (LiOH H2O: 2 eq; reaction time: 18 hrs)
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=[C:6]1[O:15][CH3:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:24])[CH:7]=[C:6]1[O:15][CH3:16]
Reactant: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 68.3 %

Procedure:
A suspension of Example 8A (0.45g, 1.48 mmol), pyridinium dichromate (2.4 g, 5.92 mmol), celite (0.53 g), 70% t-BuOOH/water (0.82 mL, 5.92 mmol) in benzene (11 mL) was stirred at 25° C. for 2 h. The benzene layer was separated and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Column chromatography on silica (5%→15% ethyl acetate/hexane) afforded the title compound (0.32 g, 67%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.17-0.41 (m, 1H), 0.60-0.81 (m, 10H), 2.16-2.36 (m, 2H), 3.56 (s, 3H), 3.84 (s, 3H), 6.04 (s, 1H), 7.41 (d, J=7.72 Hz, 1H), 7.51 (t, J=6.99 Hz, 1H), 7.60-7.75 (m, 1H), 7.89-8.09 (m, 1H)); MS (ESI) m/z 316.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[N:12][C:11]=1[C:24]([O:26]CC)=O.C[N:30](C=O)C.C(N)=O.C[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[N:12][C:11]=1[C:24]([NH2:30])=[O:26]
Reactant: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: NC=O
Solvent: CO
Solvent: O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(F)cc3F)c2cc1OC
Temperature: 100 °C
Yield: 96 %

Procedure:
To a 25 mL round bottom flask charged with a magnetic stir bar was added ethyl 4-[(2,4-difluorophenyl)amino]-6,7-dimethoxycinnoline-3-carboxylate (0.195 g, 0.50 mmol) (Method 27), anhydrous DMF (3 mL), formamide (0.135 g, 3 mmol), and 3 mL of a 0.5 M solution of sodium methoxide in MeOH. The reaction was warmed to 100° C. for 2 h before being allowed to cool to rt. The reaction was poured over water (˜50 mL) and the crude product precipitated from solution. The solid was collected via vacuum filtration using a Buchner funnel and was purified on 40 g silica using EtOAc/MeOH (4:1) as eluent providing 0.174 g (96%) of the title compound as a white solid. 1H NMR: 11.35 (s, 1H), 8.86 (s, 1H), 8.05 (s, 1H), 7.71 (s, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.18 (m, 1H), 6.69 (s, 1H), 4.06 (s, 3H), 3.50 (s, 3H); m/z 361.
Reaction SMILES: [C:1]([C:4]1[C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[O:37][C:36]([CH3:39])=[CH:35][C:34]3=[O:40])[C:6]([C:12]([O:14][C@H]2CC(=O)N(CC3C=CC=CC=3)C2=O)=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.O.Cl>C(OCC)(=O)C>[C:1]([C:4]1[C@@H:5]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[O:37][C:36]([CH3:39])=[CH:35][C:34]3=[O:40])[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)O[C@H]2CC(=O)N(Cc3ccccc3)C2=O)[C@@H]1c1cccc2c(=O)cc(C)oc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@@H]1c1cccc2c(=O)cc(C)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.555 mmol) of (3S)-1-benzyl-2,5-dioxopyrrolidin-3-yl (4R)-5-acetyl-2,6-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydropyridine-3-carboxylate are dissolved in 10 ml of ethyl acetate, and 295.7 mg (1.942 mmol) of DBU are added. The mixture is stirred at room temperature for 8 h. Water is then added, and the pH is adjusted to pH 4-5 with 1 N hydrochloric acid. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is removed in vacuo. The product obtained in this way is reacted further without purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39](O)=[O:40])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:40])=[CH:31][CH:32]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: C[C@@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (37 mg, 162 μmol) from the previous step in DMF was added DIPEA (85 μl, 486 μmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (57 mg, 243 μmol) and HATU (123 mg, 324 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give rac-trans-tert-butyl ((1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in DCM was added TFA (1:1 v/v). The reaction was aged at rt. When analytical reverse-phase HPLC indicated disappearance of starting material, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil (34 mg, 60%). MS (ESI) 348.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8](Cl)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:16].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl.[OH2:32]>CN[C@@H]1CCCC[C@H]1NC>[OH:32][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([OH:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)cc1Cl
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(O)c(C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Under nitrogen, 2.00 g (8.51 mmol) of 2,5-dichloroterephthalic acid was combined with 10 g of H2O. 0.938 g (8.85 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.31 g (12.34 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 12 mg of CuBr and 24 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 2 mL H2O under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a deep purple solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 20 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with HCl (conc.), producing a dark yellow precipitate. The yellow precipitate was filtered and washed with water. After drying, a total of 1.59 g (8.03 mmol, 94% yield) 2,5-dihydroxyterephthalic acid was collected. The purity was determined by 1H NMR to be 95%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:24][OH:25].Cl>O>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[NH2:4])[CH:3]=[N:24][OH:25]
Reactant: NO
Reactant: CC=CC(C)C1CC=CCCC=CCC(C)C=N1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC=CC(C)C(N)CC=CCCC=CCC(C)C=NO
Yield: 195.2 %

