Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:26])[N:16]([CH2:17][C:18]([NH2:20])=[S:19])[C:15](=[O:21])[C:14]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]12>C(O)(C)C>[C:15]1(=[O:21])[N:16]([CH2:17][C:18]2[S:19][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:20]=2)[C:12](=[O:26])[C:13]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:14]12
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2CC1Br
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c(s1)Cc1ccccc1-2
Yield: 50.3 %

Procedure:
In 100 ml of isopropanol, 1.64 g of 2-bromo-1-indanone was dissolved. Then, 2.0 g of phthalimidothioacetamide was added, followed by heating under reflux for 6 hours. The precipitate thus formed was collected by filtration and then distributed between chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then evaporated, whereby 1.3 g of 2-phthalimidomethyl-8H-indeno[1,2-d]thiazole was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.CCOC(C)=O.CCCCCC>CC#N>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCSCC2)c(F)c1
Temperature: 85 °C
Yield: 100.7 %

Procedure:
The 3,4-difluoronitrobenzene (2.09 mL, 18.857 mmol) was dissolved in dry CH3CN (50 mL) and then treated dropwise with N,N-diisopropylethyl amine (8.212 mL, 47.143 mmol). The resultant yellow mixture was next treated with thiomorpholine (4.74 mL, 47.143 mmol). The reaction was heated to roflux (85° C.) for 16 hours and then it was allowed to cool to ambient temperature over 3 hours, stirring under N2. At this point, the reaction was determined to be complete by TLC (15% EtOAc/hexane, UV short wave). The reaction mixture was first concentrated under reduced prossure and then adsorbed onto silica gel (50 g). The material was chromatographed on more silica gel (175 g, packed with hexane), eluting with 1 L each of 5%, 10% and 15% EtOAc/hexane to give 4.6 g (100%) of the title compound as an orange, crystalline solid with a melting point of 59.5°-60.5° C. and a HRMS (M+) calculated for C10H11N2O2FS 242.0522, found 242.0525.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH+:6]=[CH:5][CH:4]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][C:3]([N:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=[N:9]2)=[CH:4][CH:5]=1
Reactant: Clc1cc[nH+]cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2nn(-c3ccncc3)nc2c1
Temperature: 130 °C

Procedure:
A mixture of 4-chloropyridinium hydrochloride (25.0 g, 166 mmol), benzotriazole (29.6 g, 249 mmol), potassium carbonate (69.1 g, 500 mmol), and dimethylformamide (500 mL) was stirred and heated under argon at 130° C. for 3 days. After cooling, the solid was filtered off, and the solvent was evaporated under reduced pressure. The residue was treated with dichloromethane (200 mL), filtered and chromatographed using a column filled with silica gel (500 mL) and hexane/ethyl acetate (1:1) as an eluent. Fractions containing the desired product were combined, and the solvent was distilled off. The residue was triturated with ethanol, the solid was filtered off and dried in a vacuum oven to give 2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole, 6.45 (20%). 1H NMR (400 MHz, CDCl3): δ 8.80 (m, 2H, pyridine), 8.26 (m, 2H, pyridine), 7.93 (m, 2H, benzotriazole), 7.46 (m, 2H, benzotriazole).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=2)[CH2:18][CH2:17]1)=S.[S]>[Hg]=O.O1CCCC1>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]3[NH:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[N:8]=3)[CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: Nc1ccncc1NC(=S)NCCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCCCNc4nc5cnccc5[nH]4)CC3)nc3ccccc32)cc1
Yield: 29 %

