Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:20]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]([O:18][CH3:20])([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of sodium hydride suspension in mineral oil (60% wt) (3.86 g, 96 mmol) in dry THF (60 mL) were added (R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (7.5 g, 32.2 mmol) in THF (50 mL) at 0° C. slowly. After stirring for 1 h at room temperature, iodomethane (4.31 ml, 38.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. After quenched with water, the reaction mixture was extracted by ether. The aqueous layers was acidify to pH=3 by adding 6 N HCl, then extracted by EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered though Buchner funnel, and concentrated to yield crude (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoic acid (7 g, 28.3 mmol, 88%), which was used in next step reaction without purification. LC/MS (uplc): MH+ 160.1, 0.68 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([O:14][CH3:15])[CH:3]=1.C(Cl)CCl.[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].CCOC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[C:6]([NH:8][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH:20]([CH3:21])[CH3:22])=[CH:24][CH:25]=2)[CH:7]=1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: COCCNc1c(N)cc(Br)cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCNc1c(NC(=O)c2ccc(C(C)C)cc2)cc(Br)cc1OC
Yield: 98.6 %

Procedure:
A solution of 4.95 g (18 mmol) 5-bromo-3-methoxy-N*2*-(2-methoxy-ethyl)-benzene-1,2-diamine, 5.15 g (27 mmol) EDC, 3.3 g (27 mmol) 4-dimethylamino-pyridine and 2.94 g (18 mmol) 4-isopropyl benzoic acid in 150 ml dichloromethane is stirred at room temperature for 14 h. After that 400 ml EtOAc are added and the organic phase washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 7.48 g of the title compound as a reddish oil.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9][C:8]2([CH3:17])[CH3:16].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)C.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:18])=[CH:10][CH2:9][C:8]2([CH3:17])[CH3:16])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: C[Mg]Br
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 403.8 %

Procedure:
Methyl magnesium bromide (3M solution in diethyl ether, 2.5 mL, 7.50 mmol) was added slowly to a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 35, 920 mg, 3.65 mmol) in 10 mL of diethyl ether at 0° C. After stirring and warming to room temperature for 2 h, the mixture was quenched with water at 0° C., extracted with diethyl ether (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure to give a light yellow oil. The crude oil was then dissolved in 10 mL of dichloromethane and stirred with 100 mg of para-toluenesulfonic acid at room temperature for 2 h. Water (10 mL) was then added and the organic layer was washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) gave the title compound (589 mg, 65% yield) as a colorless oil:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Br:21])[C:5]([O:6][C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH2:17][OH:18])[CH:8]=2)=[C:4]([Br:22])[C:3]=1[CH3:23].C([CH:26]([C:30](Cl)=[O:31])[C:27](Cl)=[O:28])C.CCN(CC)CC.C1C[O:43][CH2:42][CH2:41]1>>[CH2:42]([O:43][C:30](=[O:31])[CH2:26][C:27]([NH:1][C:2]1[CH:20]=[C:19]([Br:21])[C:5]([O:6][C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH2:17][OH:18])[CH:8]=2)=[C:4]([Br:22])[C:3]=1[CH3:23])=[O:28])[CH3:41]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: Cc1c(N)cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c1Br
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cc(Br)c(Oc2cc(CO)c(O)c(C(C)C)c2)c(Br)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of 4-(4-amino-2,6-dibromo-3-methylphenoxy)-2-hydroxymethyl-6-isopropylphenol of Part 10B (18 mg, 0.04 mmol), ethylmalonylchloride (5.7 μl, 0.044 mmol) and THF (0.5 mL) was added Et3N (11 μl, 0.08 mmol). After 2 hours stirring at room temperature, the reaction mixture was quenched by NH4Cl (saturated aqueous solution) and the organic phase removed in vacuo. The aqueous phase was extracted with CHCl3 and the resulting two phases were separated with a phase separator (IST). Concentration gave 22 mg (98%) of N-[3,5-dibromo-4-[4-hydroxy-3-hydroxymethyl-5-isopropylphenoxy]-2-methylphenyl]malonamic acid ethyl ester as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:32]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 ml) were added triethylamine (0.084 mL) and acetyl chloride (47 mg), and the mixture was stirred at under ice-cooling for 2 hr. The solvent was evaporated under reduced pressure, distilled water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (162 mg).
Reaction SMILES: ClC1N=CC(C2CC2)=CN=1.Cl.ClC1C=C(N2C(=O)C=C(OC3CCNCC3)C(C#N)=N2)C=CC=1Cl.[Br:36][C:37]1[CH:38]=[N:39][C:40](Cl)=[N:41][CH:42]=1.Cl.[C:45]([C:47]1[CH:52]=[CH:51][C:50]([N:53]2[C:58](=[O:59])[CH:57]=[C:56]([O:60][CH:61]3[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]3)[C:55]([C:67]#[N:68])=[N:54]2)=[CH:49][C:48]=1[F:69])#[N:46]>>[Br:36][C:37]1[CH:38]=[N:39][C:40]([N:64]2[CH2:65][CH2:66][CH:61]([O:60][C:56]3[C:55]([C:67]#[N:68])=[N:54][N:53]([C:50]4[CH:51]=[CH:52][C:47]([C:45]#[N:46])=[C:48]([F:69])[CH:49]=4)[C:58](=[O:59])[CH:57]=3)[CH2:62][CH2:63]2)=[N:41][CH:42]=1
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: Clc1ncc(C2CC2)cn1
Agent: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1F
Yield: 89 %

