Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:14]=[C:15]1[O:18][C:17](=[O:19])[CH2:16]1>ClCCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:19])[CH2:16][C:15](=[O:18])[CH3:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCCl
Product: CC(=O)CC(=O)Nc1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirred solution of 10 parts of 4-[(1H-imidazol-1-yl)methyl]benzenamine in 180 parts of 1,2-dichloroethane were added dropwise 3.9 parts of 4-methylene-2-oxetanone. After stirring for 1/2 hour at room temperature, the precipitate was filtered off, washed with 1,2-dichloroethane and dried, yielding 9.8 parts (74.8%) of N-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-oxobutanamide; mp. 175° C.(interm. 57). In a similar manner there were also prepared the intermediates listed in Table 4:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O-:34][C:35]#[N:36].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35](=[O:34])([O:30][CH2:29][CH2:28][N:15]1[CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])[NH2:36]
Reactant: O=C1N(CCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (10.0 mg, 0.021 mmol) in DCM (0.3 mL) are added sodium cyanate (5.5 mg, 0.084 mmol) and TFA (6.46 μL, 0.084 mmol). The mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparatory TLC to provide the title compound; HPLC-MS calculated for C25H21ClF3N3O4 (M+H+) 520.1, found 520.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][C@@H:29]([OH:31])[C@H:28]([CH3:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:32][C@@H:28]1[CH2:27][CH2:26][C@H:25]([NH:24][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:3]=2)[CH2:30][C@H:29]1[OH:31]
Reactant: C[C@@H]1CC[C@H](N)C[C@H]1O
Reactant: FC(F)(F)c1ccncc1CNc1ncc(C(F)(F)F)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C(F)(F)F)C[C@H]1O
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Chloro-5-(trifluoromethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrimidin-2-amine (1.0 equiv.) was placed in a sealable flask with (1R,2R,5S)-5-amino-2-methylcyclohexanol (1.1 equiv.), DIEA (2.0 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up, afforded (1R,2R,5S)-2-methyl-5-(5-(trifluoromethyl)-2-((4-(trifluoromethyl)pyridin-3-yl)methylamino)pyrimidin-4-ylamino)cyclohexanol (47.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65-8.76 (m, 2H) 8.01-8.14 (m, 1H) 7.71 (d, J=5.08 Hz, 1H) 5.74 (br. s., 1H) 4.67-4.80 (m, 1H) 4.57-4.67 (m, 1H) 4.54 (br. s., 1H) 4.39 (d, J=4.30 Hz, 1H) 4.14 (br. s., 1H) 3.21-3.31 (m, 1H) 1.78 (br. s., 1H) 1.54 (br. s., 1H) 1.41 (br. s., 1H) 1.33 (br. s., 1H) 1.10-1.24 (m, 1H) 0.96 (br. s., 1H) 0.81-0.89 (m, 2H). MS (ESI) m/z 450.2 [M+1]+
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)([O-:14])=[O:13].CC(C)(C1C=CC=CC=1)CO.[N+](C1C=CC(Cl)=CC=1)([O-])=O>>[CH3:10][C:2]([CH3:1])([O:11][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(O)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(CO)c1ccccc1
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Product: CC(C)(Cc1ccccc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
By a similar manner to reference example 1, 1,1 -dimethyl-2-phenylethylalcohol and 4-nitrofluorobenzene are used in place of 2,2-dimethyl-2-phenylethylalcohol and 4-nitrochlorobenzene respectively to give 4-(1,1-dimethyl-2-phenylethyloxy)-nitrobenzene. Melting point: 78°-79° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCCCOc1ccc(F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
3-(4-Fluorophenoxy)propanoic acid (16.6 g, 90 mmol) was stirred in 100 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to 5° C. and borane (120 mL, 120 mmol, 1M in tetrahydrofuran) was added dropwise at a rate to keep the temperature of the reaction near 5° C. Once the addition was complete, the solution was allowed to stir at room temperature overnight. The reaction was then cooled below 10° C. and 18 mL of a tetrahydrofuran/water mixture was added. The tetrahydrofuran was removed by evaporation under reduced pressure and the resulting cloudy mixture was diluted with about 200 mL of water. This mixture was extracted three times with diethyl ether. The combined extracts were washed with water, twice with 10% aqueous sodium bicarbonate, and once with brine. The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give 15.24 g of a product oil. Yield: 99%. MS(FD) M+ 171.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][O:14][C:12](=[O:13])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]C(C)C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]([CH2:15][OH:14])[CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC[C@@H](CO)OC(=O)c1ccccc1
