Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[Na+]>CN(C)C=O>[Si:9]([O:8][C@H:6]1[CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])[C@H:3]([CH:2]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH2:1])[CH2:7]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(N)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triethylamine (1.87 ml) in N,N-dimethylformamide (50 ml) was dropwise added ethyl bromoacetate (1.49 ml) at ambient temperature with stirring. The mixture was stirred at 40° C. for 30 minutes and then allowed to stand at ambient temperature for 6 hours. The reaction mixture was poured into saturated aqueous sodium chloride (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was subjected to a column chromatography on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-[(ethoxycarbonylmethyl)-aminomethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.52 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:18])[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1.O1CCOCC1.[CH2:27]([NH2:29])[CH3:28]>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:29][CH2:27][CH3:28])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:18])[CH:5]=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: CCN
Reactant: COc1cc(C)c(NC(=O)c2cccnc2Cl)c(Br)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNc1ncccc1C(=O)Nc1c(C)cc(OC)nc1Br
Temperature: 140 °C
Yield: 44.2 %

Procedure:
A mixture of N-(2-bromo-6-methoxy-4-methyl-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.1 g), dioxane (10 ml), and ethylamine (0.5 g) was heated to 140° C. in a sealed tube for 5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The product was purified on a silica gel column (methylene chloride/ethyl acetate, 99:1) and crystallized by trituration with diisopropyl ether to give 0.95 g of the title compound.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12](OC(O)O)C>>[O:9]1[CH:12]=[N:11][N:10]=[C:1]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: CCOC(O)O
Reactant: NNC(=O)c1ccccc1O
Product: Oc1ccccc1-c1nnco1
Yield: 64.7 %

Procedure:
90 g (0.6 mole) of salicylic acid hydrazide and 355.2 g (2.4 moles) of orthoformic acid ethyl ester are refluxed for 22 hours. Excess of the ester is distilled off and the solid residue is recrystallized from ethanol. 62.9 g of colorless crystals (64.7% of theory) are obtained; melting point 112°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]=[N+:16]=[N-:17])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8].[CH2:19]([OH:22])[C:20]#[CH:21]>C(#N)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:21]=[C:20]([CH2:19][OH:22])[N:17]=[N:16]3)[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC#N
Product: O=C1O[C@@H](Cn2cc(CO)nn2)CN1c1ccc(I)c(F)c1
Yield: 105.1 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(azidomethyl)oxazolidin-2-one (10 g, 28 mmol) was dissolved in acetonitrile (80 mL). Propargyl alcohol (3.2 mL, 56 mmol) was added and then CuI (526 mg, 2.8 mmol) and it was stirred overnight. The solidified reaction mixture was extracted with ethyl acetate/acetonitrile, washed with water and dried over magnesium sulfate. Evaporation of solvent under vacuum gave 12.3 g crude product (quantitative).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH2:53])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.CN(C)C=O>[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH:53][C:7](=[O:9])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)SCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
1.00 g of 3-(acetylthio)propionic acid, 1.39 g of dicyclohexyl carbodiimide, 1.05 g of 1-hydroxybenzotriazole and 1.76 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine were added to 45 ml of dimethylformamide, and the solution was stirred for 5 hours at room temperature. At the end of this time, ethyl acetate was added to the reaction mixture, insoluble matter was filtered off, and the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water. The reaction mixture was then condensed by evaporation under reduced pressure, and the resulting residue was subjected to silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 1.27 g (yield 48%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[N:13][C:12](O)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[N:13]=[N:14][C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1-c1ccc(O)nn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(C)c1-c1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-dimethyl-phenyl)-pyridazin-3-ol in POCl3 is heated at 80° C. for 2 h. The volatile material is evaporated under reduced pressure and the residue is partitioned between EtOAc and diluted NaOH aqueous solution. The organic layer is separated and the aqueous layer is extracted with EtOAc once. The combined organic extract is washed with brine, dried and concentrated in vacuo. The crude product is purified by flash column (Hexanes/EtOAc 4:1) to give 3-chloro-6-(2,6-dimethyl-phenyl)-pyridazine. 1H NMR: (CDCl3) 7.59 (d, 1H), 7.38 (d, 1H), 7.25 (m, 1H), 7.14 (d, 2H), 2.06 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:29]#[C:30][CH3:31]>C1COCC1.[Cu]I>[Cl:27][C:23]1[N:24]=[CH:25][NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([C:29]#[C:30][CH3:31])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:28])=[O:21]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Reactant: C#CC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 44.8 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (70.0 mg, 0.145 mmol), Palladium dichlorobistriphenylphosphine(II) (7.55 mg, 0.014 mmol), copper(I)iodide (1.377 mg, 7.23 μmol) and TEA (0.101 ml, 0.723 mmol) in THF (4 ml) was bubbled 1-propyne (11.59 mg, 0.289 mmol) for 5 minutes and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-propyn-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (29 mg, 0.065 mmol, 45% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.60-7.81 (m, 1H), 7.40 (s, 1H), 7.28-7.38 (m, 3H), 7.16 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 1.99 (s, 3H). LC-MS (ES+) m/z 443.13, [M+H].
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:41][C:36]1[CH:35]=[C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])[CH:39]=[CH:38][C:37]=1[F:40]
Reactant: CCN(C[C@@H](N)c1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Cl)c1

