Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[F:1][C:2]1[C:10]([CH:11]2[CH2:12][O:22]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:13]
Reactant: C=Cc1ccc2c(c1F)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-5-vinyl-3H-isobenzofuran-1-one (4.0 g, 17.3 mmol) in 100 mL of DCM was slowly added mCPBA (6.0 g, 85% purity, 34.6 mmol) in 50 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred overnight. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were washed with brine and then concentrated. The residue was purified by column chromatography to give product 4-fluoro-5-oxiranyl-3H-isobenzofuran-1-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[CH:3]=3)[N:35]=2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: Oc1cccc(CCCCn2ccnc2)c1
Product: c1ccc(COc2ccc(-c3nc(COc4cccc(CCCCn5ccnc5)c4)co3)cc2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with 2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(4-benzyloxyphenyl)-4-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 87-88° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[OH-].[Na+]>ClCCl>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([CH3:6])[C:3](=[O:4])[CH2:2][Br:1])(=[O:16])[CH3:15]
Reactant: CNc1ccccc1C(C)=O
Reactant: O=C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1ccccc1N(C)C(=O)CBr
Reaction time: 0.33 h
Yield: 388.7 %

Procedure:
404 mg (2 mmol) of bromoacetyl bromide were added to a stirred, ice-cooled solution of 298 mg (2 mmol) of 2′-(methylamino)acetophenone in 5 ml of dichloromethane. The mixture was stirred for 20 minutes then 2 ml of 1M sodium hydroxide solution were added and stirring was continued for a further 15 minutes. The resulting solution was washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness to give 2.1 g of 2′-acetyl-2-bromo-N-methylacetanilide as a viscous gum. 1H NMR (400 MHz CDCl3) δ: 2.54 (3H,s), 3.16 (3H,s), 3.45-3.52 (2H,q), 7.34 (1H,dd), 7.48 (1H,dt), 7.56 (1H,dt), 7.77 (1H,dd).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].C.Cl.O>CO.[Pd](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(CCCC(=O)O)ccc1F
Reaction time: 6 h
Yield: 94.3 %

Procedure:
In methanol, 10.0 g of 4-(4-fluoro-3-methylphenyl)-4 -oxobutanoic acid were dissolved, followed by the addition of 1.5 g of activated charcoal (Norit EXW) and 12.4 ml of a palladium chloride solution (a solution obtained by dissolving 2.2 ml of concentrated hydrochloric acid and 2.5 ml of water to 1.0 g of palladium chloride with heating to give a total volume of 50 ml). The resulting mixture was subjected to catalytic reduction at room temperature and atmospheric pressure for 6 hours. After the completion of the reaction, the catalyst was filtered out by a glass filter paper, followed by washing with 12 ml of methanol. To the filtrate, 100 ml of a 5% aqueous solution of sodium hydroxide were added and the mixture was stirred for one hour. After the completion of the reaction, methanol was evaporated and the residue was adjusted to acidic with 12 ml of concentrated hydrochloric acid under ice cooling. The crystals so precipitated were collected by filtration, whereby 8.8 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: COc1cccc(-c2ccc3c(ccn3Cc3ccc(C(C)(C)C)cc3)c2)c1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 3-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 370. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.53 (s, 1H), 7.51 (d, 1H, J=8.55 Hz), 7.39 (d, 1H, J=8.55 Hz), 7.34-7.30 (m, 3H), 7.20 (d, 1H, J=7.64 Hz), 7.15-7.13 (m, 3H), 6.85 (d, 1H, J=8.25 Hz), 6.52 (d, 1H, J=3.05 Hz), 5.39 (s, 2H), 5.81 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26].O>CN(C)C=O>[CH3:15][N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:18]=2[S:17]1(=[O:26])=[O:27]
Reactant: CN1Cc2cccc(Cl)c2S1(=O)=O
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccc(SCc3ccccc3)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 12 g of potassium-t-butoxide in 100 ml of dry dimethylformamide was added 12.9 mls of benzyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 12.2 g of 2-methyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours and poured into water to give a gummy solid. The water was decanted and extracted with ethyl acetate. The gummy solid was slurried in ethyl acetate and filtered to give 5.9 g of the title compound as a light orange solid, m.p. 119°-122° C. The combined ethyl acetate extract and filtrate were washed with water and brine, dried over MgSO4 and concentrated to a solid which was slurried in ether and filtered to give an additional 7.6 g of product, m.p. 121°-124° C. Total yield was 13.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[K+]>>[N+:16]([C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccc2nccn2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24 gms. (0.122 mole) of 6-bromoimidazo [1,2-a] pyridine in 80 ml. of concentrated sulfuric acid is treated dropwise with 24 ml. of concentrated nitric acid while maintaining a temperature of 15° C. with external cooling. When the addition is complete, the reaction mixture is stirred at room temperature for 1/2 hour and poured onto 450 gm. of ice. The pH of the mixture is adjusted to pH 4 with aqueous potassium hydroxide and the resultant solids are collected by filtration. The filter cake is washed with water and dried. Recrystallization from methylene chloride-hexane yields pure 3-nitro 6-bromoimidazo [1,2-a] pyridine m.p. 160°-161° C.
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[CH:23][CH:22]=3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[CH:23][CH:22]=3)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4[nH]3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]c(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylate (100.0 mg, 0.25 mmol) in methanol (30 mL) was added sodium hydroxide (20.0 mg, 0.50 mmol) in water (1 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The solid was precipitated and filtered to afford 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid as a light yellow solid (23.5 mg, 24%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].Cl[C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CN(C)CCO
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN(C)C)nc1)c1ccccc1
Yield: 74.9 %

