Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[CH:18]3[CH:21]([CH2:22][C:23]=2[S:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH:20]([CH:31]([OH:33])[CH3:32])[C:19]3=[O:34])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:28]([NH:27][CH2:26][CH2:25][S:24][C:23]1[CH2:22][CH:21]2[CH:18]([C:19](=[O:34])[CH:20]2[CH:31]([OH:33])[CH3:32])[C:17]=1[C:15]([OH:16])=[O:14])(=[O:30])[CH3:29]
Reactant: CC(=O)NCCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)C2C(=O)C(C(C)O)C2C1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)C(C(C)O)C2C1
Yield: 91.8 %

Procedure:
A solution of 50 mg of 3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester and 25 μL of anisole in 1.5 mL of trifluoroacetic acid was stirred at room temperature for 10 min. The reaction mixture was evaporated to dryness, and trituration of the residue with ether afforded 30 mg (95%) of 3-(2-acetamidoethylthio)-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless, hydroscopic crystals. IR (Nujol mull) 1550, 1660, 1775 cm-1 ; NMR (400 MHz; acetone-d6): δ 1.24 (3H, d, J=6.5), 1.94 (3H, s), 2.98 (1H, m), 3.03 (2H, t, J=7), 3.14 (1H, ddd, J=18, 3.4, 1.2), 3.22 (1H, ddd, J=5.6, 3.9, 3.2), 3.35 (1H, dd, J=8.5, 1.7), 3.40 (2H, t, J=7), 4.05 (1H, qd, J=6.3, 4.9), 4.31 (1H, m), and 7.67 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[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+].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:33][C:29]5[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: ClCc1cccnc1
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (20 ml), and potassium carbonate (400 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 3-picolylchloride hydrochloride (180 mg) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (100 ml), and the precipitated crystals were recovered by filtration. The resulting crude crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (200 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:24]C)[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[C:8]2=[O:26])=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:24])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 1.5 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide (0.070 g, 0.181 mmol) was dissolved in 1 mL glacial acetic acid and 0.75 mL 30% by weight HBr in acetic acid solution was added. The reaction was stirred for 1.5 hours, water was added and the reaction evaporated to dryness under vacuum. The residue was purified on reverse phase and the fractions collected and evaporated. The residue was dissolved in dioxane, from which crystals formed and were collected. The crystals were dried under vacuum with heat to give the product.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=1)=[O:13])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.O>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:23][CH:24]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c(C#N)c(CC)n1C
Reactant: Nc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(=O)Nc3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add N-chlorosuccinimide (0.13 g, 1.0 mmol) to 3-(4-carboxy-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.33 g, 11.0 mmol, prepared in example E-157) and triphenyl-phosphine (0.26 g, 1.0 mmol) in methylene chloride at 0° C. with stirring. Allow the reaction to warm to room temperature. After 30 minutes, add aniline (0.18 mL, 2.0 mmol). After 2-3 hours, pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 402.0 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[CH:6]=1.S(=O)(=O)(O)O.[C:31](=O)(O)[O-].[Na+]>CO>[CH3:31][O:24][C:23]([C:4]1[C:5]([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([OH:12])=[CH:13][C:14]=3[O:15][C:16]3[C:17]=2[CH:18]=[CH:19][C:20]([CH:21]=3)=[O:22])=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:25]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 120 °C
Yield: 88.2 %

