Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25](S(C)(=O)=O)=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1.[C-:40]#[N:41].[K+].N>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]3([NH:19][C:20]([C:22]4[CH:23]=[N:24][C:25]([C:40]#[N:41])=[N:26][CH:27]=4)=[O:21])[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[C:5]([C:36]([F:39])([F:38])[F:37])[CH:4]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)(=O)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Reactant: [C-]#N
Agent: N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(C#N)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 51 %

Procedure:
A solution of 50 mg (0.089 mmol) of 2-methanesulphonyl-pyrimidine-5-carboxylic acid{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-amide (product from Example 149) in 2 mL DMF was combined with 9 mg (0.13 mmol) of potassium cyanide and then heated to 100° C. for 10 minutes in a microwave apparatus. The mixture was then combined with 2 mL concentrated ammonia solution and extracted with dichloromethane. The crude product obtained after evaporation was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:34]2[C@H:33]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:42][C@H:41]3[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:35]2)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)N[C@H]2Cc2ccccc2)cc1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Yield: 63.4 %

Procedure:
Analogously to Example 1B), by reacting 7.2 g of p-toluene-sulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester (Example 11) with 4.8 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide there are obtained 5.4 g (45%) of (3S, 4aS ,8aS)-2-[(4S ,5R)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl]-N -tert.-butyl-decahydro-isoquinoline-3-carboxamide p-tolylsuphonate, m.p. 202°-204° C.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:42][NH:43][CH3:44]>>[CH3:42][N:43]([CH3:44])[CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl ester (0.382 g, 0.731 mmol) in 2.0 M dimethylamine in THF (8 mL, 16 mmol) was stirred for 4 hours at 70° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. for 20 minutes in vacuo yielded dimethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl}-amine as a light yellow solid (0.212 g, 73.4%). Methanol, chloroform and etheric hydrochloride were added. The resulting solution was concentrated and dried for 15 hours at 78° C. in vacuo. The hydrochloride as a buff foam (0.217 g) was obtained. Mass Spectrum (+EI, [M+H]+) m/z 396. 1HNMR (500 MHz, DMSO-d6): δ14.20 (s, 1H), 10.05 (s, 1H), 8.74-8.77 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.17 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.37-4.39 (m, 2H), 3.51 (t, 2H, J=4.76 Hz), 2.83 ppm (s, 6H). Elemental Analysis for C21H21N3O3S.1.00 mol HCl.0.70 mol H2O: Calcd: C, 56.74; H, 5.31; N, 9.45; Found: C, 56.72; H, 5.33; N, 9.06.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.N.[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[N+:25]([C:10]1[CH:11]=[CH:12][C:7]2[N:6]3[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]3[C@@H:4]3[CH2:21][CH2:22][CH2:23][N:3]3[C:2](=[O:1])[C:8]=2[CH:9]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
A solution of 3.11 g of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in a mixture of 10 ml of 98 percent nitric acid and 15 ml of 98 percent sulphuric acid is heated to 100° for 6 hours. Subsequently, the mixture is cooled to room temperature, poured onto ice, neutralized with about 25 percent ammonia and extracted with chloroform. The chloroform extracts are dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields ethyl (S)-11,12,13,13a-tetrahydro-7-nitro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 193°-194°.
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:33][NH:34][C:35](=O)[CH2:36][N:37]([CH3:39])[CH3:38].C[O-].[Na+]>CO>[CH3:38][N:37]([CH2:36][C:35]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:32]3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:33][N:34]=1)[CH3:39]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4Cc5ccccc5C4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5Cc6ccccc6C5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-indan-2-ylcarboxamide.2HCl (360 mg, 0.72 mmol), N-amino-2-(dimethylamino) acetamide (254 mg, 2.17 mmol) and sodium methoxide (415 μL of a 25% w/w in methanol) in anhydrous methanol (4.0 mL) with a reaction time of 48 h. Purification of the residue by preparatory TLC using 50% ethyl acetate in methanol gave the desired product which was further purified by precipitation from methanol and ethyl acetate with hexanes and ethyl ether to give the title compound (86 mg, 25% yield) as a colorless powder 1H NMR (DMSO-d6) δ 13.9 (br s, 1H), 13.4 (br s, 1H), 8.85 (d, 1H), 8.6 (br s, 1H), 8.45 (s, 1H), 8.1-8.0 (m, 2H), 7.7-7.6 (m, 2H), 7.3-7.1 (m, 4H), 4.8-4.7 (m, 1H), 3.6 (br s, 2H), 3.25 (dd, 2H), 3.0 (dd, 2H), 2.2 (s, 6H); ES-MS (m/z) 478 [M+H]+.
