Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH2:11]Cl)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[S-:13][C:14]#[N:15].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][CH2:11][S:13][C:14]#[N:15])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: N#C[S-]
Reactant: ClCSc1nc(Cl)c(Cl)nc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CSCSc1nc(Cl)c(Cl)nc1Cl
Temperature: 75 °C

Procedure:
To a solution of 4.0 grams (0.015 mole) of 3,5,6-trichloro-2-(chloromethylthio)pyrazine in 75 milliliters of dimethylformamide was added 1.6 grams (0.02 mole) of sodium thiocyanate. The reaction mixture was heated to 75° C and monitored by nuclear magnetic resonance spectroscopy. An additional 4.8 grams (0.06 mole) of sodium thiocyanate was incrementally added until the reaction was complete (5 days). The solvent was removed by evaporation under reduced pressure and the residue remaining was dissolved in a mixture of water and chloroform. Two phases formed and the aqueous phase was extracted with chloroform. The organic fractions were combined and washed with a saturated sodium bicarbonate solution followed by washing with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the crude 3,5,6-trichloro-2-(thiocyanatomethylthio)pyrazine product was purified by elution with chloroform from a silica gel column. The product was recovered in a yield of 0.32 grams (7.5 percent of theoretical) and melted at 90°-93° C. Upon analysis, the product was found to have carbon, hydrogen, nitrogen and sulfur contents of 25.60, 1.01, 14.29 and 22.60 percent, respectively, as compared with the theoretical contents of 25.13, 0.70, 14.66 and 22.34 percent, respectively, calculated for the above-named structure.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[S:23]([C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
3-Hydroxy-Cbz-(R)-pyrrolidine (13.7 g, 0.06 mol) was dissolved in CH2Cl2 (250 mL) and cooled to 0° C. p-Toluenesulfonyl chloride (14.16 g, 0.07 mol), and triethylamine (20.7 mL, 0.15 mol) were added and the resulting solution was stirred for 4 h at 0° C. The solution was washed with 1 M HCl, saturated NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (3/1, v/v) to afford 20.4 g (88% yield) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:17])=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[O:14])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)cccc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cccc2c1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 8-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Med. Chem., 22, 816 (1979)) and 3.0 mL of 4-chlorobenzylamine is stirred 1 hour at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.52 g.
Reaction SMILES: [O:1]1[CH:12]2[C:2]1([CH3:15])[C:3]1([C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11]2)[O:7][CH:6]([CH3:8])[CH:5]=[CH:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:8][CH:6]1[CH:5]=[CH:4][C:3]2([C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:2]2([CH3:15])[OH:1])[O:7]1
Reactant: CC1C=CC2(O1)C(C)(C)CCC1OC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1C=CC2(O1)C(C)(C)CCCC2(C)O
Yield: 174.2 %

Procedure:
1.08 g (0.01 M) of 6,7-epoxy-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]dec-3-ene -- see method B, letter i-- were reduced by means of 570 mg (0.015 M) of LiAlH4 in accordance with the above process. After the usual treatments of washing, drying and evaporation, the fractional distillation of the obtained residue gave 1.9 g (ca. 90%) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]dec-3-ene-6-ol, b.p. 80°-90°/0.1 Torr.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11]C(=O)C.[I:16]I>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11]
Reactant: II
Reactant: COC(=O)c1ccc(Cl)cc1NC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)c1cc(I)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0 g in 80 mL of dry chloroform) and 2.5 g silver trifluoromethanesulfonate was added iodine (2.87 g in 40 mL chloroform) and the mixture stirred at room temperature. After 5 hours, the mixture was filtered over diatomaceous earth and the filtrate concentrated in vacuo. Purification of the resulting oil by flash chromatography on silica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the title compound (2.26 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:9]=[C:8]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)=[N+]=[N-]>C(O)C.O1CCCC1.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:9]=[C:8]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN=[N+]=[N-])ccc21
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN)ccc21
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of 550 mg of tert-butyl 5-(azidomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in a mixture of 10 ml ethanol and 5 ml tetrahydrofuran was added 110 mg of 5% palladium-calcium carbonate, and the mixture was hydrogenated at room temperature at normal pressure for 1.5 hours. After filtering off the catalyst through Celite, the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:methanol=1:0 to 9:1), to give 427 mg of the title compound as light green crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1CCN
Temperature: 0 °C
Yield: 118 %

Procedure:
To a solution of 2-[2-(5-methyl-2-phenyl-1H-imidazol-4-yl)-ethyl]-isoindole-1,3-dione (5.3 g) in ethanol (80 ml) was added hydrazine hydrate (4.0 g). The reaction mixture was stirred under reflux for 4 h, cooled to 0° C., and the precipitate was filtered off. To the filtrate was added brine and cold 2 N NaOH (20 ml), and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to dryness in high vacuum to obtain 2-(5-methyl-2-phenyl-1H-imidazol-4-yl)-ethylamine (3.8 g) as an off-white solid, which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([OH:10])[CH:9]=1.[H][H]>CCO.O=[Pt]=O>[NH2:11][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][C:8]=1[OH:10]
Reactant: COCc1ccc([N+](=O)[O-])c(O)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: COCc1ccc(N)c(O)c1