Procedure:
Following the same procedure as described in example 3, 2-(dimethylamino)ethanol (798 mg, 10 eq) and (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (300 mg, 1 eq, prepared from example 1) were reacted to get the desired product (260 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.14-7.20 (m, 2H), 7.01-7.09 (m, 5H), 6.93 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 5.84 (d, J=8.8 Hz, 1H), 4.22 (t, J=5.2 Hz, 2H), 2.70 (t, J=5.2 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 2.35 (s, 6H), 0.91 (t, J=7.6 Hz, 3H); m/z=389 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:8][CH:9]2[CH:11]([CH:10]2[NH2:13])[CH2:12]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CC2C(C1)C2NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC2C(N)C2C1
Yield: 32 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 150 as a white solid (30 mg, 32%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.64-7.36 (m, 4H), 7.29 (t, J=8.7, 2H), 3.56 (s, 3H), 3.46-3.31 (m, 2H), 3.13 (t, J=15.2, 2H), 1.93 (s, 1H), 1.41 (s, 2H). ESIMS m/z=431.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19]([Mg]Br)#[CH:20].O>O1CCCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[O:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:10]([CH:11]([OH:12])[C:19]#[CH:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccoc1-c1nn2c(Cl)cccc2c1C=O
Reactant: C#C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2occc2C)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (11.56 g, 44.3 mmol) in tetrahydrofuran (200 mL) at −78° C. was added ethynylmagnesium bromide (133 mL, 0.5 M in tetrahydrofuran, 66.5 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated to a solid residue, 1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (12.29 g, 97%). 1H-NMR (CDCl3): δ 7.97 (d, 1H), 7.48 (d, 1H), 7.16 (t, 1H), 6.96 (d, 1H), 6.42 (d, 1H), 6.18 (m, 1H), 2.78 (m, 1H), 2.6 (d, 1H), 2.46 (s, 3H). MS m/z 287 (M+1).
Reaction SMILES: O=[C:2]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:10]=2[N:11]=1)=O.FC(F)(F)C([O-])=O.[NH4+:37]>O>[CH3:23][O:22][C:12]1[C:10]2[N:11]=[C:7]([C:5]3[NH:4][CH:3]=[C:2]([CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[N:37]=3)[S:8][C:9]=2[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:14][CH:13]=1
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)Cc3cccs3)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(Cc4cccs4)c[nH]3)nc12
Temperature: 25 °C
Yield: 13.1 %

Procedure:
A mixture of 0.04 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-3-thiophen-2-yl-propyl)-amide and 0.13 g ammonium triflouroacetate was melted at 165° C. for 60 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.005 g (13%) 4-methoxy-7-morpholin-4-yl-2-(4-thiophen-2-ylmethyl-1H-imidazol-2-yl)-benzothiazole as yellow solid; MS (ISP): m/e=413 (M+H+).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].CO>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: C=Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12

Procedure:
2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (7 g.) and 2-vinylpyridine (12 g.) in 150 ml. of methanol containing 5 ml. glacial acetic acid were heated under reflux for 24 hours. After removing solvent under reduced pressure, the residue was slurried with water and the insoluble material filtered off and washed with water. After drying there was obtained 9.3 g. of the title compound. A portion recrystallized from ethanol gave a m.p. of 167°-69° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:3]1.Cl.Cl.[NH2:22][OH:23].[OH-].[Na+]>>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: CC1C=NC(c2ccccc2)CC=CCCC=CC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C=NO)CC=CCCC=CCC(N)c1ccccc1
Yield: 100 %

