Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.[CH2:13]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:14].[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[C:31]1([OH:34])[CH2:32][CH2:33][N:28]([CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:29][CH2:30]1)[CH3:14]
Reactant: CCOC(=O)C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Yield: 74.8 %

Procedure:
125 ml of 1.6M butyllithium was added dropwise to a solution of 18.5 g (0.18 mole) of N-(1-methylethyl)-2-propanamine in 75 ml of tetrahydrofuran, cooled to a temperature of -70° C. The mixture was stirred for ten minutes at this temperature then 17.5 g ( 0.15 mole ) of 2-methyl-propanoic acid ethyl ester in solution in 70 ml of tetrahydrofuran was added, keeping the temperature at -70° C. After stirring for one hour at this temperature, a solution of 26 g (0.14 mole) of 1-phenylmethyl-4-piperidinone in 70 ml of tetrahydrofuran was added. The reaction medium was stirred for 1.5 h at a temperature of -70° C. and was then allowed to return to room temperature. After evaporating off the solvents under reduced pressure, the residue was poured into a saturated solution of ammonium chloride. The organic phase was extracted with ether, washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. After purification by distillation, 32 g (yield: 76%) of the desired product was obtained as an oil. B Pt=145°-150° C. (0.05 mm Hg, i.e. about 6.66 Pa)
Reaction SMILES: O1C=CC=CN=N1.Cl[C:9]1[CH:10]=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].[CH2:20]([N:22]([CH2:34][CH3:35])[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([OH:33])[CH:24]=1)[CH3:21]>>[CH2:34]([N:22]([CH2:20][CH3:21])[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([O:33][C:9]2[CH:10]=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH:24]=1)[CH3:35]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CCN(CC)c1cc(O)cc2ccccc12
Agent: C1=CN=NOC=C1
Product: CCN(CC)c1cc(Oc2cc(OC)ccc2[N+](=O)[O-])cc2ccccc12

Procedure:
Thus, for example, a compound of the formula ##STR16## is obtained by reaction of 2-chloro-3-nitro-pyridine with 3-diethylaminothiophenol to give 2(3'-diethylaminothiophenoxy)-3-nitro-pyridine, reduction to the 3-amino compound, diazotisation and intramolecular coupling. The oxadiazepine derivative ##STR17## is obtained, for example, by reaction of 3-chloro-4-nitroanisole with 1-diethylamino-3-hydroxynaphthalene to give 1-diethylamino-3-(5'-methoxy-2'-nitro-phenoxy)-naphthalene, reduction to the 2'-amino compound, diazotisation and internal coupling.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[OH:14])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[OH:14]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)c1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(O)c1cccc(F)c1
Reaction time: 4 h

Procedure:
The aforementioned described {(S)-1-[(3-fluorophenyl)-hydroxymethyl]-3-methylbutyl}-carbamic acid tert.-butylester (4.7 g, 15.1 mmol) is dissolved in dioxane (37 mL). After addition of HCl in dioxane (37.7 mL of a 4M solution) the reaction mixture is stirred for 4 h. After evaporation of the solvent the crude product (3.7 g, 99.5%) is used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:8][C:9]2[S:10][C:11]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:22][CH2:23][C:24]([OH:26])=[O:25])[C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:34]>C(O)C>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][C:9]2[S:10][C:11]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:22][CH2:23][C:24]([O-:26])=[O:25])[C:12]=3[N:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[Na+:34]
Reactant: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of [(2-diphenylmethylthio-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetic acid (1.00 g, 1.09 mmol) in ethanol (50 mL) was added 1N-aqueous sodium hydroxide solution (2.2 mL) dropwise and the mixture was stirred at room temperature for 20 minutes. The solvent was then distilled off under reduced pressure. The residue was recrystallized from ethanol/water to provide 0.48 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[CH3:15][NH:14][C:12]([C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][O:9][C:10]=1[CH2:16][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:24])=[O:13]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 50 g. (0.155 mole) of 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide and 800 ml. acetic acid at room temperature is treated dropwise rapidly with 18.4 g. (0.185 mole) of chromium trioxide in 185 ml. water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic acid is removed in vacuo. The remainder is poured onto ice water and extracted with methylene chloride. The methylene chloride layer is washed with 2 N sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with hot ether, cooled to 0° C. and filtered to give N-methyl-5-phenacyl-3-phenyl-4-isoxazole carboxamide, m.p. 125° to 128° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and α,α,α-trifluoro-p-tolualdehyde (86 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (60.1 mg, 12.7%). 1H NMR (CDCl3): 7.70 (d, J=15.6 Hz, 1H), 7.67 (q, J=8.6, 14.9 Hz, 4H), 7.55 (d, J=15.6 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H), 7.15 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.46-4.34 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>C(OC(=O)C)(=O)C>[CH3:18][C:14]1[C:13]([CH:19]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccnc1C
Solvent: CC(=O)OC(C)=O
Product: Cc1cccnc1C=Cc1ccc([N+](=O)[O-])cc1
Yield: 53.1 %