Procedure:
Fluorescein (10 g; 30 mmol) was dispersed in methanol (30 mL) and concentrated sulfuric acid was added slowly. After the addition was complete the mixture was stirred with heating at 120° C. for 14 hours. After cooling the mixture, sodium bicarbonate was added to neutralize the mixture to give a solid. The crude product was filtered and washed with 2% sodium bicarbonate (200 mL), with water (4×) and with 1% acetic acid to give the fluorescein methyl ester (9.2 g, 26.4 mmol, 88.2% yield), m.p. 260-261° C. Step 8B. The fluorescein methyl ester (8 g, 23.1 mmol) and potassium carbonate (9.6 g, 69.3 mmol) were dissolved in dimethylformamide (50 mL) at 90° C. and to the solution was added toluenesulfonyl chloride (6.6 g, 34.7 mmol) slowly for 30 minutes. The mixture was then further stirred with heating at 110° C. for 5 hours. The mixture, after being cooled to room temperature, was poured into water (1L) to give a precipitate which was collected by filtration and washed with water to give the product(10 g, 20 mmol, 86.5% yield). Step 8c. The toluenesulfonyl fluorescein ester (2 g, 4 mmol) and indoline (1.4 g, 12 mmol) were dissolved in N-methylpyrollidinone (100 mL) and the solution was stirred with heating at 95° C. for 17 hours. After being cooled to room temperature the mixture was poured into water (600 mL) to form a precipitate. The precipitate was filtered, washed with water and dried to give the ester (1.7 g, 3.9 mmol, 96.8% yield). The desired dye was obtained by basic hydrolysis of the ester using the following method: the dye and aqueous sodium hydroxide (3 eq.) were dissolved in methanol and stirred with heating at 60° C. for 1 hour until TLC showed complete conversion. The crude product was purified by column chromatography (5% methanol in methylene chloride) to give the desired product. (1.35 g, 3.1 mmol, 78% yield) The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=431.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N+:3]=1[O-].ClC1C([N+]([O-])=O)=C(C)C=CN=1.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][O:27][C:24](=[O:26])[CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c(Cl)c1[N+](=O)[O-]
Agent: Cc1ccnc(Cl)c1[N+](=O)[O-]
Product: CC(=O)OCc1ccnc(Cl)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A 4:1 mixture of 2-Chloro-3-nitro-4-picoline-N-oxide and 2-Chloro-3-nitro-4-picoline (7.2g, 0.031 mol, based on the N-oxide) was dissolved in acetic anhydride (20 mL) and the solution was heated in a 80° C. oil bath for 70 minutes. The solvents were removed under vacuum and the dark residue was partitioned between methylene chloride (100 mL) and saturated aqueous potassium carbonate (200 mL). The aqueous layer was re-extracted with more methylene chloride (1×50 mL) and the combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated under vacuum. The crude solid was dissolved in methylene chloride (20 mL) and was loaded onto a silica gel column (E. Merck 60, 230-400 mesh, 4×36 cm). The column was eluted with methylene chloride collecting 25 mL fractions. Fractions 22-48 were combined and evaporated to give substantially pure 2-chloro-3-nitro-4-acetoxymethylpyridine (1.75 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[C:21](F)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(N(CC)CC)C>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:21]2[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:23][N:22]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)C2CCCN2c2ncc(C(F)(F)F)cc2Cl)no1
Temperature: 175 °C

Procedure:
A microwave reaction vessel is charged with (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride, 3-chloro-2-fluoro-5-trifluoromethylpyridine, triethylamine and ethanol. The mixture is heated in a microwave reactor at 175° C. for 1 h, maintaining the watts at 60 to keep the reactor from shutting down. The reaction is cooled to room temperature and concentrated in vacuo to afford an oil which is purified by reverse phase preparative HPLC. Product fractions are combined and concentrated in vacuo to afford title compound (64.4 mg). ESI m/z 417 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH2:18]([Mg]Br)[CH3:19].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(/C=N/[S@@](=O)C(C)(C)C)cc1F
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of 66 (3.0 g, 12 mmol) in THF (30 mL) at −78° C. was added a solution of ethylmagnesium bromide in THF (1N, 18 mL, 18 mmol). After stirring for 4 h, the reaction mixture was warmed to 25° C. and stirred at RT overnight. The mixture was treated with NH4Cl, and diluted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:1) to afford 1.5 g (45%) of (S)—N—((R)-1-(3-fluoro-4-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (68). LCMS (ESI) m/z: 288.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25](F)[CH:24]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[CH3:31][O:32][CH2:33][C@H:34]([NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1)[CH3:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:43][C@H:40]3[CH2:39][CH2:38][C@H:37]([NH:36][C@H:34]([CH3:35])[CH2:33][O:32][CH3:31])[CH2:42][CH2:41]3)[CH:24]=2)=[N:4][C:5]([NH:8][CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Reactant: COC[C@@H](C)N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](C)N[C@H]1CC[C@H](Nc2cc(-c3nc(NC[C@@H]4CCCOC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 110 °C

Procedure:
To a scintillation vial was added racemic tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (114 mg, 0.250 mmol), trans-N1-((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine (70 mg, 0.376 mmol) and DIPEA (0.088 ml, 0.501 mmol) followed by NMP (0.1 ml). The mixture was heated at 110° C. for 60 hr then concentrated in vacuo. The resulting residue was purified by reverse phase prep HPLC and lyapholized. The resulting white solid was free based by dissolving in EtOAc and then washing with 1M NaOH (×3), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was then purified by chiral separation chromatography to yield 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg), LCMS (m/z): 522.1/523.9 (MH+), tR=0.675 min. and 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg) LCMS 522.1/523.9 (m/z): (MH+), retention time=0.675 min.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (55 μL) and Methanesulfonyl chloride (35 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2,3-trimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 6(5), 64 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (76 mg) as a colorless powder.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:17][NH:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:17][N:18]([CH3:19])[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(C(=O)C(C)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C(C)N(C)C)cc1
Yield: 89.3 %