Reaction SMILES: FC1C(O[C:9]([C:11]2([F:30])[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[CH:19][C:14]3=[N:15][CH2:16][N:17]([CH3:18])[C:13]3=[CH:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH3:35]>CN(C=O)C>[F:30][C:11]1([C:9]([NH2:35])=[O:10])[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:14]2=[N:15][CH2:16][N:17]([CH3:18])[C:13]2=[CH:12]1
Reactant: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)C=C21
Reactant: N
Solvent: CN(C)C=O
Product: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(N)=O)C=C21
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
A reaction vial was charged with the product of Example 1, Step J, 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester (0.5229 g, 0.8585 mmol) and DMF (1 mL). Saturated aqueous ammonia (3 mL) was added to the solution, giving a white precipitate immediately. The mixture was stirred for 10 minutes and then was vacuum-filtered and suctioned to afford the white solid product (0.3509 g). Yield: 93.3%, mp 265–268° C. DEC.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[CH2:7]1)(=[O:4])=[O:3].[OH-].[Na+].I[CH3:34]>CN(C)C=O>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([CH3:34])[C:26]2=[O:30])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CI
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (0.80 g) in N,N-dimethylformamide (10 ml) was added sodium hydroxide (78 mg) under ice-cooling and the mixture was stirred at the same temperature for 20 minutes. To a solution was added iodomethane (0.34 ml) and the mixture was stirred at 30° C.-50° C. for 1 hour. The reaction mixture was poured into ice-water (30 ml) and extracted twice with ethyl acetate (30 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:l,V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.78 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[CH:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[CH:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(C=CC(=O)O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C2c3ccc(O)cc3CCC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
To a solution of ether 6e (120 mg, 0.312 mmol) in CH2Cl2 (12 mL) at 0° C. was added 1M boron tribromide in CH2Cl2 (4 mL). The mixture was stirred 1.5 h at room temperature and then quenched with ice/H2O. After stirring for 2 h, the mixture was extracted with CH2Cl2. The combined organic layers were washed with water and dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 10-20% methanol/CH2Cl2) to give phenol 6f as a white solid (45 mg, 39%): ESI m/z: 369 (M−H−, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[C:28]1([C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:1]([C:4]1[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:38]2[CH2:39][CH2:40][C:35](=[C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36][CH2:37]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
4.7 g (12 mmol) 5-acetyl-1,4-dihydro-2,6-dimethyl-3-(5-chloropentanoyl)-4-(3-nitrophenyl)-pyridine and 3 g (14 mmol) 4-diphenylmethylenepiperidine are boiled under reflux with 1.9 g (12 mmol) sodium iodide and 5 g (48 mmol) sodium carbonate in 200 ml acetone for 5 days. The mixture is filtered and concentrated, and the residue is taken up in 100 ml ethyl acetate. This solution is extracted by shaking with 40 ml sodium thiosulphate solution (5%). The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is chromatographed with toluene/acetone=6/4, The title compound is obtained as a yellow oil. Yield: 2.2 g (32%).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-chlorophenyl isocyanate (1 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 3 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (2:3 by volume)], collecting 20-cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-chlorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1 g), m.p. 124° C. is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of sodium hydride (60%, 1.7 g, 43 mmol) in dimethylformamide (200 mL) was added 4'-chloro-4-hydroxybenzophenone (5 g, 22 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, then 1-bromo-3-chloropropane (4.4 mL, 43 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (10 mL) and filtered through Celite®. The filtrate was taken up in ether (300 mL), washed thrice with water (150 mL) and dried over sodium sulfate. The solution was concentrated to give 6.1 g (90%) of 4'-chloro-4-chloropropoxybenzophenone as an amber oil. 1H NMR (CDCl3): δ7.98-6.89(m,8H), 4.19(t,2H), 3.85(t,2H), 2.29(m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g (31.9 mmol) of 2-(4-Chloro-phenyl)-ethanol was dissolved in 100 ml of pyridine and the solution was cooled to 0° C. 6.09 g (31.9 mmol) of para-toluene sulfonyl chloride was added to this solution and the reaction was stirred at 0° C. for 2 h, then at room temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated aqueous sodium chloride. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The compound was recrystallised from n-heptane/ethyl acetate. Yield: 6.23 g MS (Cl+): m/e=311, chloro pattern.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([Br:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:12][C:5]1[C:6]2[N:10]([CH3:11])[CH:9]=[CH:8][C:7]=2[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([Cl:13])[CH:15]=2)=[N:3][CH:4]=1
Reactant: Cn1ccc2c(Br)ncc(Br)c21
Reactant: Nc1cccc(Cl)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(Br)c21
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 4,7-dibromo-1-methyl-1H-pyrrolo[3,2-c]pyridine (290 mg), 3-chloroaniline (153 mg), cesium carbonate (652 mg), tris(dibenzylidineacetone)dipalladium(0) (10 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg) in dioxan (5 ml) was heated at reflux under nitrogen overnight. A further addition of tris(dibenzylidineacetone)dipalladium(0) (10 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg) was made and the mixture refluxed for 4 hrs, then a repeat addition made and reflux continued for 2 hrs. The mixture was diluted with ethyl acetate (5 ml), filtered through Celite using ethylacetate and evaporate. The residue was dissolved in ethyl acetate and passed through silica gel eluting with ethyl acetate and evaporated. Purification of the residue by chromatography on Biotage, eluting with isohexane/dichloromethane 1:1, and evaporation gave the title compound (199 mg)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: N=C(N)Nc1ccc(O)cc1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(O)cc3)ncc1CC2
Temperature: 120 °C
Yield: 3 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-hydroxy-phenyl)-guanidine nitrate (163 mg, 7.6 mmol), NaOH, (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated at 120° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a yellow solid (70 mg, 30%): mp 268-269° C. Anal. RP-HPLC: tR 12.4 min (10-70% MeCN, purity 95%). 1H-NMR (DMSO-d6): δ 9.28 (s, 1H, OH/NH), 9.07 (s, 1H, OH/NH), 8.30 (s, 1H, Py-H), 7.58 (d, 2H, J 8.9, Ph-H), 6.75 (d, 2H, J 8.9, Ph-H), 3.02 (m, 4H, CH2—CH2), 2.80 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.94, 159.64, 159.13, 156.26, 155.73, 152.35, 132.70, 120.94, 115.44, 115.19, 25.13, 23.45, 19.79. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH3:12])([O-])=O>C(O)(=O)C.[Fe]>[CH3:12][O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cccc(C)c1N

Procedure:
Solid 2-nitro-3-methylanisole (20 g) is added portion to a hot (40°-60° C.) suspension of iron (30 g) in 20% acetic acid (400 ml). The mixture is heated on a steam bath for 40 min, filtered still hot and neutralized (after cooling) with 50% aqueous sodium hydroxide. The mixture is steam distilled (2 liters of water collected). The distillate is extracted with diethyl ether and the etheral solution is dried and evaporated to give an oily residue of 2-methoxy-6-methylbenzenamine: nmr (CDCl3) δ2.15 (s, 3H), 3.7 (s, 2H), 3.8 (s, 3H) and 6.7 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:26]([O:28]C)=O)[CH:15]([OH:25])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH:15]([OH:25])[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:22][C:26]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3ccccc3C2O)CC1
Temperature: 80 °C
Yield: 77 %

Procedure:
In a 3 neck flask fitted with a nitrogen inlet, thermometer, and a mechanical stirrer, 4-[2-hydroxy-1-methoxycarbonyl-2-(2-nitro-phenyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (9.93 g, 24.3 mmoles) was dissolved in acetic acid (1.75 moles, 100 mL). Iron powder (8.90 g, 159 mmoles) was added to the vessel with stirring. The stirred mixture was slowly heated to 80° C. for 30 min and then cooled to room temperature. It was then diluted with ethyl acetate and filtered through a pad of celite. Solids were washed with 20% methanol/ethyl acetate, and then with methanol. The filtrate was concentrated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. The layers were separated. The resulting aqueous phase was extracted twice with ethyl acetate. The organic layers were combined. The mixture was washed twice with water and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the title compound as light yellow foam in 77% yield. MS m/e (M−H)−=345.1.