Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:14]
Reactant: NNc1ccccn1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NNc1ccccn1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N′-pyridin-2-ylisonicotinohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.8 mmol of pyridin-2-yl-hydrazine. LC/MS [6.90 min; 450 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: CSCc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.14 mmol) of the compound from Example 49 were introduced into 9 ml of dichloromethane while cooling in ice, 33.4 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 33 mg (63% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[OH-].[Na+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O1CCCC1.CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, prepared as described above (90 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL) was added at room temperature 20-40 mesh beads of sodium hydroxide (48 mg, 1.20 mmol) and ethyl acrylate (1.200 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 4 hours under an atmosphere of dry N2, followed by addition of a second portion of sodium hydroxide (96 mg, 2.40 mmol). The reaction was followed by LCMS and stirring was continued until all of the starting material had disappeared. Solvent was removed from the reaction mixture under reduced pressure, diluted with ethyl acetate (20 mL), and aqueous Na2SO3 (10 mL) added. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (65 mg, 0.18 mmol, 58%). LCMS mz 364.0 (M+H), 386.0 (M+Na), anal HPLC>99% in purity. 1H NMR (400 MHz; CD3CN) δ7.87 (d, J=8.2 Hz, 2H); 7.81 (d, J=8.6 Hz, 2H); 7.66 (d, J=2.3 Hz, 1H); 7.63 (m, 1H); 7.26 (d, J=8.6 Hz, 1H); 4.25 (m, 2H); 3.02 (m, 2H); 2.67 (m, 4H).
Reaction SMILES: [CH2:1]([O:3]CC)[CH3:2].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.C(OC(=O)C)(=O)C>O>[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: Cc1cc(O)ccc1C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2.4 h

Procedure:
Into 40 ml of anhydrous ethyl ether, was dissolved 7.1 g of 4-hydroxy-2-methylbenzoic acid followed by 21.3 g of acetic anhydride. The solution was stirred for 2.4 hours at room temperature. The reaction mixture was freed from the solvent under reduced pressure. The residue was admixed with hot water, then allowed to cool, and extracted with ethyl ether. The organic layer was washed with 2% hydrochloric acid, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure. The residue was recrystallized from an ethyl ether-petroleum ether mixture to obtain 7.5 g of 4-acetyloxy-2-methylbenzoic acid.
Reaction SMILES: [OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:7][C@@H:6]1[C:20]([O:22]C)=[O:21].[OH-].[Na+].[ClH:38]>CO.C(OC(C)C)(C)C>[ClH:38].[ClH:38].[OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:7][C@@H:6]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCCC4)C[C@@H]3C(=O)O)c2c1

Procedure:
0.4 gof methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylate was heated in 3 cm3 of methanol to which had been added 0.48 cm3 of 5N aqueous sodium hydroxide solution under an inert atmosphere for 16 hours. After concentrating the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 5 cm3 of 6N hydrochloric acid and then 2.5 cm3 of methanol. The brown solution obtained was evaporated under the same conditions as above. The residue which resulted therefrom was taken up in 5 cm3 of diisopropylether, filtered off, and washed with 2 times 3 cm3 of the same solvent. The solid obtained was dried under reduced pressure (13 Pa) at a temperature in the region of 60° C. 0.37 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a solid with a brown color melting while softening in the region of 170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2[C:33](=[O:42])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]2=[O:41])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCNCCOc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 120 h
Yield: 85 %

