Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:12][O:13][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[S:10][CH:11]=1>CC#N>[Br:6][C:7]1[CH:8]=[C:9]([CH2:12][OH:13])[S:10][C:11]=1[Cl:4]
Reactant: CC(C)(C)[Si](OCc1cc(Br)cs1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: OCc1cc(Br)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuryl chloride (0.6 ml) was added to a solution of ((4-bromothiophen-2-yl)methoxy)(tert-butyl)diphenylsilane (2.0 g) in CH3CN (20 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated sodium thiosulfate solution (40 ml) at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (182 mg) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[OH-].[Na+].CCO.Cl>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Anal. Found: C, 53.27; H, 3.48; N, 5.14. Calc for C12H9Cl2NO2 : C, 53.36; H, 3.36; N, 5.19. ##STR169## Ethyl 1,4-dichloro-7-isoquinolinecarboxylate (500 mg, 1.85 mmol) in THF (2 mL) was treated with an aqueous solution of NaOH (3.7 mL, 1 M) and EtOH (few drops) added to give a single phase mixture. After stirring at room temperature overnight, HCl (3.7 mL, 1 M) was added to give a thick slurry which was filtered off, washed with water, and crystallised from i-PrOH. The fluffy white crystalline solid was triturated with hexane and dried to afford 1,4-dichloro-7-isoquinolinecarboxylic acid (240 mg, 0.99 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([CH2:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:28][N:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([CH2:30][CH2:31][P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])=[CH:28][N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CCc1cn(-c2ccccc2)nc1O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(CCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.38 g), diethyl 2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethylphosphonate (0.47 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature. The mixture was stirred at room temperature for 6 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethylphosphonate as a colorless oil (0.60 g, yield 80%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v).
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C@H:8]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C@@H:8]2[CH2:9][C:7]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=C(O)CC[C@@H]1CC1(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
As in Example 111, (R)-2,2-diphenylcyclopropanepropanoic acid (6.1 g) and 4-nitrophenol (3,8 g) in dichloromethane (100 mL) was treated with 1,3-dicyclohexylcarbodiimide (4.7 g) and the mixture was stirred at 30° C. for 1 hour. The product obtained from the usual work up was crystallized from 2-propanol to yield 6.4 g of (R)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester, mp 77.5°-76.5° C.; [α]D25 +93.7° (c, 1.0, MeOH)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]2[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.[NH2:14][C:15]1[C:20]2[CH:21]=[C:22](Br)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[CH:21]=[C:22]([C:2]3[CH:3]=[C:4]([CH:7]4[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]4)[S:5][CH:6]=3)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1
Reactant: N#CC1CCOC1c1cc(Br)cs1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Product: N#CC1CCOC1c1cc(-c2cc3c(N)ncc(C(N)=O)c3s2)cs1

Procedure:
87 was prepared from 2-(4-bromo-thiophen-2-yl)tetrahydro-furan-3-carbonitrile 86 and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in a similar manner to that described in Example 18. 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (s, 1H), 7.90 (bs, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.26 (bs, 1H), 7.12 (s, 2H), 5.30 (d, J=7.49 Hz, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 2.49 (m, 1H), 2.33 (m, 1H). MS (EI) m/z (M+H+) 371.
Reaction SMILES: COC([CH:5]1[C:12](=[O:13])[NH:11][C:8]2([CH2:10][CH2:9]2)[C:7]2([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:6]1=[O:24])=O>C(#N)C.O>[C:20]([O:19][C:17]([N:15]1[CH2:16][C:7]2([C:6](=[O:24])[CH2:5][C:12](=[O:13])[NH:11][C:8]32[CH2:10][CH2:9]3)[CH2:14]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C1C(=O)NC2(CC2)C2(CN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)C(=O)CC(=O)NC21CC1

Procedure:
8,10-Dioxo-6,11-diaza-dispiro[2.0.3.4]undecane-6,9-dicarboxylic acid 6-tert-butyl ester 9-methyl ester (160 mg; 0.47 mmol) in acetonitrile/water (3 ml/0.3 ml) is refluxed for 1 hour and evaporated to dryness to deliver the title compound as off-white crystals (125 mg; 94%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)(=[O:29])=[O:28])[CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[O:25][CH3:26].Cl[CH2:46][C:47](Cl)=[O:48].O>CN(C=O)C>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[N:14]1[C:47](=[O:48])[CH2:46][O:7][C:8]2[CH:9]=[C:10]([S:27]([N:30]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])[CH:11]=[CH:12][C:13]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3OC)c(O)c2)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1

