Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.CCN(C(C)C)C(C)C.Cl[CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34]>C1COCC1>[Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:6]=2[CH:10]=1
Reactant: Cc1cccc(Sc2cc3nc[nH]c3cc2Cl)c1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCn1cnc2cc(Sc3cccc(C)c3)c(Cl)cc21
Temperature: 23 °C
Yield: 66.9 %

Procedure:
To a cooled solution (0° C.) of 6-chloro-5-m-tolylsulfanyl-1H-benzoimidazole (2.14 g, 7.78 mmol) and THF (39 mL) was added DIPEA (2.71 mL, 15.6 mmol). 1-Chloromethoxy-2-methoxy-ethane (0.977 mL, 8.56 mmol) was added dropwise, and the reaction mixture was allowed to warm to 23° C. over 16 h. The reaction mixture was concentrated. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (1.89 g, 67%) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C18H19ClN2O2S, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.95 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.22-7.18 (m, 3H), 7.16-7.13 (m, 2H), 7.11-7.05 (m, 3H), 5.56 (s, 2H), 5.47 (s, 2H), 3.57-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.48-3.45 (m, 2H), 3.44-3.42 (m, 2H), 3.35 (s, 3H), 3.30 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CNc1ccccc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccccc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.05 g, 0.2 mmol) and 2-chloro-N-methylaniline (0.034 g, 0.24 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 0.66 mL) was added and the reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction was concentrated in vacuo, taken into DMF at 100 mg/ml and purified by preparative RP-HPLC to give 165bp. Yield=28% of theoretical. MS: (ESI+)=374.8
Reaction SMILES: Br[C:2]1[N:3]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[N:5]=2.[CH3:26][O-:27].[Na+]>CO>[CH:14]1([CH2:13][O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:27][CH3:26])[N:3]3[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)=[C:8]([NH2:11])[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1nc(OCC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1C1CCCCO1
Temperature: 70 °C

Procedure:
8-Bromo-2-[(cyclohexylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.8151 g) was refluxed with 30% (w/v) sodium methoxide in methanol (1.1 mL) diluted with anhydrous methanol (6.0 mL). The suspension was refluxed (70° C. external) overnight. The reaction was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (50 mL). The organic layers were combined and washed with brine (50 mL) and separated before then being dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave crude title compound as foam (0.7132 g) used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cccnc1F
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Yield: 92.8 %

Procedure:
To a solution of [(3-bromophenyl)ethynyl](trimethyl)silane (2.28 g, 9.0 mmol) in DME (150 mL) is added (2-fluoropyridin-3-yl)boronic acid (1.41 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.5 mmol) and a solution of sodium carbonate (3.8 g, 36.0 mmol) in H2O (15 mL) at room temperature. After refluxing for 3 h, the reaction mixture is cooled, quenched with saturated sodium carbonate, diluted with EtOAc. The two layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude mixture is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.25 g, 91%) as an oil. MS(+) APPI: 270 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>N1C=CC=CC=1>[CH2:27]([CH2:29][NH2:30])[OH:28].[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: NCCO
Solvent: c1ccncc1
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (600 mg) and ethanolamine (600 mg) were added to pyridine (2,500 mg), and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (6 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (603 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.C(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCCCCCCCCCCCCCCCCBr
Reactant: CCCCCCOc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Yield: 83.4 %

Procedure:
12.8 g (66 mmol) of 2-hexyloxyphenol, 23.3 g (73 mmol) of 16-bromohexadecan-1-ol and 20.0 g (99 mmol) of tri-n-butylphosphine were added to 350 mL of dehydrated methylene chloride followed by cooling with ice in the presence of argon. After adding 25.0 g (99 mmol) of 1,1′-(azodicarbonyl) dipiperidine a little at a time while stirring, 150 mL of methylene chloride were added. After stirring for 30 minutes at room temperature in the presence of argon, the reaction solution was refluxed for 6 hours. After cooling, the reaction solution was dropped into 100 mL of hexane and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 26.5 g of a clear liquid.
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:15][O:14][C:12]1[C:11]([OH:16])=[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[N:9]=[N:8][CH:13]=1
Reactant: COc1cn(Cc2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Yield: 81 %