Procedure:
The procedure is carried out in the manner described in Example 1(b) but with the use of 122.7 g (0.5 mol) of 3-methyl-12-(3-penten-2-yl)-1-aza-1,5,9-cyclododecatriene, 41.1 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water. There is obtained on further processing 135.9 g (0.488 mol) of 2-methyl-11-(3-penten-2-yl)-11-amino-undeca-4,8-dienal-oxime; yield 97.6% of theory; nD20 =1.5091.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:17])[N:13]([O:15][CH3:16])[CH3:14])(=O)OCC)C.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.N1C2C(=CC=CC=2)C=C1>C1COCC1>[CH3:16][O:15][N:13]([CH3:14])[C:12](=[O:17])[CH:11]=[CH:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[NH:18][CH:19]=[CH:20]2
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: CON(C)C(=O)C=Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (0.44 g of a 60% suspension in mineral oil, 11 mmol) and diethyl-(N-methoxy-N-methyl-carbamoylmethyl)-phosphonate (3.0 g, 3 equiv.) in anhydrous THF was stirred at room temperature for 30 minutes. A solution of indole-5-carboxaldehyde (0.61 g, 4.18 mmol) was added dropwise to the mixture. The reaction was complete after 2 h after the addition of the starting indole. The mixture was quenched with water (50 ml), then diluted with ether. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-3-(indol-5-yl)acrylamide as a yellow oil which solidified on standing to an off-white solid (1.53 g, quantitative yield. 1H NMR (CDCl3): δ8.55 (br, 1H), 7.87 (d, J=18.6 Hz, 1H), 7.85 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.23 (m, 1H), 7.0 (d, J=18.6 Hz, 1H), 6.58 (m, 1H), 3.78 (s, 3H), and 3.32 (s, 3H). FIMS: 229.1 (M−H)−, reverse-phase HPLC purity: 88%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>CS(C)=O.O>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 70 °C
Yield: 63.9 %