Procedure:
[2-(4-Nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amine (253 mg) and 2-(6-bromohexyl)-1H-isoindole-1,3(2H)-dione (1186 mg) were dissolved in DMF (4 ml) and basified by the addition of DIPEA (0.665 ml). The reaction was stirred for 120 h. The reaction mixture was evaporated to dryness and the residue dissolved in DCM, the solution was absorbed onto a pad of silica and purified on a silica cartridge (12 g) eluting with the following gradient: (A=DCM, B=methanol) t=0 min: B=10%; t=7.5 min: B=0%; t=22.5 min: B=5%. The desired product eluted at ˜15% B (isocratically) and evaporation of the solution to dryness gave the title compound (0.364 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:34])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:32][CH3:33]>>[F:21][CH:22]([F:34])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:26][C:25]=1[O:32][CH3:33]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: COc1cc(C=O)ccc1OC(F)F
Product: COc1cc(CN2C(=O)C(C)CC2c2c(OC)cccc2OC)ccc1OC(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(difluoromethoxy)-3-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 422.01 g/mol.
Reaction SMILES: C(O[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](/[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:15]/[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:9]=1)(=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1COCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:17]1([CH2:16]/[CH:15]=[C:14](/[C:10]2[N:9]=[C:8](/[CH:7]=[CH:6]/[CH2:5][N:29]=[N+:30]=[N-:31])[CH:13]=[CH:12][CH:11]=2)\[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(=O)OC/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CN=[N+]=[N-])n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-yl acetate (136 mg, 0.365 mmol) in a mixture of THF/water (5:1, 5 ml) was treated with sodium azide (28 mg, 0.44 mmol) and tetrakis(triphenylphosphine) palladium(0) (17 mg, 0.015 mmol). The reaction was stirred at room temperature for 18 hours. Solvent was removed under reduced pressure to leave a dark brown residue. The product was purified by column chromatography on silica-gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield {3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enyl}-azide as a brown gum (110 mg, 85%). 1H-NMR; δ (CDCl3), 7.67 (1H, m), 7.56 (1H, m), 7.40 (2H, m), 7.24 (2H, d, J=8.2 Hz), 7.19 (1H, t, J=6.8 Hz), 7.10 (2H, m), 6.91 (1H, dt, J=15.8, 6.6 Hz), 6.73 (2H, m), 4.02 (2H, d, J=8.8 Hz), 3.35 (2H, m), 2.70 (2H, m), 2.41 (3H, s) and 1.82 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 1.77 g (0.01 mol) 5-hydroxy-indole-2-carboxylic acid in 25 ml DMF were cooled to 0° C. and treated with 3.53 g (0.011 mol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborat, 0.96 g (0.011 mol) morpholine and 8.6 ml (0.05 mol) N-ethyldiisopropylamine. The mixture was allowed to warm to room temperature and stirred for additional 16 h. After evaporation to dryness the residue was taken up in 75 ml ethyl acetate, 75 ml THF, 100 ml water and 50 ml 10% NaHCO3 solution. The aqueous phase was extracted with 50 ml ethyl acetate and 50 ml THF. The combined organic layers were washed with 100 ml NaCl satur.aq., dried with Na2SO4, filtered and evaporated to dryness. The residue was suspended in 30 ml of a mixture of ethyl acetate/methanol 9/1, filtered and again suspended in 20 ml of a mixture of ethyl acetate/methanol 9/1. The residue was washed in diethyl ether and dried at 40° C. under vacuum to yield 2.04 g (83%) of the title compound as white solid. MS (m/e): 247.4 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)[F:33])(=O)=O.F[N+]1C=CC=CC=1.[NH4+].[Cl-].CCOCC>ClC(Cl)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([F:33])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: Cc1c(F)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To a solution of 21 mg (0.054 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of dichloroethane were added 16 mg (0.065 mmol) of 1-fluoropyridinium triflate. After stirring at RT for 72 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 2.5 mg (11%) of 2-(1-benzyl-3-fluoro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown waxy solid. MS: 404 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]2[N:8]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: Cc1cnc2c(c1)nc(C)n2-c1ccccc1
Yield: 80.6 %

Procedure:
Method A applied to 2-chloro-5-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown solid (90 mg, 81%). mp 77-79° C. 1H NMR (DMSO) δ 2.44 (s, 3H), 2.54 (s, 3H), 7.56-7.63 (m, 5H), 7.95 (s, 1H), 8.20 (s, 1H); 13C NMR δ 13.1, 17.9, 124.4, 127.5, 129.5, 129.6, 129.8, 132.9, 145.1, 145.7, 153.2. HRMS (FAB): cal. for C14H14N3 [M+H+]: 224.1187; found: 224.1184.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=O.Cl.[NH2:16]O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]#[N:16]
Reactant: NO
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C#N)cn2C
Yield: 70.9 %