Procedure:
Example 41 was prepared in 89% yield according to procedures described in Example 21 substituting 2-chloro-5-cyclopropylpyrimidine and 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl for 5-bromo-2-chloropyrimidine and 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt. 1H NMR (400 MHz, CDCl3) δ ppm 0 1.90-2.01 (m, 2H) 2.01-2.19 (m, 2H) 3.78-3.91 (m, 2H) 3.99-4.19 (m, 2H) 4.52-4.93 (m, 1H) 6.32 (s, 1H) 7.60-7.71 (m, 2H) 7.71-7.82 (m, 1H) 8.31 (s, 2H). MS (ESI) 497 (M+H).
Reaction SMILES: FC(F)(F)C1C=CC=CC=1N=C=S.FC(F)(F)C1C=CC=CC=1NC(=S)NN.ClC(OCC)=O.[OH:35][C:36]1[N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[C:39]([SH:51])=[N:38][N:37]=1.Br[C:53]1[S:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][N:57]=1>>[OH:35][C:36]1[N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:48])([F:50])[F:49])[C:39]([S:51][C:53]2[S:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][N:57]=2)=[N:38][N:37]=1
Reactant: Oc1nnc(S)n1-c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: CCOC(=O)Cl
Agent: FC(F)(F)c1ccccc1N=C=S
Agent: NNC(=S)Nc1ccccc1C(F)(F)F
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2-c2ccccc2C(F)(F)F)s1
Yield: 25.8 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 5 starting with 2-(trifluoromethyl) phenyl isothiocyanate. The intermediate 4-[2-(trifluoromethyl)phenyl]-3-thiosemicarbazide (2.04 g) was treated with ethyl chloroformate (1.09 g) as in example 5. The reaction product 3-hydroxy-5-mercapto-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole (0.78 g) was reacted with 0.63 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole, a yellow solid, MP 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:1](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: C#Cc1ccc(C)cc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl benzylsulfide. The title compound was obtained in 70% yield following oxidation. 1HNMR (CDCl3) δ 2.48 (3H, s), 4.60 (2H, s), 6.68 (1H, d, JH,H=11.94), 7.20-7.65 (9H aromatic+1H ethylenic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[C:14](O)(=O)CC(O)=O.C(N(CC)CC)C.C(=O)=O>O>[OH:7][C:6]1([CH3:14])[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=2)[C:9](=[O:10])[O:8]1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: O=C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)OC2(C)O
Temperature: 73 °C