Procedure:
Compound 61 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-chloro-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [390 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.16 (s, 1H), 9.00 (d, 1H), 8.56 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 7.71 (dd, 1H), 7.52-7.43 (m, 1H), 7.35 (t, 1H), 5.44 (s, 1H), 3.16 (dd, 1H), 2.96 (dd, 1H), 2.57 (dt, 2H), 0.98 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)=[N:8][C:9]([C:13]([O:15]CC)=O)=[N:10]2)=[CH:5][CH:4]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1.C1COCC1>CC(N(C)C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:13]([C:9]2[N:8]=[C:7]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[O:15])=[CH:28][CH:27]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc(C)[nH]n2)c2ccc(OC)cc2n1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3cc(C)[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Yield: 95 %

Procedure:
To ethyl 7-methoxy-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (379 mg, 1.16 mmol) in dry DMA (16 mL) cooled in a −30° C. bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (4.05 mL, 4.05 mmol). After 4 h the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and diethyl ether to give a yellow solid (415 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (br. s., 3H) 3.92 (br. s., 3H) 6.48 (br. s., 1H) 7.27 (br. s., 2H) 7.39 (br. s., 2H) 8.07 (br. s., 2H) 8.62 (br. s., 1H) 10.50 (br. s., 1H) 12.15 (br. s., 1H) LC-MS (ESI) m/z 378 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@H:19](C=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])OCC.C(=O)(O)[O-].[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@@H:19]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:32]([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
To a solution of (1R,3S,4S)-3-((S)-2-tert-Butoxycarbonyl-1-formyl-ethylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (698 mg) in dichloromethane (10 ml) was added triethyl orthoformate (720 mg) and p-toluenesulfonic acid monohydrate (6 mg). The resulting mixture was stirred at ambient temperature until no aldehyde remained by TLC. Saturated aqueous sodium bicarbonate solution was then added and the organic phase removed. This was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave the sub-title compound as a pale yellow oil (635 mg, 78%); 1H NMR (400 MHz, d-6 DMSO) δ 0.96-1.15 (6H, m), 1.26-1.84 (16H, m), 2.20-2.50 (2H, m), 3.40-3.81 (5H, m), 4.10-4.28 (2H, m), 4.37 (1H, m), 4.88-5.14 (2H, m), 7.20-7.40 (5H, m), 7.65 (0.5H, d), 7.80 (0.5H, d).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.I[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)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.[Cu]I.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:15]3[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH3:22])=[CH:17][CH:16]=3)=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: C#Cc1ccc(OCC2CC2)cn1
Reactant: C[C@@H](COc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](COc1ccc(C#Cc2ccc(OCC3CC3)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of 5-(cyclopropylmethoxy)-2-ethynylpyridine (591 mg), tert-butyl [(1S)-2-(4-iodophenoxy)-1-methylethyl]carbamate (1.67 g), bis(triphenylphosphine)palladium(II) dichloride (120 mg), copper(I) iodide (32.5 mg), triethylamine (518 mg) and DMF (10 mL) was stirred at 60° C. overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, filtered through celite, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (1.40 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][S:16](=[O:23])(=[O:22])[C:15]=3[C:24]=2[CH3:25])=[O:10])[CH:5]=[N:4]1)[CH3:2].[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]([O:8][C:26]([CH2:27][CH2:28][CH3:29])=[O:30])=[C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][S:16](=[O:23])(=[O:22])[C:15]=3[C:24]=2[CH3:25])=[O:10])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)S(=O)(=O)CCS3(=O)=O)c1O
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Oc1c(C(=O)c2ccc3c(c2C)S(=O)(=O)CCS3(=O)=O)cnn1CC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
1.5 g (3.9 mmol) of 1-ethyl-5-hydroxy-4-(8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz[1,4]dithiin-7-yl)carbonylpyrazole were suspended in 20 ml of methylene chloride, and 0.42 g (3.9 mmol) of butyryl chloride and 0.39 g (0.42 mol) of triethylamine were added. After five hours of stirring at 20° C., the mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and water, dried and filtered off, and the solvent was distilled off. The residue was subsequently chromatographed over silica gel (mobile phase: ethyl acetate/cyclohexane=2/3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]2=1.[CH2:20](I)[CH3:21]>>[CH2:20]([N:12]1[C:11]2[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:21]
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: CCI
Product: CCn1c2c(c3cc(OC)ccc31)CSc1ccccc1-2