Procedure:
502 g (1.98 mols) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene are added dropwise in the course of 1.5 hours to 220 g of 37% hydrochloricacid at a rate such that the temperature does not rise above 80° C. The mixture is then cooled to room temperature (20°-25° C.) and 140 g (2.02 mols) of hydroxylamine hydrochloride are added. About 185 g (4.6 mols) of solid sodium hydroxide are added in the course of one hour, the mixture being cooled with a waterbath, until the pH of the aqueous solution is 10-11. The organic phase which separates out is separated off and washed with water until neutral. 567 g (1.98 mols) of 2-methyl-11-phenyl-11-amino-undeca-4,8-dienal oxime are obtained in the form of a highly viscous liquid; yield 100% of theory.
Reaction SMILES: Br[C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Cl)[C:5]1=[O:11].[OH-:14].[Na+]>>[Br:13][C:2]([Br:12])=[CH:3][CH:4]1[C:7]([CH3:8])([CH3:9])[CH:6]1[C:5]([OH:11])=[O:14]
Reactant: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Reactant: [OH-]
Agent: [Na+]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 800 mg (0.02 mole) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chlorocyclobutan-1-one and 5.6 ml of 5% by weight of aqueous sodium hydroxide solution is stirred for 18 hours at 0° C. and subsequently for one additional hour at 80° C. Then the reaction mixture is cooled to room temperature washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract is washed with water and dried over magnesium sulphate. After evaporation of the diethyl ether there is obtained 0.59 g (100% of theoriy) of 2-(2',2'-dibromovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid consisting to 80% of the cis-isomer and to 20% of the trans-isomer.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[CH2:16]1[CH:23]2[C:19]3([C:25](Cl)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH:7][C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: O=C(Cl)C12CC3CC(CC1C3)C2
Reactant: Cc1nsc(N)c1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)C23CC4CC(CC2C4)C3)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 4-bromo-3-methylisothiazol-5-amine (prepared as described in J. Chem. Soc. 1963, p 2032) (1.93 g, 10.1 mmol) in tetrahydrofuran (25 mL) with triethylamine (1.7 mL, 12.2 mmol) at 0° C. was added slowly a solution of Example 4A (1.9 g, 10.3 mmol) in tetrahydrofuran (15 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was evaporated to dryness, partitioned between H2O/ethyl acetate and the aqueous extracted again (2×) with ethyl acetate. The organics were combined, dried (MgSO4), filtered and solvent evaporated. Flash chromatography over silica gel eluting with 15% ethyl acetate/hexane provided 0.3 g of the title compound plus 1.8 g of diacylated compound. The latter was heated to reflux in methanol for 3 h, cooled, solvent evaporated and flash chromatographed over silica gel eluting with 20% ethyl acetate/hexane to provide an additional 0.99 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.63-1.76 (m, 4H), 1.87-1.98 (m, 4H), 2.10-2.15 (m, 2H), 2.45 (s, 3H), 2.81 (t, 1H), 8.23 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)CBr
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (0.34 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and ethyl bromoacetate (0.16 ml) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (50 ml). The crystals precipitated were recovered by filtration. The resulting crude crystals were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (360 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[C:13]=3[C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[C:11]4[C:17]([CH3:18])=[N:16][CH2:15][CH2:14][N:12]4[C:13]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)-c1c(ccn1CCNC(C)=O)CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: COc1ccc2c(c1)-c1c(cc3n1CCN=C3C)CC2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
N-[2-(4,5-Dihydro-8-methoxy-1H-benzo[g]indol-1-yl)-ethyl]acetamide (4.7 g) was treated with 15 ml of phosphorus oxychloride under argon and the mixture was stirred at 50° C. for 30 minutes. The cooled mixture was added to 2000 g of ice-water and treated with 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 4.2 g of residue were chromatographed on 250 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 3.8 g of crude product were dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 4.7 g (84%) of 5,6,10,11-tetrahydro-2-methoxy-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 175°-177° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH2:15][C:16]([C:18]([F:21])([F:20])[F:19])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.1 g, 0.73 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-4,4,4-trifluoroacetoacetate (0.216 g, 1.17 mmol) and sodium carbonate (0.140 g, 1.32 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.