Procedure:
1-Benzyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (15.0 g) and palladium hydroxide on carbon (5.88 g, palladium 20%, 50% water moistened product) were suspended in tetrahydrofuran (500 mL) and methanol (300 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated and solidified with ethanol/hexane to give the title compound (9.10 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[CH:10][C:11]=2I)[CH2:6]1)=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:11]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(N1CCc2c(I)cc([N+](=O)[O-])cc2C1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2c(cc([N+](=O)[O-])cc2-c2ccccc2Cl)C1)C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
2,2,2-Trifluoro-1-(5-iodo-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone (1MK1, 750 mgs, 1.88 mmoles) was dissolved in toluene (25 mls) and 2-chlorophenyl boronic acid (352 mg, 2.25 mmoles), anhydrous potassium carbonate (311 mg, 2.25 mmoles) and finally palladium tetrakis catalyst (111 mg, 0.099 mmoles, 5 mol %) was added. The reaction mixture was flushed with nitrogen and heated to 95° C. overnight. Starting material was still present therefore further 2-chlorophenyl boronic acid (88 mg, 0.56 mmoles), potassium carbonate (78 mg, 0.56 mmoles) and catalyst (28 mg, 0.025 mmoles) were added and the reaction continued for a further 2 hours. The reaction was then cooled and filtered through a pad of Celite. The filtrate was washed with saturated sodium bicarbonate solution (25 mls), water (25 mls) and brine (25 mls). The organic layer was dried over anhydrous magnesium sulphate, filtered and evaporated to give an oily residue. The oil was triturated with ether followed by isopropanol:hexane 1:1. The dark yellow solid (724 mg, 100% yield) was used without further purification. LC-MS (retention, 4.2 mins M+H 386).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.C[Sn](C)(C)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Reactant: C[Sn](C)(C)c1nccs1
Product: Nc1nc2ccccc2n1-c1cccc(-c2nccs2)c1

Procedure:
2-Amino-1-[3(2-thiazolyl)phenyl]benzimidazole was prepared from 1-(2-amino-1-benzimidazolyl)-3-iodobenzene and 2-trimethylstannylthiazole by method C. mp 224°-226° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39]CC)=[O:38])[CH:31]=3)=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]2[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)=[CH:20][CH:19]=1)=[O:42])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3cccc(CC(=O)OCC)c3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OC/C=C/C#Cc2ccc(C#C/C=C/COc3cccc(CC(=O)O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E)(E) [3-(5-{4-[5-(3-ethoxycarbonylmethyl-phenoxy)-pent-3-en-1-ynyl]-phenyl}-pent-2-en-4-ynyloxy)-phenyl]-acetic acid ethyl ester (example 21) (200 mg, 0.35 mmol) in THF (2 mL) and ethanol (6 mL) was added 1N sodium hydroxide (1 mL). After stirring at room temperature for 3 h, the reaction mixture was added 1N hydrochloride acid and ethyl acetate. The title compound was isolated by filtration of the mixture in 50 mg yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]([N:19]=[C:20]=S)([CH3:18])[CH3:17].C(OCC)(=O)C>O>[CH:16]([NH:19][C:20]1[NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=2[S:12](=[O:14])(=[O:13])[N:15]=1)([CH3:18])[CH3:17]
Reactant: Nc1cc(C(F)(F)F)ccc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-trifluoromethylbenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 294-297° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.20 (d, 6H, CH(CH3)2), 3.95 (m, 1H, CH(CH3)2), 7.42 (br., 1H, NH), 7.56 (m, 2H, ArH), 7.99 (d, 1H, ArH), 10.55 (br.s, 1H, NH); MS: m/e 307 (M+, 33%); (C11H12N3F3O2S1.H2O) calc. C, 40.6; H, 4.3; N, 12.9; found C, 41.0; H, 4.1; N, 13.1.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].Cl.C([O-])(=O)C.[Na+]>O.CC(=O)CC>[C:13]([CH2:14][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:15])[CH3:12]
Reactant: CC(=O)CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)CSc1nc2ccccc2[nH]1

Procedure:
2-Mercaptobenzimidazole (14.6 g, 0.1 mole) and chloroacetone (9.25 g, 0.1 mole) were added to 2-butanone (400 ml) and refluxed for 5 hrs. On cooling the product hydrochloride, 21.24 g, 88% was isolated by filtration, washed with acetone and air dried. The salt was dissolved in water (150 ml) and added to a solution of sodium acetate (7.2 g, 0.088 mole) in water (100 ml). The oil obtained was extracted into ethyl acetate, filtered to remove some insoluble material (0.4 g), dried and evaporated to dryness. The residue was crystallised from ethanol to give three crops of 2-(acetylmethylthio)benzimidazole (2), as colourless crystals, 15.0 g, 73%, mp. 112°-113° C. PMR was consistent with a tautomeric mixture of the open chain and ring closed forms.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:15][CH2:16][CH2:17][C:6]=1[C:7]=23)(=O)C.C[O-].[Na+]>CO>[CH3:1][O:4][C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:15][CH2:16][CH2:17][C:6]=1[C:7]=23
Reactant: CC(=O)Oc1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A 16 ml portion of methanol solution of 6-acetoxy-2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (0.60 g, 1.64 mmol) was mixed with sodium methoxide and stirred at a room temperature for 3 hours. After neutralization of the reaction solution with an ion exchange resin Amberlite 15, the resin was removed by filtration and the solvent was evaporated under a reduced pressure. The thus obtained oily substance was dissolved in 4 ml of acetone, and the solution was mixed with 2 ml of methyl iodide and 2 ml of potassium carbonate aqueous solution and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with 1 N hydrochloric acid. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained oily substance was purified by a silica gel column chromatography (100 cc; elution with ethyl acetate-hexane=1:2) to obtain 0.31 g of the title compound (56% in yield).
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42]I.[H-].[Na+].Cl>CN(C=O)C>[C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH3:42])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)N(C)C(=O)OC(C)(C)C