Procedure:
To 5-bromo-2-nitropyridine (1.0 g, 4.93 mmol, Eq: 1.00) in DMSO (10.0 ml) was added 1-isopropylpiperazine (632 mg, 4.93 mmol, Eq: 1.00), and the resulting solution was heated at 70° C. for 18 hours. The solution was cooled to room temperature. The solution was diluted with 50 ml water. The resulting solid was filtered. The solid was washed with water and dried under vacuum. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 3% MeOH/DCM gradient) to give 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (788 mg, 64%). LC/MS-ESI observed [M+H]+ 251.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[N:42]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4[CH2:21][C:20](=[O:22])[NH:19][C:18]5[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=5[N:16]=4)[CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:5][N:4]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: C1CCNC1
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(-c3ccnc(CN4CCCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with pyrrolidine in DMF according to the general procedure of example 288. Obtained as a light brown solid (225 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH2:11](N(CC)CC)[CH3:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:31][C:30](=[O:32])[O:29][C:27](=O)[CH2:26]2)=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([CH2:12][CH:25]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[CH2:31][C:30]([O:29][CH2:27][CH3:26])=[O:32])[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CC(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The solution of commercial 4,5-dichloro-1,2-phenylenediamine (0.36 g) and triethyl amine (0.32 ml) in 1,4-dioxane (1.5 ml) was added to a solution of 3-(4-chlorophenyl)glutaric anhydride (0.45 g) in 1,4-dioxane (1 ml) with ice cooling. The resulting mixture was stirred at rt for 0.5 h and at 40° C. for 0.5 h. Again under ice cooling 1M HCl (3 ml) was added dropwise. A gummy precipitate is formed. After 0.5 h of cooling the aqueous layer is removed by decantation and the residue is dissolved in methanol. The dark solution is decolorized with activated carbon, filtered, and the filtrate concentrated in vacuo. The amorphous solid is redissolved in ethanol (6 ml) and conc. HCl (2 ml) and stirred at reflux for 16 h. After cooling to rt the pH is adjusted to 8 by addition of first NaOH solution, then sat. sodium bicarbonate solution. The aqueous layer is extracted with dichloromethane (40 ml) and the organic layer is washed with sat. sodium chloride solution and dried (sodium sulfate). After concentration the crude (0.46 g) is purified by flash chromatography ((dichloromethane/2% methanol/1% triethyl amine) on silica gel to afford ethyl 4-(5,6-dichloro-2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (0.33 g) as yellowish, amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([CH2:26][CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[O:25])[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[OH-].[Na+]>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The title compound from Step A above (4.61 g) (7.5 mmoles) was dissolved in methanol (40 ml) and a 10% (v/v) conc. H2SO4 in dioxane solution (100 ml) was added. The mixture was stirred at 25° C. for 2 h and then basified with conc. aqueous NaOH. The mixture was extracted with dichloromethane and the latter was washed with water, dried over MgSO4, filtered and evaporated to dryness. The product was chromatographed on silica gel using 10% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.86 g; 74%).
Reaction SMILES: Cl.[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].S1C2C=CN=CC=2C=[C:14]1C(O)C.N1C2=NC=CC=C2C(CN)=C1>>[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH:11]([NH2:12])[CH3:14]
Reactant: CC(O)c1cc2cnccc2s1
Reactant: NCc1cc2cnccc2s1
Agent: Cl
Agent: NCc1c[nH]c2ncccc12
Product: CC(N)c1cc2cnccc2s1

Procedure:
Intermediate D′ was prepared from 1-(thieno[3,2-c]pyridin-2-yl)ethanol (D′-4) following similar procedures for synthesizing intermediate A from A-3, as described above.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11]/[C:12](=[C:19]3\[C:20](=[O:31])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34].CCN(C(C)C)C(C)C>C(O)(=O)C.O>[C:33]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11]/[C:12](=[C:19]3\[C:20](=[O:31])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH2:1]1)(=[O:35])[CH3:34]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc2c(c1)CCNC2)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)ccc2C1

Procedure:
Prepared from 3-{(Z)-1-[(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amino]-1-phenylmethylidene}-5-nitro-2-indolinone×HCl×H2O in glacial acetic acid with acetic anhydride in the presence of Hunig's base.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15]O>ClCCl>[CH3:12]/[C:13](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:15][Cl:1]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4.75 g (35.6 mmol) of N-chlorosuccinimide in 180 mL of dichloromethane at -35° C. (internal thermometer) under argon was added 3.3 mL (45.4 mmol) of dimethyl sulfide over 10 minutes. The mixture was allowed to warm to 0° C. for 15 minutes then cooled again to -35° C. A solution of 5.0 g (32.4 mmol) of (E)-3,7-dimethyl-2,6octadien-1-ol (geraniol) in 25 mL of dichloromethane was added dropwise over 10 minutes. After addition, the reaction was allowed to warm gradually to 0° C. over 2 hours. After 1 hour at 0° C., the reaction was quenched with ice-cold water, diluted with 500 mL of hexane, and the organic layer was separated. The hexane extract was washed with water, brine, dried over MgSO4 and evaporated to provide 5.21 g (93%) of title compound in the form of a yellow liquid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13]C)=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][CH2:21][NH:20][C:11](=[O:13])[C:10]2[CH:15]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Product: COC(=O)c1cc(C(=O)NCCN2CCOCC2)cc(-n2cccc2)c1
Temperature: 120 °C
Yield: 25.6 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (1.0 g) and 4-(2-aminoethyl)morpholine (0.65 g) was heated at 120° C. for 2 hours. The residue was purified by column chromatography on silica gel (50 g) with chloroform-methanol (30:1) as an eluent. The fractions containing object product were combined and evaporated in vacuo. The crystalline residue was recrystallized from ethanol-ether to afford N-[2-(morpholin-4-yl)ethyl]-3-methoxycarbonyl-5-(pyrrol-1-yl)benzamide (353 mg).