Procedure:
A mixture of 18 parts of N-(4-amino-3-pyridinyl)-N'-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-butyl]thiourea, 7 parts of mercury(II)oxide, 1 part of sulfur and 180 parts of tetrahydrofuran was stirred and refluxed for 5 hours. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of tetrahydrofuran and trichloromethane, yielding 5 parts (29%) of N-[4-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]butyl]-1H-imidazo-[4,5-c]pyridin-2-amine; mp. 228.2° C. (compound 121).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:38])[CH2:36]O.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:38])[CH2:36][O:33][C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 95.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (100 mg, 0.22 mmol) and (2S)-2-amino-1-propanol (0.10 mL, 1.28 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)—N-[(4-fluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (100 mg, 95%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (80 mg, 99%) as a white solid, 1H NMR (CDCl3) δ 11.43 (br, 1H), 10.28 (br, 1H), 8.35 (s, 1H), 7.28 (m, 2H), 6.97 (m, 2 E), 5.29 (m, 1H), 4.55-4.38 (m, 5H), 3.89 (apparent t, J=10.8 Hz, 1H), 3.70 (m, 1H), 1.45 (d, J=5.6 Hz, 3H); ES+ MS: 386 (M−1),
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26]1([CH2:29][C@H](O)CO)[CH2:28][CH2:27]1>ClCCl>[I:25][C:26]1([CH2:29][C@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)[CH2:28][CH2:27]1
Reactant: COC(C)(C)OC
Reactant: OC[C@@H](O)CC1(I)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)OC[C@H](CC2(I)CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate are added to a solution of (S)-3-(1-iodocyclopropyl)propane-1,2-diol dissolved in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution 0.16 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 2 mL of dichloromethane, 0.14 g of tert-butyl (piperidin-4-yl)carbamate, 41 μL of acetic acid and 0.23 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour 30 minutes. The reaction mixture was charged with chloroform and a saturated aqueous sodium hydrogen carbonate solution and adjusted to pH 8.5, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=19:1 to obtain 0.23 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:30]([O:32]C)=O)[CH2:13][C@H:14]1[N:18](C(OC(C)(C)C)=O)[C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:13][C@H:14]2[N:18]([C@H:17]([C:26]([O:28][CH3:29])=[O:27])[CH2:16][CH2:15]2)[C:30]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C[C@@H]1CC[C@@H](C(=O)OC)N1C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COC(=O)[C@@H]1CC[C@H]2CC(NC(=O)OCc3ccccc3)C(=O)N21
Temperature: 95 °C
Reaction time: 0.75 h

Procedure:
1500 mg of 1-tert-butyl 2-methyl (2S,5S)-5-(2-benzyloxycarbonylamino-2-methoxycarbonylethyl)pyrrolidine-1,2-dicarboxylate were mixed with 0.2 ml of thioanisole. Then 10 ml of trifluoroacetic acid were added, and the mixture was stirred for 45 min. The solvents were then removed in vacuo, and the residue was taken up in 10 ml of pyridine. 1.1 ml of diisopropylethylamine were added, and the mixture was heated at 95° C. for 3 h. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH2:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[CH3:25]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH:17][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: CI
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Product: CNOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
Using the procedure of Example 59 but substituting other 1-[(aminooxy)methyl]- 6-phenyl- or 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines for 8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and other alkyl halides for methyl iodide other 1-[[(monoalkylamino)oxy]methyl]-6-phenyl- or 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines of formula III can be prepared.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14]C(=O)C1C=CC=CC=1)=[O:6].[CH3:27][NH:28][CH3:29].[OH-].[K+]>C(Cl)Cl.O>[NH2:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[C:5]([C:4]1[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=1[CH2:2][N:28]([CH3:29])[CH3:27])=[O:6]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)c1ccccc1CBr)c1ccccc1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Reaction time: 16 h

Procedure:
To a solution of N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6 mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl4 (150 mL) was added 2,2′-azobisisobutrylnitrile (0.2 g, 1.5 mmol). The solution was refluxed for 4 h. The solution was then cooled to room temperature, diluted with CH2Cl2 (150 mL) and washed with H2O (3×50 mL). The organic portion was dried over Na2SO4 and evaporated to dryness in vacuo to provide N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g, 74%). A solution of the benzamide (2.3 g, 5.4 mmol) in CH2Cl2 (50 mL) was saturated with dimethylamine, stirred for 16 h and evaporated to dryness in vacuo. The resulting residue was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H2O (5 mL) was added. The solution was refluxed for 24 h. The solution was concentrated in vacuo and then diluted with EtOAc (150 mL) and H2O (50 mL). The organic portion was washed with H2O (3×50 mL), dried over Na2SO4 and purified by column chromatography (silica gel, 18:80.2 MeOH:CH2Cl2:NHOH) to provide lq (0.9 g, 53% yield) MS m/z=289 (M+H).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)=O>C(O)C>[N+:25]([C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc([N+](=O)[O-])c3)cs2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution (24 mL) of the compound (2.2 g, 10.2 mmol) obtained in Example 1b and 2-bromo-1-(3-nitrophenyl)ethanone (3.0 g, 12.3 mmol) in ethanol was heated under reflux overnight, and the mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and the produced crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (3.4 g, 78%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[CH2:32]([N:35]([CH2:44][CH2:45][CH3:46])[C:36](=[O:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH3:34]>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([F:30])[CH:27]=1)[CH2:23][C@H:9]([NH:8][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][C:36]([N:35]([CH2:32][CH2:33][CH3:34])[CH2:44][CH2:45][CH3:46])=[O:43])[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)CCCC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(OC)c1