Temperature: -78 °C
Yield: 73.7 %

Procedure:
To a solution of 101 (0.780 g, 3.8 mmol) in 13 mL dry THF was slowly dropwise added 1.0 M diisopropyl aluminiumhydride (4.7 mL, 4.7 mmol) in toluene at −78° C. The reaction mixture was stirred at −78° C., and as soon as the starting material was completely consumed (TLC, 2 hours), methanol (2 mL) was slowly added in order to quench the reaction. The cooling bath was removed, 15 mL of a saturated aqeous sodium potassium tartrate solution and 25 mL of EtOAc were added and the mixture stirred vigorously for 3 hours. The organic layer was washed with water and brine, and concentrated under vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:2) to afford 102 (590 mg, 2.8 mmol) as a colorless oil, in 75% yield, which was characterized as follows:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)OCC)cc1
Reaction time: 15 h
Yield: 95.8 %

Procedure:
2 g (12 mmole) of ethyl 4-hydroxybenzoate were added to a N,N-dimethylformamide (10 ml) suspension including 0.32 g of sodium hydride under ice cooling. Furthermore, a N,N-dimethylformamide (5 ml) solution including 2.2 g (13 mmole) of ethyl bromoacetate was added dropwise thereto, and reaction was then carried out for 15 hours. After the reaction mixture had been concentrated, partition was carried out between ethyl acetate and water. The organic layer was then treated in an ordinary manner to obtain 2.9 g (yield: 96%) of ethyl 4-(2-ethoxy-2-oxo-ethoxy)benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccccc2)c2ccc(OCCc3ccc(F)cc3)cc2o1

Procedure:
A mixture of 4-benzyloxy-7-hydroxycoumarin (5.36; 0.02 mole) anhydrous potassium carbonate (4.0 g) and 1-bromo-2-(4-fluorophenyl) ethane (4.06 g) in acetone (100 ml) was stirred at reflux for 20 hours and the inorganic material filtered off. Evaporation of the filtrate in vacuo gave an oil which rapidly set solid on scratching. Chloroform (200 ml) was added and the mixture filtered to remove unchanged 4-benzyloxy-7-hydroxycoumarin. Reevaporation of the filtrate afforded a white solid, 3.34 g (43%) of m.p. 120°, νmax (mull) 1715, 1675, 1620 cm-1 ; τ(CDCl3); 6.93 (2H, t, J 6.7 Hz); 5.80 (2H, t, J 6.7 Hz); 4.87 (2H, S); 4.38 (1H, ); 3.29-2.49 (6H, m) 2.32 (1H, d, J 10 Hz); (Found C, 73.75 H, 5.14 C24H19FO4 requires; C, 73.84; H, 4.91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([C:39]([F:50])([F:49])[CH2:40]OS(C(F)(F)F)(=O)=O)[CH:36]=[CH:37][CH:38]=1>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:40][C:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=3)([F:49])[F:50])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)c1cccc(Cl)c1)C(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3cccc(Cl)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.8 %

Procedure:
To a mixture of 230 mg (0.67 mmol) of 2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester and 227 mg (1.62 mmol) of potassium carbonate in 6 ml of acetone and 1.7 ml of DMF was added slowly a solution of 437 mg (1.65 mmol) of the compound of step 2. The reaction mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 20 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.CON(C)[C:25]([C:27]1[C:32]([NH2:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26].Cl>C1COCC1>[NH2:33][C:32]1[C:27]([C:25]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:26])=[N:28][CH:29]=[CH:30][N:31]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1nccnc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nccnc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.9 M 4-chlorophenyl magnesium bromide in THF/toluene (9.15 ml, 8.24 mmol) is added dropwise to a solution of 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide (0.5 g, 2.74 mmol) in THF (15 ml) at 0° C. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture is cooled to 0° C. and 2 M HCl (20 ml) is added. The product is extracted into EtOAc (3×40 ml), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields (3-Amino-pyrazin-2-yl)-(4-chloro-phenyl)-methanone as a yellow solid.
