Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]4[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=4[N:20]=[C:14]3[C@H:13]2[CH:33]([CH3:35])[CH3:34])[N:3]=1.[C:36]([O-])(O)=[O:37].[Na+]>CO>[CH:33]([C@H:13]1[N:12]([C:4]2[N:3]=[C:2]([O:37][CH3:36])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH2:17][CH2:16][N:15]2[C:18]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=3[N:20]=[C:14]12)([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(Cl)n1)[C@@H]3C(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(OC)n1)[C@@H]3C(C)C
Temperature: 60 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of (R)-methyl 2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.028 mmol) in methanol (4 mL) was added NaHCO3 (25 mg, 0.29 mmol). The mixture was stirred at 60° C. for 20 h. The mixture was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (13.0 mg, 87.2% yield) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:13]#[C:14][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1ccc(C#Cc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-iodo-phenyl)-methanesulfonamide (0.46 g, 1.54 mmol), Pd(PPh3)2Cl2 (54 mg, 0.077 mmol) and CuI (14.7 mg, 0.077 mmol) in TEA/THF (10 mL/3 mL) was treated with 1-ethynyl-4-methyl-benzene (0.29 mL, 2.32 mmol). The reaction mixture was degassed and stirred at room temperature for 30 min. The solvent was removed under the reduced pressure. The residue was diluted with EtOAc and water. After the usual work-up, the obtained crude material was purified by chromatography (35% EtOAc/hexanes) to give the desired product. MS (EI) 286 (M+H)+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[I:20]N1C(=O)CCC1=O>>[F:9][C:10]1[C:18]([F:19])=[CH:17][C:16]([I:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 2.5 °C
Reaction time: 0.05 h
Yield: 82.8 %

Procedure:
A 500 mL, 3 neck round bottom flask, equipped with an overhead stirrer is charged with trifluoromethanesulfonic acid (100 g), cooled to 0-5° C. in an ice bath, and treated with 2,3-difluorobenzoic acid (18.96 g). To this mixture is added N-iodosuccinimide (32.4 g) portion-wise over a 10 min period. After an additional 3 min, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After a total of 5 h, the reaction mixture is poured into 600 mL of vigorously stirred crushed ice/water containing 100 mL of 10% sodium sulfite solution. The beige colored precipitate is collected, washed with ice water and dried at 50° C. in a vacuum oven overnight to produce 28.2 g (83%) of the title compound. Physical characteristics: 1H NMR (CDCl3) δ10.35, 8.12, 7.76; MS (ESI−) m/z 283 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1)[C:24]([OH:26])=[O:25]
Reactant: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Yield: 68.5 %

Procedure:
A mixture of 0.108 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40), 0.08 g (0.00048 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.11 g of 3-methoxy-4-[9-(2-methoxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-40a) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][F:36])[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:26]2[CH:27]=[CH:22][N:23]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH:30]3[CH2:35][F:36])[N:25]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: FCC1COCCN1Cc1nccc(Cl)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOCC4CF)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (26 mg, 0.09 mmol) and 4-[(4-chloropyrimidin-2-yl)methyl]-3-(fluoromethyl)morpholine (21.70 mg, 0.09 mmol) as starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.6 %

