Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH:11]([OH:49])[CH2:12][N:13]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20][N:19]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:15][CH2:14]1)C1C=CC=CC=1.O>CO.[Pd]>[CH3:8][NH:9][CH2:10][CH:11]([OH:49])[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:17][CH2:18][N:19]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CNCCc2ccccc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CNCC(O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
69.2 g (100 mmol) of 10-(3-benzylmethylamino-2-hydroxypropyl)-1,4,7-tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 500 ml of methanol, mixed with 40 ml of water, and 10 g of palladium catalyst (20% Pd/C) is added. It is hydrogenated for 8 hours at 50° C. under normal pressure. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][CH:28]3[CH2:29][CH2:30][CH2:31][O:27]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)CC1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (62 mg, 56%), MS (ISP) m/z=439.4 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and rac-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=1
Reactant: Cc1ncoc1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Product: Cc1ncoc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-methyl-5-phenyl-oxazole (1.6 g, 10 mmol), prepared according to the literature (Heterocycles, 1977, 7, 77-80), was dissolved in chlorosulfonic acid (10 mL) and stirred at room temperature for 4 h. The reaction mixture was added to crushed ice (50 g) and the product was extracted with ether (3×50 mL). The combined organic extract was dried over anhydrous Na2SO4 and ether was evaporated. The product was purified by flash chromatography (silica-gel, 5-20% ethylacetate/hexane mobile phase) to yield 0.91 g of the desired-title compound light yellow solid. MS: m/z 258.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.I[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a vial containing the title compound of Example 1 Step B (3.0 g, 11.36 mmol), were added 3-iodobenzotrifluoride (1.97 mL, 13.6 mmol), copper iodide (218 mg, 1.14 mmol), potassium phosphate (5.05 g, 23.9 mmol), and 1,2-trans-N,N-dimethylcyclohexane diamine (0.718 mL, 4.54 mmol). The reaction mixture was placed under a nitrogen atmosphere, and anhydrous toluene (11.4 mL, deoxygenated via nitrogen sparge) was added. The vial was then capped and placed in a pre-heated oil bath (110° C.) and stirred rapidly for 19 h. The mixture was allowed to cool to room temperature, then was filtered. The supernatant was washed extensively with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography (10% EtOAc in hexanes) afforded the title compound: LCMS B, tr=3.02 min, m/z 408.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.74-7.72 (m, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.26 (dd, J=9.0, 2.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 2.94 (t, J=7.5 Hz, 2H), 1.68 (quint., J=7.5 Hz, 2H), 1.38-1.28 (m, 6H), 0.88 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][C:32]([NH:36][S:37]([C:40]1[S:44][C:43]([NH2:45])=[N:42][C:41]=1[CH3:46])(=[O:39])=[O:38])([CH2:34][OH:35])[CH3:33]>>[OH:35][CH2:34][C:32]([NH:36][S:37]([C:40]1[S:44][C:43]([NH:45][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])=[N:42][C:41]=1[CH3:46])(=[O:39])=[O:38])([CH2:31][OH:30])[CH3:33]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(CO)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) according to general procedure II. Light yellow solid. MS (ISP) 681.2 [(M−H)−]; mp 220° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and benzoyl chloride (52.64 mg, 0.37 mmol) were mixed together in dichloromethane (5 mL) under nitrogen and then diisopropylethylamine (0.12 mL, 0.67 mmol) was added to afford clear solution. The resulting solution was stirred for 4 hours at room temperature and then concentrated. Ethyl acetate (20 mL) was added and the mixture was washed with water (20 mL) and brine solution (20 mL) and then dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude residue which was purified using an ISCO (12 g) column, eluting with 5-35% ethyl acetate in hexanes, to afford [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (133 mg, 88.8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 7.93-8.03 (m, 5 H), 7.88 (s, 1 H), 7.51-7.68 (m, 3 H), 7.48 (dd, J=8.6, 1.8 Hz, 1 H), 7.23 (d, J=8.5 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 3.97 (s, 2 H), 3.66 (s, 3 H), 2.10 (s, 3 H). HRMS calcd. for C27H23ClNO3 [(M+H)+] 444.1361, obsd. 444.1361.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[N:5]1([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[N:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of thiophosgene (150 μL, 1.76 mmol, 1.2 equiv) in CHCl3 (2.7 mL) is added to a vigorously stirred mixture of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.303 g, 1.47 mmol) in CHCl3 (7.5 mL) and a saturated aqueous solution of NaHCO3 (7.5 mL). The resulting dark mixture is stirred at RT for 1 h. The layers are separated and the aqueous phase is extracted with CHCl3. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a dark oil: ES-MS: 249.0 [M+H]+; single peak at tR=6.90 min (System 1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][CH3:33]>CC(C)=O>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH2:31][O:32][CH3:33])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc(C[C@@H]2CNCCO2)cc1Br
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), (70 mg, 0.19 mmo) was dissolved in acetone (1.5 mL) and treated with potassium carbonate (78 mg, 0.56 mmol) and 2-bromoethylmethyl ether (78 mg, 0.56 mmol) was added and the resulting reaction was shaken at 55° C. for 16 hrs. The reaction was filtered and concentrated under a flow of nitrogen. The crude residue was dissolved in tetrahydrofuran (8 mL) with polymer supported diphenylphosphine (0.5 g) and shaken for 4 hrs. The reaction was then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.5 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 36 as a colorless oil (31 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=1>[Pt].CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:21])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH2:17])[CH:11]=1
Reactant: Cc1nsc(NC(=O)Cc2ccc(O)c([N+](=O)[O-])c2)c1Cl
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)Cc2ccc(O)c(N)c2)c1Cl
Yield: 79 %