Procedure:
A mixture of N-[4-(2-chloro-1-oxopropyl)phenyl]acetamide (0.19 mol), N-methylmethanamine hydrochloride (1:1)(0.38 mol) and K2CO3 (78.8 g) in CH3CN (1400 ml) was stirred and refluxed for 12 hours. The mixture was cooled, poured into water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent was evaporated, yielding 39.77 g (89%) of (±)-N-[4-[2-(dimethylamino)-1-oxopropyl]phenyl]-acetamide (interm. 9).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[C:33]([O:45][CH3:46])[CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[O:56])=[C:33]([O:45][CH3:46])[CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(OC)c2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(OC)c2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.42 g) was dissolved in methylene chloride (12.6 ml), and a solution of m-chloroperbenzoic acid (133 mg) in methylene chloride (8.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 255) (0.18 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=1.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C.C(Cl)Cl>[Br:23][C:13]1[S:12][C:11]([C:8]2[S:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:9]=2)=[CH:15][CH:14]=1
Reactant: c1csc(-c2ccc(-c3cccs3)s2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Using 2,2′:5′,2″-terthiophene (7, FIG. 3): N-Bromosuccimide (3.147 mg, 17.681 mmol) were added portion in portions during 5 hours to an solution of 2,2′:5′,2″-terthiophene (4.315 g, 17.373 mmol) in 10 ml DMF at −20° C. After about 90 min, a precipitate was formed. After stirring for 14 hours at room temperature, the reaction mixture was dissolved in 300 ml CH2Cl2 and washed twice with 100 ml 1N HCl. The aqueous layers were extracted with CH2Cl2 and the organic layers were dried (MgSO4) and concentrated. Purification by FC (hexanes) gave 5.222 g (56 mmol, 92%) 5-bromo-2,2′:5′,2″-terthiophene, 92%) as yellow solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>>[N:14]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=3[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2[nH]c(N3CCOCC3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-nitro-1H-benzimidazole (300 mg) and morpholine (1 ml) was stirred at 50° C. for 8 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was washed with isopropyl ether and collected by vacuum filtration to give 2-(morpholin-4-yl)-4-nitro-1H-benzimidazole (288 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20](I)[CH:19]=1>>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: COC(=O)c1ccnc(I)c1
Product: COC(=O)c1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 70 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (58 mg, 0.32 mmol) was converted (using 2-iodo-isonicotinic acid methyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 70 mg, 70%) which was obtained as a light brown solid. MS: m/e=319.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=[O:11])[O:9][CH:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pd]>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[C:10]([OH:11])=[O:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1cccc2c1C(=O)OC2c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(Cc2ccccc2)c1C(=O)O

Procedure:
The phthalide (30 g.) is dissolved in ethanol (500 ml.) by warming, 5% palladium-on-charcoal (3 g.) is added and the solution is hydrogenated until hydrogen uptake ceases. After removal of the catalyst by filtration, the ethanol is evaporated, and the residue is crystallised from chloroform-petroleum ether (b.p. 60°-80°C.) to give 2-benzyl-6-methoxy-benzoic acid m.p. 159°-161°C.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:16])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:16][CH2:20][O:21][CH3:22])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)c2c1Sc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c2c1Sc1ccccc1S2
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 4-Bromo-thianthren-1-ol (1.0 g, 3.21 mmol) in DMF (12 ml) was added NaH (60% dispersed in mineral oil, 0.23 g, 9.63 mmol) portionwise over 30 minutes and stirred for a further 30 minutes at this temperature. Chloromethylmethylether (0.26 g, 3.241 mmol) was then added and the reaction allowed to stir at room temperature for 2 hours. Water was added to the mixture which was then extracted using EtOAc (3×50 ml). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a mild amber liquid. The crude residue was purified by flash chromatography (SiO2) (10:1, Hexanes/EtOAc) to give the title compound as a mild amber oil that crystallised upon standing (1.11 g, 97%). m/z (LC-MS, ESP):, RT=5.55 min, (M++1)=355.