Procedure:
A solution of 2 (20 g, 108 mmol) in EtOH (300 mL) was hydrogenated over PtO2 (300 mg) in Parr pressure apparatus until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration through a pad of Celite, and the filtrate was concentrated in vacuo to a solid (21 g, 100%). This solid was combined with material obtained from a smaller run then passed through a pad of silica gel (500 g) eluted with ether. Fractions containing pure product were combined, dried then concentrates, yield 20 g (89%) m.p. 108–108.5° C. (uncorrected).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH3:12][NH2:13]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:13][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of methyl 4-chloropyridine-2-carboxylate (29.9 g, 174.9 mmol) in MeOH (15 mL) at 0° C. was added 2M methylamine in THF (437 mL, 874 nunol) dropwise. The reaction was allowed to stir at 0° C. for 3 h. The mixture was then concentrated and extracted with EtOAc (2×). The organic solutions were combined, washed with brine, dried over Na2SO4 and concentrated to give 4-chloro-N-methylpyridine-2-carboxamide (25 g, 84%). 1H NMR (300 MHz, d6-DMSO) δ: 8.85 (br s, 1H), 8.61 (d, 1H), 8.00 (d, 1H), 7.74 (dd, 1H), 2.81 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].OB(O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[C:17]([F:25])[CH:16]=1.Cl>[Pd].CO>[F:25][C:17]1[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][O:10][CH3:11])=[C:2]([F:1])[CH:3]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCOc1ccc(B(O)O)cc1F
Reactant: COCOc1ccc(Br)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCOc1ccc(-c2ccc(OCOC)c(F)c2)cc1F

Procedure:
First, 10.0 g (32.4 mmol) of 3,3′-difluoro-4′-methoxymethoxy-4-propoxybiphenyl [which was obtained by cross-coupling reaction of 3-fluoro-4-methoxymethoxybromobenzene with dihydroxy(3-fluoro-4-propoxyphenyl)borane in the presence of Pd catalyst], 50 ml of methanol, and 10 ml of a concentrated hydrochloric acid were heated to reflux for 3 hours. Then, 50 ml of water was added to the reaction solution and extracted with 150 ml of diethyl ether. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution twice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure to obtain 8.5 of a crude 3,3′-difluoro-4′- hydroxy-4-propoxybiphenyl. (Yield: 99.8%)
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13](C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].I[C:23]1C=C[N:25](C)[N:24]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[CH:13][N:24]([CH3:23])[N:25]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cn1ccc(I)n1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cn1ccc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1

Procedure:
The title compound was prepared by a similar method to 3-(1,3-Dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4), replacing 3-bromobenzonitrile with 3-iodo-1-methyl-1H-pyrazole in Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([O:9][C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1cc(I)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(I)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
2-Chloro-5-iodophenol (2.50 g, 9.83 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (2.97 g, 14.7 mmol) and triphenylphosphine (5.15 g, 19.6 mmol), were suspended in THF (50 mL) and cooled to 0° C. Diethyl azodicarboxylate (3.08 mL, 19.6 mmol) was then added dropwise, the reaction was stirred under a N2 atmosphere for 18 h. The reaction was then partitioned between H2O and EtOAc. The organic layer was separated, washed with saturated brine, dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-50% EtOAc/cyclohexane, to afford the title compound (3.43 g, 80%). (Method 3): Rt 4.98 min, m/z 337.9 [M-BOC+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=O)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:5]2[C:22]1[NH:23][CH2:24][CH2:25][N:21]=1
Reactant: Clc1ccc2[nH]c(Sc3ccccc3)cc2c1
Reactant: CC(=O)N1CCNC1=O
Product: Clc1ccc2[nH]c(Sc3ccccc3)c(C3=NCCN3)c2c1

Procedure:
Treatment of 5-chloro-2-(phenylthio)-1H-indole (3.8 mmol, 1 g) with N-acetyl-4,5-dihydro-1H-imidazol-2-one as described in Example 89, Step 3 gave 5-chloro-2-phenylthio-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indole (0.19 g): MS:327M−; m.p.178° C.; yield (13,4%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:18])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#C[C@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (1R*,5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 39b; 44 g, 140 mmol), 10% palladium on charcoal (11 g, 10 mmol), ethyl acetate (200 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1.5 hours. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The Celite™ cake was well washed with dichloromethane to dissolve solid product. The filtrate was concentrated to give the title compound.
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[C:32]3[S:26][C:27](=[S:28])[NH:29][C:30]3=[O:31])=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2cccc3ccccc23)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2cccc3ccccc23)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(naphth-1-yl)methoxy]benzaldehyde (5.25 g, 20 mmol) was dissolved in 100 ml of acetic acid. To this solution was added sodium acetate (5.74 g, 70 mmol) and rhodanine (2.66 g, 20 mmol). The reaction mixture was raised to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chomratography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([CH3:15])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[C:6]([CH3:19])[C:5]2=1.I[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][CH3:22])[C:10]1[C:9]([CH3:15])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[C:6]([CH3:19])[C:5]2=1
Reactant: CCI
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1[nH]c1ccc(Br)cc12
Product: CCn1c2ccc(Br)cc2c2c(C)c([N+](=O)[O-])cc(C)c21