Procedure:
N-(4-Chloro-3-methyl-5-isothiazolyl)-4-hydroxy-3-nitrophenylacetamide (374 g, 0.114 mol) was hydrogenated at 15 bar over a 3% w/w platinum on carbon catalyst (15 g) in N,N-dimethylformamide (180 ml). Once the reduction was complete, the catalyst was removed by filtration and the filtrate was evaporated in vacuo to give N-(4-chloro-3-methyl-5-isothiazolyl)-3-amino-4-hydroxyphenylacetamide (26.8 g) as a pale brown solid, which used without further purification in the next step.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1)[CH3:21]>C(Cl)Cl.CO>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:15][CH:14]=3)=[CH:31][C:30]=2[C:36]([F:39])([F:37])[F:38])[CH2:24][CH2:23]1)[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.00 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10](=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1C)[O-].[CH3:20]O>>[CH3:20][N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1N=[N+]([O-])c1ccccc1C
Reactant: CO
Agent: [Na+]
Agent: [SH-]
Product: Cc1ccccc1N(C)Nc1ccccc1
Temperature: 75 °C
Yield: 84 %

Procedure:
90 Parts of an aqueous solution of technical sodium hydrosulfide (35 percent NaHS, 10 percent Na2S2O3) were added to a mixture of 45.2 parts of 2,2'-dimethylazoxybenzene in 150 parts methanol at 70° C to 75° C. Subsequently, the reaction mixture was refluxed at 75° C for 4 hours with pH kept between 9 and 9.4. Thereafter, the reaction mixture was cooled down to 0° C to 5° C, and the resulting precipitate filtered off and washed with water until alkali-free. The press-cake was dried below 70° C. There were obtained 35.6 parts of 2,2'-dimethylhydrazobenzene of a melting point of 162° C to 164° C, this representing a yield of 84 percent of the theory, of acceptable purity.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:16][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[NH2:1])[C:8](=[O:9])[O:7][CH:6]2[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)c([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(N)c(N)cc21