Reaction SMILES: [CH:1]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrCBr.C1(=O)CCCCCCCCCCCC1>[Ti](Cl)(Cl)(Cl)Cl.[Zn].O1CCCC1>[CH2:14]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=CC1CCCCCCCCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C1CCCCCCCCCCCC1
Agent: [Zn]
Solvent: BrCBr
Solvent: C1CCOC1
Product: C=C1CCCCCCCCCCCC1

Procedure:
The cyclotridecanecarbaldehyde listed above is also a novel compound which is prepared in the following manner: Titanium tetrachloride is added to a mixture of zinc dust, anhydrous tetrahydrofuran and dibromomethane. To the resulting mixture is added cyclotridecanone to yield methylene cyclotridecane which is then epoxidized with m-chloroperbenzoic acid. After purification, the epoxidized product is reacted with boron trifluoride-ether complex in anhydrous dichloromethane to yield cyclotridecanecarbaldehyde.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH3:17]>CS(C)=O>[NH2:17][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: COC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of methyl (2E)-3-(4-chloro-3-nitrophenyl)acrylate (from Step 1, 1 eq) in DMSO (0.4 M) at 140° C., ammonia gas was bubbled through for 6 h. The reaction mixture was cooled to RT, degassed with nitrogen, and poured into ice cold water. The precipitate formed was filtered washed with cold water and dried under vacuo to afford the title compound (89%) as a solid. 1H-NMR (400 MHz; DMSO-d6, 300 K) δ 3.70, (s, 3H), 6.46 (d, J 16, 1H), 7.04 (d, J 8.8, 1H), 7.60 (d, J 16, 1H), 7.82-7.86 (m, 3H), 8.25 (s, 1H); MS (ES−) m/z 221 (M−H)−.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCC(=O)N(C)OC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methyl magnesium bromide (3M in ether, 3 eq.) was added dropwise to a stirred mixture of N-methoxy-N-methylhept-6-enamide 58 in THF (0.1 M) cooled at 0° C. After sting for 1 h at 0° C., the mixture was poured into sat. aq. NH4Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc, the combined organic layers were washed with brine and dried (Na2SO4). Evaporation of the solvent at 30 mbar afforded the title compound (96%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.81 (ddt, J 17.1, 10.3, 6.7, 1H), 5.02 (dd, J 17.1, 1.5, 1H), 4.97 (d, J 10.3, 1H), 2.46-2.43 (m, 2H), 2.15 (s, 3H), 2.10-2.05 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.37 (m, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:13]=[C:12](Cl)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1.C(O)(=[O:20])C>>[Cl:3][C:4]1[NH:13][C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(Cl)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Aqueous 2M NaOH (22.2 mL, 44.4 mmol) was added to 2,4-dichloro-6-nitro-quinazoline (3.61 g, 14.8 mmol). The mixture was sonicated, stirred at room temperature for 3 h, and filtered, rinsing with water (60 mL). Acetic acid (3.81 mL, 66.6 mmol) was added to the filtrate to yield a precipitate, which was collected and dried in a vacuum oven to yield the titled compound (2.99 g, 90% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCl3): 9.07 (s, 1H), 8.56 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[NH2:25]
Reactant: Clc1cccc2[nH]ncc12
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nn1ncc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