Procedure:
In a 10-mL round bottom flask under N2 was dissolved cesium carbonate (807 mg, 2.48 mmol) and 3-hydroxy-4-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (350 mg, 0.619 mmol) in 4 mL of DMF followed by a slow addition of chloroacetyl chloride (0.099 mL, 1.24 mmol) at rt. After 1 h the reaction mixture was neutralized with H2O and ice and the product 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was collected as a solid and dried under reduced pressure and used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[C:10](=[O:12])[NH:30][CH2:29][C:28]([F:32])([F:31])[F:27]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (4.58 g, 22.6 mmol) in methylene chloride (50 mL) was added EDC HCl (4.75 g, 24.8 mmol) followed by 2,2,2-trifluoroethylamine (2.67 g, 27.0 mmol) and DMAP (3.03 g, 24.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then washed with aqueous 5% NaHSO4 (2×), aqueous 10% HCl (1×) and aqueous saturated NaHCO3 (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (2.97 g, 46%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[C:22]([C:23](=[O:25])[NH2:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]([NH2:24])=[O:25])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Yield: 101.9 %

Procedure:
Dissolve {2-[4-(3-carbamoylpyridin-2-yloxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.518 g, 1.45 mmol) in dichloromethane (8.4 mL). Add TFA (8.4 mL) and stir at room temperature for 4 hours. Concentrate the reaction mixture. Load the product onto an SCX column with methanol. Wash the column with methanol then elute with 50% (2.0 M NH3 in methanol) in methanol to give the title compound (0.38 g, 100%): TOF MS ES+ 258.1 (M+H)+, base peak TOF ES+ 241.1 (M-NH2)+, HRMS calcd for C14H16N3O2 258.1243 (M+H)+, found 258.1228, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=13.4 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]1([C:59]#[CH:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:60]#[C:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(C#Cc4ccccc4)cc23)cc1
Yield: 32 %

Procedure:
A mixture of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.375 g, 1.0 mmol), triethylamine (1.5 mL), tri-o-tolylphosphine (0.122 g, 0.4 mmol), tri(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.1 mmol) and phenylacetylene (0.204 g, 2.0 mmol) in dried acetonitrile (10 mL) under nitrogen was heated to reflux overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 10–15% ethyl acetate/hexane) to provide the title compound (0.127 g, 32% yield). 1H NMR (CDCl3) δ 8.16 (t, 1H), 7.93–7.97 (m, 2H), 7.54–7.64 (m, 4H), 7.34–7.37 (m, 3H), 7.21 (t, 2H) 5.77 (dd, 1H), 4.08 (m, 1H), 3.79 (m, 1H), 2.62 (m, 1H), 2.11–2.21 (m, 2H), 1.57–1.83 (m, 3H); ES-MS (m/z) 397 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.S(=O)(=O)(O)O.[C:20]1(C)[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1CCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Yield: 89 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 390 parts of benzene is added to a mixture of 135 parts of 85% strength by weight phosphoric acid, 270 parts of 85% strength by weight sulfuric acid and 10 parts of p-toluenesulfonic acid at from 75° to 80° C, whilst stirring thoroughly. After a further 4 hours at from 75° to 80° C the organic phase is separated off and 81 parts (89% of theory) of o-benzyltoluene (nD25 : 1.5739) are isolated by distillation at from 98° to 100° C at 0.2 mm Hg.
Reaction SMILES: C(O[CH:4]=[C:5]([C:10]#[N:11])[CH:6]=[CH:7][C:8]#[N:9])C.[ClH:12]>C(O)(=O)C>[Cl:12][C:8]1[CH:7]=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:9]=1
Reactant: CCOC=C(C#N)C=CC#N
Reactant: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
A solution of 30 g of ethoxymethylene-glutacononitrile in 300 ml of glacial acetic acid was cooled to 0° C. and saturated with HCl gas. The mixture was allowed to rise to room temperature and left to stand overnight. It was concentrated and the residue was stirred together with 70 ml of water and neutralized with NaHCO3 solution. After being filtered off and recrystallized from ethanol, 2-chloro-5-cyanopyridine was obtained in 73.5% of the theoretical yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(Br)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.3 %