Procedure:
5.4 g of 3-methoxy-phthalic acid anhydride [see A. V. R. Rao et al., Indian J. Chew. 20B, 248 ff. (1981)], 4.7 g of malonic acid and 9 ml of triethylamine are heated slowly. The suspension becomes stirrable at 55° C. and, from 68° C., moderately vigorous CO2 evolution occurs. The internal temperature is maintained at 73° C. until gas evolution ceases (about 1 hour) and the reaction mixture is then heated at reflux temperature (internal temperature 85° C.) for a further 4 hours. When it has cooled, the reaction mixture is treated with water and extracted with ethyl acetate. The aqueous phase is then adjusted to pH 1.7 and extracted three times with fresh ethyl acetate, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. Fractional crystallisation (ethyl acetate/n-hexane) yields 3-hydroxy-7-methoxy-3-methyl-phthalide, m.p. 156°-158° C.; IR spectrum (CHCl3): C=O 1772 cm-1.
Reaction SMILES: [CH3:1][Sn:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][C:5]([NH:7][NH2:8])=[O:6].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][Sn:2]([CH3:10])([CH3:9])[CH3:1])[CH3:14]
Reactant: CC(C)=O
Reactant: C[Sn](C)(C)CCC(=O)NN
Product: CC(C)=NNC(=O)CC[Sn](C)(C)C

Procedure:
4.0 g (0.016 mole) of 3-trimethylstannylpropionic acid hydrazide of Example 1 and 5.0 ml (0.068 mole) of reagent grade acetone were placed in a 50 ml single-neck flask equipped with a stirrer. The flask was stoppered and the solution was then stirred for about fifteen minutes, at which time the reaction mixture turned solid. Recrystallization of the air-dried solid from acetone-water mixture containing 50% by weight of acetone gave 3.8 g of 3-trimethylstannylpropionic acid 1-methylethylidenehydrazide, Compound 1 of Table I. The infrared spectrum (KBr disc) showed the characteristic bands at 3200 and 3050 cm-1 for N--H and at 1655 and 1550 cm-1 for carbonyl absorption of ##STR9## The carbon-tin bond was characterized by infrared absorption bands at 760, 522, 515 and 503 cm-1. Nuclear magnetic resonance spectroscopy suggested that the compound exists as a tautomeric mixture in CDCl3 solution with one form predominating over the other. The NMR spectra of the dominant isomer showed the following: a broad singlet at 8.38 delta (1H, N--H); a triplet centered at 2.82 delta (2H, --CH2CO); two 3-proton signlets at 1.82 delta and 1.92 delta (--N=C(CH3)2); a triplet centered at 1.02 delta (2H, --CH2Sn); a singlet at 0.06 delta (9H, Sn(CH3)3) flanked by the J(117/119Sn--CH3) doublets.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: Cl
Reactant: COc1cc(C)nc(N)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 25.4 g of 2-amino-4-methyl-6-methoxypyrimidine in 150 ml concentrated hydrochloric acid was cooled to ca. 0° C. and treated with a solution of 25.3 g of sodium nitrite in 50 ml water, added over a period of 30-40 minutes. The thick orange reaction mixture was stirred at room temperature for 4-5 hours and then adjusted to pH 10 by addition of 12.5N sodium hydroxide solution. The precipitate was filtered and extracted thoroughly with approximately 600 ml of hot ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 7.2 g of 2-chloro-4-methyl-6-methoxypyrimidine as a white, crystalline solid, m.p. 36°-38° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11]O.[BrH:13]>>[BrH:13].[BrH:13].[NH2:8][CH2:9][CH2:10][CH2:11][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: NCCCO
Agent: Br
Product: NCCCSc1ccccn1