Procedure:
A mixture of 4-nitrobenzaldehyde (30.2 g) and 2,3-lutidine (42.8 g) in acetic anhydride (100 ml) was refluxed for 9.5 hours under stirring. After cooling the reaction mixture, the precipitate was collected by filtration. The residue was washed with diethyl ether to give 3-methyl-2-[2-(4-nitrophenyl)vinyl]pyridine (25.5 g).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:6]=[CH:7][N:8]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:9]=1[CH2:10][CH2:11][CH3:12])=[O:4].O>C(O)C>[OH:4][CH2:3][C:5]1[N:6]=[CH:7][N:8]([S:13]([N:16]([CH3:17])[CH3:18])(=[O:14])=[O:15])[C:9]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1c(C=O)ncn1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(CO)ncn1S(=O)(=O)N(C)C
Yield: 93.7 %

Procedure:
Sodium borohydride (139 mg) was added to a stirred solution of 4-formyl-N,N-dimethyl-5-propyl-1H-imidazole-1-sulphonamide (450 mg) in absolute ethanol (5 ml) under nitrogen. After 3 h the mixture was poured into water (30 ml) and extracted with dichloromethane (3×15 ml). The combined, dried organic extracts were evaporated to give a solid (425 mg) which was triturated with ether (2×10 ml) to give the title compound (350 mg), m.p. 86°-88°.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17](O)([CH3:19])[CH3:18]>>[ClH:1].[CH:17]([O:7][C:6](=[O:8])[CH:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: CC(C)O
Reactant: N[C@@H](CC1CCCCC1)C(O)C(=O)O
Agent: Cl
Product: CC(C)OC(=O)C(O)[C@@H](N)CC1CCCCC1

Procedure:
Hydrogen chloride was passed into a solution of 100 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride in 12 ml of isopropyl alcohol with stirring under ice-cooling, and the mixture was heated under reflux for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =15/1 by volume), and the eluate was acidified by adding hydrochloric acid. The mixture was evaporated to dryness under reduced pressure to obtain 108 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2hydroxybutyric acid isopropyl ester hydrochloride as a white powder.
Reaction SMILES: [OH:1][CH:2]1[CH:10]([N+:11]([O-])=O)[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:11][CH:10]1[C:9]2[CH2:8][C:7](=[O:14])[CH:6]=[CH:5][C:4]=2[CH2:3][CH:2]1[OH:1]
Reactant: O=C1C=CC2=C(C1)C([N+](=O)[O-])C(O)C2
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1C2=C(C=CC(=O)C2)CC1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80 mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.00 g, 79%). 1H NMR (CD3OD): d 6.85 (d,1H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
390 mg (0.90 mmol) of tert-butyl(+/−)-cyclopentyl(4-{[2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]methyl}phenyl)ethanoate were initially charged in 2.7 ml of dichloromethane, and 690 μl of trifluoroacetic acid were added. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 523 mg of product, which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:36])/[CH:25]=[CH:26]/[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].O>CN(C)C=O>[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:36])/[CH:25]=[CH:26]\[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)/C=C/C(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(C(=O)/C=C\C(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 6.5 h
Yield: 45 %

Procedure:
A solution of 2-{2-isopropyl-4-[trans-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (100 mg) in dimethylformamide (10 ml) is allowed to stand for 6.5 hours by a window in order to be exposed to direct sunlight. To the mixture is added water, the precipitated crystals are collected by filtration, and recrystallized from ethanol to give 2-{2-isopropyl-4-[cis-3-(4-methyl-1-piperazinyl)carbonylacryloyl]phenoxymethylcarbonylamino}benzothiazole (45 mg).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCC=C(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCC=C(C)C)[nH]n1