Procedure:
Dissolve the compound obtained in Step C of Example 10 (1 eq.) and CH3I (2 eq.): in 55 ml of anhydrous DMF and place in an ice bath at 0° C. Add NaH (1.5 eq.) in portions. Allow to return to ambient temperature. Hydrolyse, acidify with 1N HCl and filter. Purify the resulting crude product by chromatography on silica gel (eluant:diethyl ether/toluene 2/8).
Reaction SMILES: [CH2:1]([C:3]([N:19]([CH3:21])[CH3:20])([CH2:16][CH:17]=[CH2:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]([N:19]([CH3:21])[CH3:20])([CH2:16][CH2:17][CH3:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=CCC(CC)(C(=O)c1ccc(OCCO)cc1)N(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(CC)(C(=O)c1ccc(OCCO)cc1)N(C)C

Procedure:
32.6 g (0.11 mol) of 2-ethyl-2-dimethylamino-1-(4-(2-hydroxyethoxy)phenyl)-pent-4-en-1-one according to Example A2 are dissolved in 220 ml of ethyl acetate, 1.6 g of palladium-on-carbon (5%) are added thereto and the mixture is then hydrogenated at 30° C. under normal pressure. After approximately 3 hours the absorption of hydrogen ceases (2.58 liters, 103% of the theoretical amount). The catalyst is removed by filtration and the solvent is distilled off using a rotary evaporator (RE). The oily residue is purified by flash-chromatography (petroleum ether/ethyl acetate 2:1). 27.4 g (84%) of a slightly yellowish oil remain.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[ClH:10].[CH3:11]O>>[ClH:10].[NH2:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3]([O:5][CH3:11])=[O:4]
Reactant: CO
Reactant: CCC(N)(CC)C(=O)O
Agent: Cl
Product: CCC(N)(CC)C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 2-amino-2-ethylbutanoic acid (3.00 g, 22.9 mmol) in MeOH (200 mL) was saturated with HCl (g). The resulting mixture was heated at reflux for 24 h, during which time it was allowed to cool to ambient temperature and was again saturated with HCl (g) twice. After 24 h at reflux, the cooled mixture was concentrated in vacuo to provide the title compound. MS: m/z=146 (M+1).
Reaction SMILES: C[O-].[Na+].[Na].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[N:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]>O.CO>[N:16](/[C:19](=[CH:14]\[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH:6]=[CH:7]2)/[C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc2[nH]ccc2c1)N=[N+]=[N-]
Reaction time: 5 h
Yield: 76.7 %

Procedure:
Under nitrogen, to a sodium methoxide solution (prepared from 15 ml of methanol and 0.66 g (29 mmol) of sodium) a mixture of 1.02 g (7 mmol) of indole-5-carbaldehyde [Helv. Chim. Acta, 1616. (1968)], 3.34 g (29 mmol) of methyl azido-acetate and 7 ml of methanol is added dropwise at 0° C. and the so obtained mixture is stirred at this temperature for 5 h. Then the reaction mixture is diluted with 50 ml of water, and extracted three times with 50 ml of chloroform. The combined organic layers are washed with 20 ml of water, filtered through a phase separating filter-paper and concentrated to yield 1.3 g (77%) of the title compound. Mp.: 130-133° C. (chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:23]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:24]=4[N:25]([CH3:28])[C:26]=3[CH:27]=2)[C:8](=[O:12])[CH:7]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2Cl)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5Cl)cc4=O)cc31)CCNCC2
Temperature: 135 °C
Reaction time: 48 h
Yield: 40.6 %

Procedure:
A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (103 mg, 0.381 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (131 mg, 0.347 mmol), CuI (79 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and Cs2CO3 (124 mg, 0.381 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 48 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et2O (100 mL) was added to a solution of the tan solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 17 h. The suspension was filtered, and the solid was washed with Et2O and freeze dried to afford 66 mg (38%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.02 (br s, 2H), 7.74 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.45 (d, J=1.5 Hz, 1H), 6.96 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H), 6.00 (d, J=3.0 Hz, 1H), 5.19 (s, 2H), 3.69 (s, 3H), 3.42-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 468 [M+H]+.