Procedure:
6-bromo-1,4-dimethyl-3-nitro-9H-carbazole (prepared as described in Chem. Pharm. Bull 35(1), 425-428 (1987), (4.8 g, 0.015 mol) was reacted with iodoethane by working in a similar manner to Example 1a).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([S:13]CCCC)[CH2:10][CH2:11][CH3:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: CCCCSCCCC
Reactant: Cc1ccc(I)cc1
Product: CCCCSc1ccc(C)cc1

Procedure:
The general procedure was used to convert 4-iodotoluene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (331 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.15–7.12 (d, J=8.2, 2H; Ha, Ha′), 6.98–6.96 (d, J=7.9, 2H; Hb, Hb′), 2.79–2.74 (t, J=7.1, 2H; Hc), 2.20 (Methyl Protons), 1.55–1.45 (m, 2H; Hd), 1.39–1.15 (m, 2H; He), 0.83–0.78 (t, J=7.1, 3H; Hf). 13C NMR (75 MHz, CDCl3) δ 135.6 (C4), 133 (C3), 129.6 (C1, C1′), 129.47 (C2, C2), 33.8 (methyl protons), 31.2 (C5), 21.8 (C6), 20.8 (C7), 13.54 (C8). Anal. Calcd. for C11H16S: C, 73.27; H, 8.94; S, 17.78; Found C, 73.21; H, 9.15; S, 17.57.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:27]=[N+:28]=[N-:29].[Na+].CCOC(C)=O>CN(C=O)C>[N:27]([C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (135 mg, 0.33 mmol, prepared according to Example 30, Step 16.1) and sodium azide (108 mg, 1.66 mmol) in DMF (1 mL) was heated at 60° C. and stirred for 4 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (144 mg, 0.33 mmol, quant.) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=2.77.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O>>[CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Reactant: COc1ccc(C=O)cc1OC
Product: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCN(Cc1ccc(OC)c(OC)c1)CC2
Yield: 38.2 %

Procedure:
The title compound (8 mg) was prepared from 1-butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 67, 14 mg) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C26H32ClN3O2, 453.22; found, m/z 454.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 6.91-6.90 (br m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.98 (t, J=7.3 Hz, 2H), 3.82 (d, J=7.0 Hz, 6H), 3.66 (s, 2H), 2.78-2.72 (br m, 8H), 1.67 (m, 2H), 1.27 (m, 2H), 0.86 (t, J=7.3 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Br[CH:22]=[C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:24].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:22]=[C:23](/[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)\[CH3:24])[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(O)CCN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(CCC(C)(C)O)CC2)c1ccc(F)cc1
Temperature: 95 °C
Yield: 65.6 %

Procedure:
4-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl-)2-methyl butan-2-ol (292 mg, 1.0 mmol), 1-((1-bromoprop-1-en-2-yl)-4-fluorobenzene (322 mg, 1.5 mmol), L-proline (23 mg, 0.2 mmol), Cuprous (I) iodide (19 mg, 0.1 mmol), potassium phosphate (636 mg, 3.0 mmol) in DMF (5 mL) were charged in a reaction vessel and nitrogen gas purged into the reaction mixture. The reaction mixture was heated at 95° C. overnight. The reaction was monitored by TLC/LCMS. The reaction mixture was diluted with water (20 mL) and the desired compound extracted with DCM (20 mL×3). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the crude compound which was purified by reverse phase HPLC to obtain 280 mg of desired product as the free base. The free base compound was converted to HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.68 (m, 2H), 7.58 (s, 1H), 7.20 (m, 4H), 6.98 (s, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.98 (m, 1H), 3.61 (m, 1H), 3.55 (m, 2H), 3.20 (m, 2H), 2.06 (m, 2H), 1.96 (s, 3H), 1.35 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 84.3 %

Procedure:
To a solution of 1.0 g (3.87 mmol) of 4-[3-(N-benzylamino)propylthio)-pyridine and 0.65 ml (4.64 mmol) of triethylamine in 25 ml of methylene chloride, 0.49 ml (4.64 mmol) of acetyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 980 mg of the desired compound (yield: 84.2%, yellow oil).