Procedure:
Hydrazine hydrate (0.41 mL, 8.48 mmol) was added to a stirring room temperature solution of 49 (0.1.9190 g, 8.48 mmol) in EtOH (8.5 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (½ h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes: 2N NH3 in EtOH): 1H (CDCl3, 400 MHz): δ 12.73 (1H, broad s), 6.57 (1H, s), 5.09 (1H, t, J=6.8 Hz), 4.32 (2H, q, J=7.1 Hz), 2.70 (2H, t, J=7.5 Hz), 2.29 (2H, q, J=7.5 Hz), 1.63 (3H, s), 1.52 (3H, s), 1.30 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.27, 106.11, 60.65, 31.49, 27.53, 25.52, 17.51, 13.10 ppm. HPLC: 9.986 min.
Reaction SMILES: [N:1]([O-:3])=[O:2].F[B-](F)(F)F.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.O>C(#N)C>[N+:1]([C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][NH:9]2)([O-:3])=[O:2]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1c(O)ccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Under a nitrogen atmosphere, a solution of tetrafluoroborate nitrite (110 mg, 0.783 mmol) in acetonitrile (3 ml) was added dropwise to a suspension of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in acetonitrile (4.0 ml) at −35° C. over a period of 10 minutes, and the resulting mixture was slowly heated to 0° C. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with ethanol/diisopropyl ether by repulping to obtain 4-nitro-1H-indazol-5-ol (59.8 mg, 45%).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]#[C:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)=[CH:19][N:20]=3)[C:15]2=[O:32])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[N:27]1([CH2:26][C:25]#[C:24][C:18]2[CH:17]=[C:16]3[C:21]([CH:22]=[CH:23][N:14]([CH2:13][C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:33])=[O:5])=[CH:12][CH:11]=4)[C:15]3=[O:32])=[N:20][CH:19]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ccc3ncc(C#CCn4ccnc4)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2ccc3ncc(C#CCn4ccnc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[7-(3-imidazol-1-ylprop-1-ynyl)-1-oxo-1H-5-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester (0.38 g, 0.86 mmol, Example 13A) is treated with trifluoroacetic acid (6 mL) and stirred at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid is collected by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][C:8](OC)([O:30]C)[CH2:7][C:6]=2[CH:34]=1.Cl.O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][C:8](=[O:30])[CH2:7][C:6]=2[CH:34]=1
Reactant: COC1(OC)CCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)Cc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
To a solution of 7-chloro-4,4-dimethoxy-1-[6-(2-methylbenzoyl-amino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in acetone (10 ml) is added 1N hydrochloric acid (5 ml), and the mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is neutralized with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-4-oxo-1-[6-(2-methylbenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OC)c(CO)c1
Solvent: ClCCl
Product: COc1ccc(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
In a nitrogen atmosphere, 2.00 g (11.9 mmol.) of 2,5-dimethoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 0.87 ml (12.0 mmol.) of thionyl chloride in 2 ml of dichloromethane. The mixture was then stirred at room temperature for 1.5 hour. The mixture was placed under reduced pressure at room temperature to distill off the solvent to give 2.22 g of the desired compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.[Cl:21][C:22]1[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=1O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:28][C:26]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:12]3)[O:4]2)=[C:22]([Cl:21])[CH:27]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cc(Br)ccc1OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reaction time: 13 h
Yield: 95 %

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (compound 1, 50 gm, 0.18 mole) was dissolved in toluene (300 ml) at room temperature. To this 44 gms of 2-chloro-4-bromophenol in toluene (150 ml) was added at room temperature 28° C. in the presence of ParaToluenesulfonic Acid (PTSA, 3.5 gm). Reaction mixture was refluxed with stirring for 13 hrs. It was then cooled and filtered. The filtrate was given water wash to bring the pH to neutral. Toluene was removed under vacuum to obtain a thick brick red colored product 95% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>CO>[Cl:22][C:18]1[N:17]=[C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
160 (100 mg, 0.315 mmol) is dissolved in 4 ml of methanol and treated with a solution of NaOH (1 ml, 2N). The mixture is stirred 1 hour at room temperature. The reaction mixture is acidified with HCl (1 ml, 2N) and evaporated. The crude mixture is used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:31]1([NH:41]N)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:32]4[C:31](=[C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]5=[CH:34][CH:33]=4)[NH:41][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 516.4 (M+H)+.