Procedure:
A solution of 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.68 g, 18.16 mmol) in DCM (2 mL) was treated with TFA (25 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, dissolved in 1 N aqueous HCl and washed with EtOAc. The aqueous a phase was basified with ammonium hydroxide and extracted into EtOAc. The combined extracts were dried over Na2SO4 and concentrated under vacuum to give 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.58 g) as a yellow solid. 1H NMR (300 MHz, DMSO) δ 8.54 (br s, 1H), 8.18 (d, J=3.1 Hz, 1H), 7.60-7.53 (m, 1H), 7.45 (d, J=8.8 Hz, 1H), 4.76-4.65 (m, 1H), 3.30-3.19 (m, 2H), 3.11-3.00 (m, 2H), 2.15-2.03 (m, 2H), 1.89-1.74 (m, 2H). LCMS (m/z, Method A) ES+ 213.1 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67])=[O:20])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Yield: 20.55 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) and HATU (80 mg, 0.209 mmol) was added DMF (3 mL) and the resulting solution was treated with DIPEA (0.091 mL, 0.523 mmol) and after 5 min by 2-aminopropane-1,3-diol (31.8 mg, 0.349 mmol). The reaction was concentrated in vacuo, residue partitioned between water and EtOAc. the phases were separated and the aqueous extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3 (3×) then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH) and the residue triturated with Et2O to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide (17 mg, 0.036 mmol, 20.55% yield) as a very pale yellow solid. LCMS (HpH, 2 min), Rt=0.74 min, MH+=475.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([OH:26])=O)[CH2:18][O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl>C(OCC)(=O)C>[NH:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:17]([C:24]([NH:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:26])[CH2:18][O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
2.75 ml of triethylamine and 2.63 ml of chloroformic acid isobutyl ester are added to 5.9 g of Z-Ser(But)-OH in 20 ml of ethyl acetate at -10°C. After 10 minutes, 4.0 g of H-Leu-OMe-HCl and 3.05 ml of triethylamine are added. After stirring for 11/2 hours in an ice bath, the mixture is extracted by shaking with phosphoric acid and sodium bicarbonate solution and after drying over sodium sulphate the ethyl acetate is evaporated completely. 8.2 g of a waxy mass are obtained. Melting point (after crystallisation from hexane): 56°-58°C.
Reaction SMILES: [CH3:1][Li].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10](=[O:12])[CH3:1])[CH2:8][CH2:9]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1CCC(O)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Methyllithium (1M in THF) (120 mL, 3.5 eq.) was added to a solution of 4-hydroxy-cyclohexanecarboxylic acid (cis/trans mixture) (5.00 g, 1 eq.) in THF (350 mL) at −78° C. After stirring at −78° C. for 45 min, the cooling bath was removed and the resulting mixture was warmed to room temperature and stirred overnight. After total 24 h, the resulting reaction mixture was poured into ice/water (800 mL). This mixture was vigorously stirred. The separated aqueous phase was extracted with MeOH/EtOAc (˜ 1/20). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (50% to 100% EtOAc/hexanes) to give 1-(4-hydroxy-cyclohexyl)-ethanone (2.08 g, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
3-Hydroxybenzaldehyde (1.15 g, 9.4 mmol), 1-fluoro-4-nitrobenzene (1.0 mL, 9.4 mmol) and K2CO3 (2.61 g, 19 mmol) were combined in DMF (20 mL) and heated at 80° C. After 6 hours, the reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The separated aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with 1N NaOH, brine, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a yellow solid (1.98 g).
Reaction SMILES: [CH:1]1([C:4]23[O:11][CH2:10][C:7]([CH2:12][OH:13])([CH2:8][O:9]2)[CH2:6][O:5]3)[CH2:3][CH2:2]1.[CH:14]1(C#N)CCC1>>[CH:1]1([C:4]23[O:5][CH2:6][C:7]([CH2:12][OH:13])([CH2:8][O:9]2)[CH2:10][O:11]3)[CH2:3][CH2:2][CH2:14]1
Reactant: OCC12COC(C3CC3)(OC1)OC2
Reactant: N#CC1CCC1
Product: OCC12COC(C3CCC3)(OC1)OC2
Yield: 51 %

Procedure:
The same procedure as in the steps (37a) to (37c) of Example 37 was repeated using cyclobutanecarbonitrile to obtain the title compound (15 g, total yield: 51%) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[O:13])=[C:4]([OH:14])[CH:3]=1.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21](O)[C:17]=1[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>>[OH:15][C:16]1[CH:24]=[CH:23][C:22]2[N+:12]([O-:13])=[C:5]3[C:4](=[CH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[O:14][C:21]=2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=Nc1c(O)cc(O)c2ccccc12
Reactant: O=C(O)c1c(O)cccc1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(O)ccc2c1oc1cc(=O)c3ccccc3c-1[n+]2[O-]