Sodium hydride (60 % wt suspension in mineral oil; 0.33 g, 8.3 mmol) is suspended in dry tetrahydrofuran (THF, 10 mL) and is cooled to 0° C. A mixture of 4-chloroindazole (1.05 g, 6.9 mmol) and THF (10 mL) is added to the slurry at 4° C. After the addition is completed, the mixture is stirred for 30 min. Then a mixture of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) and THF (10 mL) is added slowly, at a temperature below 5° C. After the addition is completed, the reaction mixture is allowed to reach room temperature and is subsequently stirred for 3 h. Then the mixture is cooled again to 0° C., and a second aliquot of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) in THF (10 mL) is added slowly. The mixture is allowed to reach ambient temperature and is subsequently stirred overnight. The reaction mixture is worked up by adding it to water, extracting into ethyl acetate, and drying over sodium sulfate. The crude product (1.2 g) is obtained after filtration of the drying agent and evaporation of the solvent. This material is used for the next reaction step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][NH:37][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 93.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimido-propanoic acid (869 mg, 2.36 mmol), N,N′-carbonyldiimidazole (410 mg, 2.53 mmol) and O-benzylhydroxylamine hydrochloride (444 mg, 2.78 mmol) in tetrahydrofuran (6 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide as a white solid (1.05 g, 94% yield): mp, 165.0–166.0° C.; 1H NMR (CDCl3) δ 1.44 (t, J=7.0 Hz, 3H, CH3), 2.95 (dd, J=5.8, 14.0 Hz, 1H, CHH), 3.49 (t, J=12.1 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.07 (q, J=7.0 Hz, 2H, CH2), 4.77 (br s, 2H, PhCH2), 5.83 (dd, J=6.0, 10.0 Hz, 1H, NCH), 6.79 (d, J=8.0 Hz, 1H, Ar), 7.06–7.09 (m, 2H, Ar), 7.25–7.85 (m, 5H, Ar), 7.66–7.71 & 7.74–7.79 (2 ms, 4H, Ar), 8.34 (br s, 1H, NH); 13C NMR (CDCl3) δ 14.68, 35.66, 51.54, 55.88, 64.34, 78.13, 111.32, 12.52, 120.08, 123.29, 128.52, 128.67, 129.06, 131.26, 131.76, 133.98, 134.98, 148.31, 149.15, 167.38, 168.26. Anal. Calcd for C27H26N2O6: C, 68.34; H, 5.52; N, 5.90. Found: C, 68.36; H, 5.47; N, 5.74.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 35 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-methyl-3-nitrophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde (35% yield) as a light cream solid. ESI/MS 315 (M+H); 356 [(M+1+CH3CN) adduct]; RT 3.35 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[O:1][C:13]1[C:12]([Cl:11])=[CH:30][C:16]2[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=2[CH:14]=1)([OH:7])=[O:6]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(C(=O)O)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp 288.1-289.2° C. 1H NMR (acetone-d6/300 MHz) 7.92 (m, 2H), 7.75 (s, 1H), 7.68 (d, 1H, J=1.4 Hz), 7.62 (t, 1H, J=7.9 Hz), 7.41 (m, 1H), 6.72 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.4 (d, J=6.5 Hz) ESHRMS m/z 413.0027 (M−H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6: C, 52.13; H, 2.43; Cl, 8.55. Found: C, 51.88; H, 2.48; Cl, 8.65.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 3.4 %

Procedure:
A mixture of isophthalonitrile (1.00 g, 07.8 mmol), methyl thiosalicylate (1.97 g, 12 mmol), triethylamine (1.34 g, 13 mmol) and toluene (5 ml) was heated and refluxed for 5 hours under a nitrogen flow. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethanol to give the title compound (0.07 g, 2%) as crystals.