Procedure:
A solution of 2-mercaptopyridine (2.2 g.) and 3-aminopropanol (1.14 ml.) in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25 hours. The reaction mixture was evaporated to dryness and the oily residual solid recrystallised twice from ethanol to give 2-(3-aminopropylmercapto)pyridine dihydrobromide (3.2 g.) m.p. 186°-188°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:39]5[CH:38]=[N:37][C:36]([N:33]6[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]6)=[CH:41][CH:40]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(N5CCN(C)CC5)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.75 g, 1.5 mmol), 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.5 g, 17 mmol), Na2CO3 (2 M, 3.6 mL), and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in toluene/ethanol (1:1, 12 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 60% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:28])[O:23][C:22](=[O:24])[CH:21]([CH2:25][CH3:26])[C:20](=[O:27])[O:19]1.C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:21]2([CH2:25][CH3:26])[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:23][C:22]2=[O:24])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC1(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)OC1=O
Yield: 87.3 %

Procedure:
(5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 3.48 mmol) was added to a solution of 2,2-dimethyl-5-ethyl-1,3-dioxane4,6-dione (600 mg, 3.48 mmol) and triethylamine (0.51 mL, 3.66 mmol) in dimethyl sulfoxide (40 mL) under nitrogen. The reaction mixture was stirred over night and water (100 mL) was added. Filtration of the precipitate gave [5-(5-ethyl-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (1.15 g, 87%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:14])[CH2:12]Cl)=[C:8]([CH3:15])[S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:12][C:11]([NH:10][C:9]3[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][C:8]=3[CH3:15])=[O:14])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: COC(=O)c1csc(C)c1NC(=O)CCl
Product: Cc1scc(C(=O)O)c1NC(=O)COc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In analogy to Example 2, the title compound was prepared using 4-(2-chloro-acetylamino)-5-methyl-thiophene-3-carboxylic acid methyl ester [23964-99-0] and 4′-fluoro-biphenyl-4-ol. MS (m/e): 384.0 (M−H).
Reaction SMILES: Br[C:2]1[C:12](Br)=[CH:11][C:10]2[C:14]3[C:3]=1[C:4](=[O:16])[C:5](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:32]1(C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[C:17]1([C:2]2[C:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:11][C:10]3[C:14]4[C:3]=2[C:4](=[O:16])[C:5](=[O:15])[C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C(=O)c2c(Br)c(Br)cc3cccc1c23
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1C(=O)c2c(-c3ccccc3)c(-c3ccccc3)cc3cccc1c23
Yield: 57.5 %

Procedure:
An amount of 6.8 g (20 mmol) of 3,4-dibromoacenaphthenequinone, 6.1 g (50 mmol) of phenylboronic acid, and 1 g of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 80 ml of toluene and 20 ml of ethanol. Then, 40 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 3.85 g (11.5 mmol) of 3,4-diphenylacenaphthenequinone. The yield was 57.5%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Li]CCCC.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][C:5]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:4][CH:3]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1csc(-c2ccncc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of 4-thiophen-2-yl-pyridine (3.33 g, 20.7 mmol) in THF (137 mL) at −78° C. is added n-BuLi (8.7 mL of a 2.5 M solution in hexanes, 21.7 mmol). After stirring for 15 minutes, SO2 gas is bubbled through the solution for 30 minutes. The solution is then allowed to warm to room temperature and stirred overnight. The solution is concentrated to dryness and the resulting solid is suspended in hexane (100 ml). To the ice-cooled solution is added sulfuryl chloride (1.7 mL. 21.7 mmol). The ice bath is removed and the suspension is stirred for 2 hours. The mixture is then concentrated to dryness and diluted with ethyl acetate and washed with saturated NaHCO3 (aq), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a yellow solid as the title product (3.39 g, 13.1 mmol) which is used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:45][CH2:44][CH:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH2:42][CH2:41]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCOCC4)CC3)ccc2[nH]1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-(piperidin-4-yl)-morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (72%).