Procedure:
2.50 g (11.9 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 75 ml of dioxane, 1.86 g (13.1 mmol) of N-bromosuccinimide was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with a mixed solution of chloroform and methanol. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=40:1) to give 170 mg (4.3%) of Compound 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:28][CH2:29]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ncccn4)CC3)c(OC)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.67-3.70 (m, 4H), 3.90 (s, 3H), 3.95-3.97 (m, 4H), 4.13 (s, 3H), 6.53 (t, J=4.8 Hz, 1H), 7.11-7.23 (m, 4H), 7.30 (d, J=9.3 Hz, 1H), 8.33 (d, J=4.8 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][N+:19]#[C-:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[K+].O>COCCOC>[CH:2]([C:1]1[O:5][CH:20]=[N:19][C:18]=1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)(=[O:16])=[O:17])([CH3:4])[CH3:3]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(S(=O)(=O)c2ncoc2C(C)C)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
1.1 g (0.0103 mole) of isobutyryl chloride in 10 ml of 1,2dimethoxyethane is added rapidly at a temperature between 15° and 20° C. to a mixture of 2.1 g (0.01 mole) of 4-methoxy benzenesulfonyl methylisonitrile in 10 ml of 1,2-dimethoxyethane in the presence of 0.65 g (0.0116 mole) of potassium hydroxide. The mixture is stirred for 3 h at about 20° C., cooled in an ice bath and water is added. An oil precipitates which solidifies in the presence of a little methanol. In this manner, 0.45 g of 5-isopropyl 4-(4-methoxy benzenesulfonyl)oxazole is obtained which is recrystallized from 5 ml of isopropanol to give 0.4 g, i.e. a yield of 14.2%. M.p.: 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1SCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1SCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 113 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g, 13.6 mmol), K2CO3 (2.3 g, 16.6 mmol), KI (200 mg) and CH3CN (100 ml) was stirred at reflux under nitrogen for 7.5 hours and then was left at ambient temperature for 65 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed twice with water, once with brine and dried over MgSO4. The solvent was removed in vacuo to afford 6.8 g of a light brown oil. The sample was purified by flash chromatography. Concentration of appropriate fractions yielded 3.0 g. Recrystallization from ethanol provided 2.4 g (41%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone as a beige solid, m.p.=93°-95° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[CH2:15][C:14](=[O:16])[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:20][CH:21](OCC)OCC)(=O)[CH3:18]>>[CH2:17]([O:20][CH:21]=[C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:13][C:14]1=[O:16])[CH3:18]
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2cc(-c3ccccc3)cnc2N1
Product: CCOC=C1C(=O)Nc2ncc(-c3ccccc3)cc21

Procedure:
This compound was synthesized from 5-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 10.93 (s, 1H); 8.24 (s, 1H); 7.86-7.82 (m, 2H); 7.62-7.56 (m, 2H); 7.44 (m, 2H); 7.34 (m, 1H); 4.40 (m, 2H); 1.35 (m, 3H).
Reaction SMILES: [C:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][NH:7][CH2:8]2)(=[O:3])[CH3:2].[CH2:12](Cl)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:4]1[CH:5]2[CH2:11][CH2:10][CH:9]1[CH2:8][N:7]([CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C2CCC1CNC2
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1C2CCC1CN(CC=Cc1ccccc1)C2

Procedure:
N8 -acetyl-3,8-diazabicyclo[3.2.1]octane was reacted with equimolar amounts of cinnamyl chloride, in the presence of potassium carbonate in acetone under reflux, checking the reaction by thin layer chromatography (TLC). When the reaction was completed, the inorganic salt was filtered off and the filtrate evaporated to dryness. The residue was purified by chromatography (1:1 CHCl3 /Ethyl acetate). N8 -Acetyl-N3 -cinnamyl-3,8-diazabicyclo[3.2.1]octane was obtained, the elementary analysis being in accordance with the desired compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=C.[Na].FC(F)(F)C([O-])=O>C(O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccncc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCN1CCc2c(c3ccccc3n2-c2ccncc2)C1
Yield: 3.6 %

Procedure:
The title compound was prepared according to General Method 3. 2-Ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (200 mg, 1 mmol), 4-vinylpyridine (0.26 mg, 2.5 mmol), and sodium (15 mg, 0.65 g atom) in ethanol (2 mL) at 150° C. overnight (16 h) to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][C:3]=1[CH3:11].[Br:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].[C:3]1([CH3:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
905 g (5.83 mol) of 2-fluoro-5-nitrotoluene and 1038 g (5.83 mol) of N-bromosuccinimide were introduced as initial charge in 5.83 l of chloroform, 47.8 g (0.29 mol) of 2,2′-azobis[isobutyronitrile] were added and the reaction mixture was heated at reflux for 18 h. After cooling to RT, the liquid was filtered off from the solid by suction and the filtrate was divided into three portions. These were absorbed in each case on 1.5 kg of silica gel (0.06-0.2) and chromatographically purified on in each case 10 kg of silica gel with 160 l of ethyl acetate:petroleum ether (2.5:97.5). The product fractions were combined and evaporated to dryness on a rotary evaporator, and the residue was extracted by stirring with petroleum ether for 10 min. The solid was filtered off with suction, after-washed with petroleum ether and dried in vacuo. 385 g (28%) were obtained.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:3]1.[H-].[Na+].[CH3:30]I>CN(C=O)C.O>[CH3:30][CH:3]1[C:2](=[O:1])[N:11]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)C(C)N3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
To a solution of diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (360 mg, 0.97 mmol) in DMF (20 mL) at 0° C. was added NaH (193 mg, 4.8 mmol), MeI (0.3 mL, 4.8 mmol) and stirred at rt for 16 hours. The solution was diluted with water (20 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated to afford diethyl 2-methyl-1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (300 mg, 80%) as a crude oil. MS [M+H]+ 388.