Procedure:
Following the general procedure of EXAMPLEs 6 and making non-critical variations and using (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 5) with 5-(dipropylamino)-5-oxopentanoic acid (DX), the title compound is obtained, MH+=534.2.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.[Pd]>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[CH3:15])[C:6]([NH:5][CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[CH:22][C:2]=1[NH:1][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18]
Reactant: Brc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2Nc2ccccc2)cc(OC)c1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 40.3 %

Procedure:
To a suspension of Pd(P(t-Bu3)2 (3.3 mg, 0.0065 mmol) and cetyltrimethylammonium bromide (1.2 mg, 0.0033 mmol) in toluene (2 mL) was added compound 1g (250 mg, 0.65 mmol), bromobenzene (0.072 mL, 0.68 mmol), potassium hydroxide (55 mg, 0.98 mmol), and water (0.018 mL, 0.98 mmol). The reaction mixture was heated at 90° C. for 24 h. Additional Pd(P(t-Bu3)2 (5 mg) and cetyltrimethyl-ammonium bromide (3 mg) was added and heating was continued for 18 h. Additional Pd(P(t-Bu3)2 (5 mg) was added, and the reaction was heated to 100° C. for 12 h. The reaction mixture was filtered through a column of silica gel in ethyl acetate and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30-40% v/v ethyl acetate/hexane) to give compound 8a (120 mg, 40%) as a colorless solid. ESI-MS m/e 459.2 (M+1).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[CH2:11](I)[CH2:12][CH2:13][CH3:14].C(O)(=O)C>O>[CH2:11]([S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydro-1H-pyrimidin-4-one (12.8 g) was added to a solution of NaOH (8.0 g) in water (70 mL). After complete dissolution of the solids butyl iodide (12.4 mL) was added to the solution and the resulting mixture was stirred at RT overnight. A second aliquot of butyl iodide (1.2 mL) was then added and the reaction mixture was stirred for 24 h. A third aliquot of butyl iodide (1.2 mL) was added and the resulting mixture was stirred for 6 days. Glacial acetic acid (5.5 mL) was added and the reaction mixture was stirred for 30 min, it was then stored at 4° C. overnight. The precipitate formed was collected by filtration and dried under reduced pressure to give 12.3 g of 2-butylsulfanyl-3H-pyrimidin-4-one.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:43])[C:14]3[N:15]([CH3:42])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26](=[O:41])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC5C=CC=CC=5)=[O:32])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[H][H]>CO>[CH3:44][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:43])[C:14]3[N:15]([CH3:42])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:26](=[O:41])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: [H][H]
Reactant: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)CCCCC(=O)OCc4ccccc4)ccc3n(C)c12
Solvent: CO
Product: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)CCCCC(=O)O)ccc3n(C)c12
Yield: 112 %

Procedure:
2 g of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-(5-benzyloxycarbonylpentan-oyloxy)-6H-pyrido[4,3-b]carbazole dissolved in 600 ml of methanol are hydrogenated in the presence of 0.2 g of palladium-on-barium sulphate for 36 hours under 3.5×105Pa of hydrogen at room temperature. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is taken up in ethanol and concentrated almost to dryness, and diethyl ether is added. The precipitate is suction-filtered and dried at 40° C. under 133 Pa. 1.9 g of the desired product are obtained, m.p.(cap): 88-90° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15](OCC)=[O:16])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/C=C/c1ccc(OC(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)Oc1ccc(/C=C/C=C/CO)cc1

Procedure:
In substantially the same manner as in Reference Example 7, ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienate was reduced with diisobutylaluminium hydride to give (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-ol. Recrystallization from isopropyl ether gave colorless needles. Melting point 91-92° C.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4CCCCC4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.161 g, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then re-cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 45 min before the addition of cyclohexanesulfonyl chloride (0.064 g, 0.352 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL) and the combined organic extracts dried over a phase separating column and concentrated. The residue was then purified by MDAP (basic conditions), to afford the title compound (22 mg). LCMS (A) m/z: 431 [M+1]+, Rt 1.16 min (basic).