Procedure:
Following the procedure as in Example 33, using 8-methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (1.00 g, 3.75 mmol) and EtI (878 mg, 5.63 mmoL) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:47])([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38])#[N:33]>>[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:47])([F:48])([F:44])([F:45])[F:46])[CH:42]=1)[C:37]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]2[C:15]3[N:16]([N:17]=[C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=5)[CH:12]=4)[CH:14]=3)[C:18]([CH3:29])=[CH:19]2)[CH:22]=1)=[O:38])#[N:33]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(C#N)cc(S(F)(F)(F)(F)F)c6)ccc5C)cc(C)n4n3)cn2)cc1

Procedure:
100 mg (0.24 mmol) of the compound of Example 9A and 66 mg (0.24 mmol) of the compound of Example 23A were reacted and worked up analogously to the procedure of Example 48A. This gave 153 mg (77% pure, 73% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[C:3]1=[O:31].[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1Br)(=[O:34])[CH3:33]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:35][CH2:36][C:37]1[C:42]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:41][C:40]([F:57])=[CH:39][C:38]=1[C:6]1[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:20][N:19]=2)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 29.9 %

Procedure:
In a 10-mL glass vessel equipped with a magnetic stirring bar were placed 197f (244 mg, 0.58 mmol), 197d (200 mg, 0.46 mmol), Pd(PPh3)4 (33 mg, 0.030 mmol) in 2 N Na2CO3 (1 mL) and DME (2 mL). The vessel was sealed with a septum and placed into the microwave cavity. After the reaction mixture was stirred at 125° C. for 7 min., it was purified by flash chromatography (dichloromethane:methanol, 85:15) to give 30% (90 mg) of 197g as a solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Na].Cl[CH2:17]/[CH:18]=[CH:19]/[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31]>CN(C)C=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:17]/[CH:18]=[CH:19]/[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/COc1ccc(-n2ccnc2)cc1

Procedure:
A solution of 16.0 g of 4-(1H-imidazol-1-yl)phenol in 250 ml of dimethylformamide, is treated with 4.2 g of 60% NaH. To the suspension of the sodium salt, 23.5 g of (E)-2-[4-chloro-2-buten-1-yl)-1H-isoindole-1,3(2H)-dione is added, and the reaction mixture stirred and heated on the steam bath for 16 hours. The dimethylformamide is removed in vacuo, and the residue stirred with 250 ml of water. The insolubles are collected, washed with water, and dried. Recrystallization from ethanol gives the desired product as a solid, m.p. 170°-171° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1.CCCCCC>CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cccc(Br)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the general procedure Coupling-1 using 4-pyridinylboronic acid and 1,3-dibromobenzene. Flash chromatography (Hexane:EtOAc, 70:30) afforded the title compound.
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].C(=O)(O)[O-].[K+]>CCO.O>[Br:1][C:2]1[CH:8]=[C:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1
Reactant: C#CC(=O)OCC
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Br)no1
Yield: 78 %

Procedure:
Dibromoformaldoxime (407 mg, 2.07 mmol) (prepared via the procedure of J C Rohloff, et. al., Tetrahedron Lett 1992, 33:3113-6), and ethyl propiolate (311 mg, 3.17 mmol) were dissolved in 10 ml of 50% aqueous EtOH. While stirring, a solution of 243 mg (2.43 mmol) of potassium bicarbonate in 5 ml of water was added dropwise over 1 h. The resulting solution was stirred for an additional 4 h, diluted with 25 ml of water, and extracted with chloroform (3×25 ml). The combined organic extract was dried over sodium sulfate and concentrated in vacuo to a colourless oil, 345 mg (78% yield) as a 7:1 mixture of the 5- and 4-carboxylates.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1O)[CH3:17].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)/C(=C/c1ccc(O)c(OCC)c1)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
808 μL (4.8 mmol) of triflic anhydride are added to a solution of 1.5 g (4 mmol) of ethyl 2-[1-(3-ethoxy-4-hydroxyphenyl)meth-(E)-ylidene]butyrate and 1.6 mL (12 mmol) of triethylamine in 20 mL of dichloromethane at 0° C. The reaction mixture is stirred at room temperature for 1 hour. The reaction medium is hydrolyzed in sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 1.7 g (100%) of ethyl 2-[1-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)meth-(E)-ylidene]butyrate are obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(O)(=[O:13])C>>[CH3:9][C:5]1[C:6](=[O:13])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:10])[CH:4]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 51 %

Procedure:
500 mg of 2,3,5-trimethylphenol and 10 mg of RuCl3.3H2O was reacted in 5 ml of acetic acid in the same manner as in Example 1, followed by the same treatment as in Example 1, whereby 100 mg of unreacted starting material and 230 mg (51% yield) of trimethylbenzoquinone was obtained.