Procedure:
5-Methoxy-1-methyl-1H-indole-3-carbaldehyde [76 g, Reference Example 2(a)] and hydroxylamine hydrochloride (55.9 g) were stirred together in dimethylformamide (900 mL) under reflux for 1 hour. The mixture was allowed to cool, then poured into water and then extracted with ethyl acetate. The combined extracts were washed with water then evaporated to give the title compound (53 g) as a pale brown solid, m.p. 100-104° C. 1H NMR [(CD3)2SO]: δ 8.17 (1H, s); 7.54 (1H, d, J=9.0 Hz); 7.09 (1H, d, J=2.4 Hz); 6.97 (1H, dd, J=9.0 and 2.4 Hz); 3.82 and 3.84 (6H, s).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([O:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:6])[CH3:5].O>CS(C)=O>[C:4]([O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: CC(=O)Oc1c(CBr)cccc1Oc1ccccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Oc1c(CC#N)cccc1Oc1ccccc1Cl
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Powdered sodium cyanide (3.65 g) was added to a solution of 2-chlorophenyl 2-acetoxy-3-bromomethylphenyl ether (22 g) in dimethylsulfoxide (80 ml) with stirring at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water (200 ml) was added to the reaction mixture and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated to give oily 2-[2-acetoxy-3-(2-chlorophenoxy)phenyl]acetonitrile (19 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-hydroxy benzoic acid methyl ester (4.665 g, 25 mmol), benzyl bromide (5.13 g, 30 mmol) and potassium carbonate (6.91 g, 50 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. The reaction mixture was poured onto crushed ice (ca. 300 g) and the product was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and precipitated by addition of hexane. Yield: 6.47 g (94%) white powder. 1H-NMR (400 MHz, CDCl3) δ=3.90 (s, 3H, —OCH3); 5.23 (s, 2H, —CH2Ar), 6.99 (d, J=9.0 Hz, 1H), 7.31-7.48 (m, 5H), 7.89 (dd, J=9.0, 2.3 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:13]([O:17]C)(=[O:16])[CH:14]=[CH2:15]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:15][CH2:14][C:13]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a stirred solution of 3-phenyl-1-propanol (1.36 g, 10 mmol) in THF (50 mL) at room temperature was added sodium hydride dispersion in oil (60%, 400 mg) portonwise. The cloudy solution warmed sightly and was stirred at room temperature for 30 minutes, and cooled to 0° in an ice-salt bath. Methyl acrylate (1.1 equivalents) was added, the ice bath was removed and stirring was continued for 30 minutes. The mixture was then cautiously treated with water (10 mL) and stirring was continued at room temperature overnight. The solvents were removed under reduced pressure and the residue was partitioned between water (100 mL) and ether (100 mL). The aqueous portion was made acidic to <pH 1 with concentrated HCl, and extracted with ether(2×50 ml). The ether extract was dried (MgSO4), filtered and evaporated under educed pressure to yield the title compound as a mobile colourless oil (0.684 g, 33%). 1H NMR (CDCl3) δ 9.19 (br s, 1H), 7.4-7.0 (5H, m, ArH), 3.60 (2H, t, J 6.2 Hz, OCH2), 3.36 (2H, t, J 6.2 Hz, OCH2), 2.54 (4H, m, 2×CH2), 1.79 (2H, m, CH2). 13C (CDCl3) δ 177.4, 141.7, 128.4, 128.3, 125.7, 70.1, 65.7, 34.8, 31.4, 32.1, 31.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl.O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: Cc1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)C(C)(C)C
Yield: 93 %

Procedure:
A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield (m.p. 109°-110° C).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][C:7]2[C:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](=O)[CH3:21])[CH2:15][C:14]=3[C:23](=[O:25])[O:24][C:6]=2[CH:5]=1)[CH3:2].[CH3:26][NH:27][CH3:28].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl.Cl>CO>[ClH:41].[ClH:41].[CH3:26][N:27]([CH3:28])[CH:20]([CH3:21])[CH2:19][N:16]1[CH2:17][CH2:18][C:13]2[C:7]3[CH:8]=[C:9]([O:10][CH2:11][CH3:12])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[O:24][C:23](=[O:25])[C:14]=2[CH2:15]1
Reactant: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CC(C)=O)C3
Reactant: CNC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CC(C)N(C)C)C3

Procedure:
Prepared by the method described in Example 38 from 1,2,3,4-tetrahydro-8,9-diethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (35.9 g, 0.10 moles) and dimethylamine (50 g, 1.11 moles). The product is converted to the dihydrochloride with gaseous hydrogen chloride in methanol. An additional recrystallization from methanol/diethyl ether yielded the final product (6.8 g), mp 210° C. (dec.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH:26]([NH2:29])([CH3:28])[CH3:27].O>C(O)C>[CH:26]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.774 mmol) in ethanol (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and isopropylamine (137 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (227 mg, 99% yield).