Procedure:
2.84 g. 1,3-dihydroxy-4-nitrosonaphthalene, 2.31 g. 2,6-dihydroxybenzoic acid, 1.29 g, pyrolusite and 1.6 ml. concentrated sulphuric acid are reacted analogously to Example 1(a). Yield 2.8 g.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1.C1COCC1.O.[OH-].[Li+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[N:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)nicotinate (0.70 g, 1.84 mmol) in a mixed solvent of THF (6 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.39 mg, 9.2 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was quenched with aqueous 2N HCl to pH 5. The precipitate formed was collected by filtration, washed with water, dried to provide 2-(4-(benzo[d]thiazol-2-ylamino)-phenoxy)nicotinic acid as off-white solid. MS (ESI, pos. ion) m/z: 364.0 (M+1). IC50 (uM) +.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH2:20][C:21]([NH2:23])=O)[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([NH:15][C:16]1([CH2:20][CH2:21][NH2:23])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCC1(NCc2ccccc2)CCC1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
LiAlH4 (570 mg, 15.0 mmol) was added portionwise to a solution of [1-(benzoylamino)cyclobutyl]acetamide (687 mg, 3.00 mmol) in THF (30 mL) at room temperature over the course of 30 minutes, and the mixture was heated to reflux for 5 hours. The mixture was cooled in an ice-water bath, aqueous THF and few drops of water were added, and the mixture was allowed to stand overnight. The mixture was filtered through celite and the solution was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to give the title compound as a pale yellow oil (609 mg, 99%). 1H-NMR (400 MHz, CDCl3) δ 1.65-1.80 (2H, m), 1.82 (2H, t, J=7.3 Hz), 1.86-2.02 (4H, m), 2.82 (2H, t, J=7.3 Hz), 3.65 (2H, s), 7.20-7.38 (5H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][O:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH:11]12[O:25][CH:10]1[CH2:9][O:8][CH:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:14]([O-:16])=[O:15])[CH2:13][CH2:12]2
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC=CCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CCC2OC2CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
To a solution of 1-methyl-4-nitro-5-(2,3,4,7-tetrahydrooxepin-2-yl)pyrazole (1.00 g, 4.74 mmol) in DCM (25 mL) was added m-CPBA (70-75%, 1.75 g, 7.11 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL), washed with saturated aqueous NaHCO3 (50 mL), water (50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave racemic 5-(5,8-dioxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-pyrazole as a colourless solid (490 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.22-7.87 (m, 1H), 5.07 (d, J=9.9 Hz, 1H), 4.50 (dd, J=14.5, 3.1 Hz, 1H), 4.05 (s, 3H), 3.93 (d, J=14.4 Hz, 1H), 3.35 (t, J=4.5 Hz, 1H), 3.13 (t, J=3.6 Hz, 1H), 2.55-2.47 (m, 1H), 2.31-2.21 (m, 1H), 2.16-2.04 (m, 1H), 1.79 (dd, J=14.4, 1.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[O:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](O)=[O:26]>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:25]([C@H:21]4[CH2:22][CH2:23][CH2:24][O:20]4)=[O:26])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)[C@H]3CCCO3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and (R)-tetrahydrofuran-2-carboxylic acid, the title compound was prepared as white powder. MS: m/e=379(M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.O>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
0.5 g of 2-chloro-5-nitro-pyridine (3.15 mmol), 1.2 g of tributyl-vinyl-stannane (3.78 mmol), 0.036 g of tetrakistriphenylphosphinpalladium(0) (0.03 mmol), and 0.024 g of triphenylphosphin (0.09 mmol) were dissolved in 20 ml of toluene and stirred for 2 h under reflux. Upon cooling to room temperature, 10 ml of water were added, the agueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (10%). Fractions containing the product were combined, the solvent evaporated to yield 0.528 g of the desired product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[CH:31](OC1C=CC=CC=1NCCNCC1C=C(C(N2CCCCC2)=O)C=CC=1)(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:30])[CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1N(C)CCNCc1cccc(C(=O)N2CCCCC2)c1
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Product: CC(C)Oc1ccccc1N(C)CCN(C)Cc1cccc(C(=O)N2CCCCC2)c1

Procedure:
The title compound was prepared as in Example 27 substituting [3-({2-[(2-isopropoxy-phenyl)-methyl-amino]-ethylamino}-methyl)-phenyl]-piperidin-1-yl-methanone for (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)piperidin-1-yl-methanone. MS (ESI): mass calculated for C26H37N3O2, 323.29; m/z found, 324.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.71 (dd, J=5.9, 3.3 Hz, 1H), 7.53 (dd, J=5.9, 3.3 Hz, 1H), 7.30-7.33 (m, 2H), 6.93-6.82 (m, 4H), 4.59 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.52 (s, 2H), 3.31 (br s, 2H), 3.25 (t, J=7.3 Hz, 2H), 2.80 (s, 3H), 2.63 (t, J=7.3 Hz, 2H), 2.19 (s, 3H), 1.67 (br s, 6H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[CH:13]=[C:14]([C:17]([C:19]3([NH2:38])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28]C)[CH:26]=4)[N:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:20]3=[O:37])=[O:18])[N:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].B(Br)(Br)Br.CO>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[CH:13]=[C:14]([C:17]([C:19]3([NH2:38])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=4)[N:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:20]3=[O:37])=[O:18])[N:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(N)(C(=O)c1cc3c4ccccc4n(C(C)=O)c3cn1)C(=O)N2c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)n1c2ccccc2c2cc(C(=O)C3(N)C(=O)N(c4ccc(F)cc4)c4ccc(O)cc43)ncc21
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
In 40 ml of dichloromethane was suspended 1.54 g (3.04 mmole) of 3-{9-acetyl-9H-pyrido[3,4-b]-indol-3-yl-carbonyl}-amino-5-methoxy-1-(4-fluorophenyl)-2-indolinone, and to the suspension was added dropwise under ice cooling a solution of 1.1 ml (4 mole equivalent) of boron tribromide dissolved in 10 ml of dichloromethane. After completion of the dropwise addition, the mixture was stirred for 10 minutes under ice cooling and then stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was treated with methanol under ice cooling, and then the solvent was removed under reduced pressure. Methanol was added to the residue, and the precipitates were collected by filtration to obtain 1.07 g of a hydrobromide of the title compound as pale yellow crystals. Melting point: 239° to 241° C., IR (Nujol) (cm-1): 1720, 1680, FAB-MS (m/z): 495 (MH+, base)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][O:22][CH3:23])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:23][O:22][CH2:21][O:20][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[O:19][N:18]=1
Reactant: COCOc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1cc(-c2ccc(O)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed solution of 5-(4-(benzyloxy)phenyl)-3-(methoxymethoxy)isoxazole (1.44 g) in methanol (15 ml) and tetrahydrofuran (15 ml), 200 mg of 10% palladium-carbon catalyst was added, and the reaction solution was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-50:50)) to afford the title compound as a pale yellow solid.