Procedure:
To a suspension of 3.75 g (15 mmol) of compound obtained in Example 22 in 150 ml of 95% ethanol there is added Raney nickel catalyst to hydrogenate at a hydrogen pressure of 1 kg/cm2. After the absorption of hydrogen has ceased, the catalyst is filtered off, and the filtrate is concentrated to dryness. The residue is crystallised from dilute ethanol, giving the title product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:14][CH2:15][C:16](=[O:23])[CH2:17][C:18](OCC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[K].[C:25]([C:29]1[CH:34]=[CH:33][C:32](CI)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:27])[CH3:26]>C(OCC)C.O1CCCC1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([CH2:18][CH2:17][C:16](=[O:23])[CH2:15][CH2:14][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CC(=O)CCC1CCCCCC1
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
454 mg (4.06 mmol) of potassium-t-butoxide were added to 10 ml of a tetrahydrofuran solution containing 1.00 g (4.16 mmol) of ethyl 5-cycloheptyl-3-oxovalerate (prepared as described in Preparation 5). The mixture was then stirred for 10 minutes to prepare the corresponding potassium salt. 1.11 g (3.47 mmol) of 2-t-butyl-5-iodomethyl-1-nitrobenzene (prepared as described in Preparation 51) were added to the mixture in an ice bath, and the mixture was stirred for 2 hours at the temperature of the ice bath. The reaction solution was diluted with diethyl ether and washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 10 ml of ethanol. 1.73 ml of a 2N aqueous solution of sodium hydroxide were added, and the mixture was heated for 4 hours under reflux. The reaction mixture was then cooled in an ice bath, sufficient concentrated aqueous hydrochloric acid was added to adjust its pH to a value of 5.0, and the mixture was heated for a further 2 hours under reflux. At the end of this time, the reaction solution was diluted with diethyl ether and washed with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 70 g of silica gel. Elution with a 2:1 by volume mixture of methylene chloride and hexane afforded 850 mg (yield 68%) of the title compound as an oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.O.[NH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[NH2:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Nc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(-c2ccnc(N)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 100 ml flask was added 4-bromopyridin-2-amine 36.A (432 mg, 2.50 mmol, available from Apollo), 3-aminophenylboronic acid hydrate 36.B (465 mg, 3.00 mmol, available from Oakwood), tetrakis(triphenylphosphine)palladium(0) (288 mg, 0.25 mmol), DMF (5 mL) and saturated aqueous K2CO3 (5 mL). The reaction mixture was stirred at 80° C. overnight. The reaction was then extracted with DCM (2×50 mL), the organic layers combined, washed with brine and dried on MgSO4. The DCM was removed under vacuum, leaving a crude solution of 4-(3-aminophenyl)pyridin-2-amine in DMF to which was added more DMF (10 mL), (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (662 mg, 2.5 mmol, available from Aldrich), diisopropylethylamine (1.74 mL, 10 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (1.90 g, 5.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then partitioned between water (50 mL) and EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography to afford tert-butyl (S)-1-(3-(2-aminopyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 36.C (200 mg, 15% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11](OC(C)=O)=[O:12]>C(Cl)Cl>[C:11](=[O:12])([S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(S)c1
Solvent: ClCCl
Product: COc1cccc(SC(C)=O)c1
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 3-methoxybenzenethiol (5 g, 35.66 mmol) and TEA (7.45 ml, 53.49 mmol) in DCM (60 ml) was added Ac2O (4 g, 39.23 mmol) at room temperature and stirred for 3 hours. The reaction mixture was washed with 1 N HCl (50 ml×2), water (50 ml×2) and brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated to afford product as a yellow solid (6.5 g, 100%). MS (ESI): m/z 183.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[CH:21]=O)[C:18]2[CH2:23][CH2:24][CH2:25][CH2:26][C:17]=2[S:16]3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:27]([NH:35][NH2:36])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[CH:21]=[N:36][NH:35][C:27]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:34])[C:18]2[CH2:23][CH2:24][CH2:25][CH2:26][C:17]=2[S:16]3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NNC(=O)c1cccnc1
Reactant: COc1cc(-c2nc3sc4c(n3c2C=O)CCCC4)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2nc3sc4c(n3c2C=NNC(=O)c2cccnc2)CCCC4)cc(OC)c1OC

Procedure:
Next, 0.37 g of 5,6,7,8-tetrahydro-2-(3,4,5-trimethoxyphenyl)-3-formylimidazo[2,1-b]benzothiazole, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was extracted with chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from methanol to obtain the desired substance in an amount of 0.40 g (yield of 81.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])OCC[O:9]2)=[CH:4][C:3]=1[CH:14]([C:16]1[N:17]([CH3:27])[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[OH:15]>CC(C)=O.C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:13])=[CH:4][C:3]=1[CH:14]([OH:15])[C:16]1[N:17]([CH3:27])[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1
Reactant: Cn1nc(-c2ccccc2)nc1C(O)c1cc(C2(C)OCCO2)ccc1F
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Yield: 131.1 %

Procedure:
Intermediate 416.3 (500 mg, 1.36 mmol) was heated in a solution of Acetone:Acetic Acid:H2O (2:1:1, 8 mL) at 125° C. for 30 min using a PC microwave. The reaction product was then concentrated and purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 580 mg of Intermediate 416.4. LCMS (2 min gradient) RT=1.59 min, 326.31 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25]Br)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:27].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC[N:51]3[CH:55]=[CH:54][N:53]=[CH:52]3)N=2)C=CC=1OC>>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][N:51]3[CH:55]=[CH:54][N:53]=[CH:52]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(CCCCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 58 as described for compound 113. M.p. 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.[Cl:18]N1C(=O)CCC1=O.O.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:17]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2cn3c(n2)CCCC3)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3n(c2Cl)CCCC3)c(Cl)c1
Temperature: 70 °C

Procedure:
A mixture of 1.0 g (3.7 mmol) of 2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine and 0.6 g (4.5 mmol) of N-chlorosuccinimide was stirred in 15 ml of dimethylformamide at room temperature overnight followed by heating at 70° C. for 20 minutes. An excess of water was added and the aqueous mixture extracted with 200 ml of ethyl acetate. The separated organic layer layer was washed with water, saturated aqueous sodium bicarbonate, and brine. After drying over magnesium sulfate, the solvent was removed in vacuo to give a oily residue. Silica gel column chromatography (3:1 followed by 1:1 hexane/ethyl acetate followed in turn by 2:1 ethyl acetate/hexane) afforded the title compound as the main component (0.65 g, m.p. 99°-101° C.).