Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2nccn2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2nccn2)nc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
31.9 mg (corresponding to 0.170 mmol) of 5-acetyl-2-(2H-1,2,3-triazole-2-yl)pyridine was dissolved in 1.0 mL of dichloromethane and 71 μL of triethylamine, and then 44.1 μL (corresponding to 0.51 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then, the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 1.0 mL of tetrahydrofuran, and 33.3 mg (corresponding to 0.17 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 20.2 mg (corresponding to 0.076 mmol) of 5-(2-bromoacetyl)-2-(2H-1,2,3-triazole-2-yl)pyridine (FIG. 2, step 2).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C(OC(=O)C)(=O)C>[CH3:28][C:27]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:29]
Reactant: CC(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (10 (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([C:14]([NH:16][C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[CH:20][N:21]=2)=O)=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([NH:8][C:9]1[S:10][C:11]([CH2:14][NH:16][C:17]2[S:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[CH:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cnc(NCc4ccccc4)s3)s2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc(NCc3cnc(NCc4ccccc4)s3)s2)cc1
Yield: 18.2 %

Procedure:
BMS (0.2 mL, 2.1 mmol) was added to a solution of 2-(benzylamino)-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (170 mg, 0.42 mmol) in THF (6 mL) at RT. The resulting solution was stirred at reflux overnight. The reaction was then quenched with MeOH (2 mL) and 1N HCl was added until the pH reached 2. After stirring the reaction mixture at reflux temperature for 12 hrs, the organic solvents were evaporated and the aqueous solution was neutralized with 1N NaOH, extracted with CHCl3, dried with Na2SO4 and concentrated. The crude product was purified by column (AcOEt), yielding N-benzyl-5-((5-p-tolylthiazol-2-ylamino)methyl)thiazol-2-amine (30 mg, 18%).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:43][N:44]([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=O)[C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(OC)(C)(C)C>O1CCCC1.O>[CH3:43][N:44]([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: c1ccc(CCCCCCCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(CCCCC=O)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCCC=CCCCCCCCCCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Compound 12 (6.5 g) was dissolved in tetrahydrofuran (18 mL). Potassium-tert-butoxide (1.2 g) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. After cooling the reaction solution to 0° C., the solution of Compound 14 (1.7 g) in tetrahydrofran (3 mL) was added drop wise thereto, followed by the stirring at the same temperature for 2 hours. To the reaction solution, tert-butylmethylether (40 mL) and water (30 mL) were added. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethylacetate=1:1→1:2) to obtain the title compound (2.7 g) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH3:11]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)c1cccc(Br)n1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc(Br)n1
Temperature: 70 °C
Yield: 45 %

Procedure:
6-Bromopicolinic acid (1000 mg, 4.95 mmol) was suspended in thionyl chloride (15 mL) and heated at 70° C. for 5 h. The reaction was cooled to room temperature and the volatiles were condensed under reduced pressure. A solution of ammonia (2M in dioxane (15 mL) was added to the residue and then the solvents were removed under reduced pressure. The crude residue was purified by MPLC with a gradient of 0 to 20% MeOH/dichloromethane to give 6-Bromo-pyridine-2-carboxylic acid amide as a white powder (555 mg, 45%). MS ES (MH+=201.0/203.0).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:15][CH3:16])=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:15][CH3:16])=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:24][N:23]=[N:22][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(CC#N)cccc1OCc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1c(Cc2nnn[nH]2)cccc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-dimethylbenzyloxy)-2-methoxyphenyl)acetonitrile (Step D, 3.2 g, 12.7 mmol), sodium azide (0.86 g, 13.2 mmol) and ammonium chloride (0.696 g, 13.0 mmol) in dry DMF (10 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, and concentrated under reduced pressure and purified by flash chromatography on a silica gel column (chloroform:methanol 9:1) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:13][C:14]#[C:15][CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[NH:20][C:19]2[CH:29]=[CH:30][CH:31]=[N:32][C:18]1=2)[CH2:4][CH3:5])[CH3:2].C.[H][H].N>C(O)C.[Pd].ClCCl.C1CCCCC1.CO>[CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[NH:20][C:19]2[CH:29]=[CH:30][CH:31]=[N:32][C:18]1=2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC1CCCCN1CC#CCN1c2ccccc2C(=O)Nc2cccnc21
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCN(CC)CC1CCCCN1CCCCN1c2ccccc2C(=O)Nc2cccnc21

Procedure:
4.3 g (0.01 mol) of 11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-but-2-ynyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were dissolved in 40 ml of ethanol and after the addition of 0.5 g of 10% palladium on animal charcoal the mixture was hydrogenated under 3 bar of hydrogen pressure and at ambient temperature until the uptake of hydrogen had ceased. The mixture was filtered, the filtrate was evaporated down in a water jet vacuum and the oily residue remaining was purified by column chromatography on silica gel (Macherey-Nagel 60, 0.063-0.2 mm) using firstly ethyl acetate, then ethyl acetate/methanol/conc. ammonia 90/10/2 as eluant. From the fractions, after evaporation of the solvent and recrystallisation of the residue from diisopropyl ether, colourless crystals were obtained, m.p. 112° C., RF 0.75 (Merck, ready-made TLC plates, silica gel 60F-254; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2 v/v/v/v). Yield: 2.2 g (50.5% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>O>[Br:19][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 184 %

Procedure:
A 5000 mL, three neck round bottom flask (RBF) equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated H2SO4 (600 mL). To this solution was added 1,3-dibromo-5,5 dimethylhydantoin (130.7 g, 0.455 mol) over ten minutes with vigorous stirring. The reaction was vigorously stirred at ambient temperature for 5 hours. The reaction mixture was then added to water (4000 mL), and the mixture was cooled in an ice bath over 30 minutes. This mixture was then filtered, and the solids were washed twice with water and further dried under vacuum to yield 217.7 g (99.8%) of an off-white solid. 1H NMR (CDCl3) δ 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:19])[CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:20].[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].Cl>C(Cl)Cl.N1C=CC=CC=1>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:19][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:21])=[O:23])=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c3ccc(O)cc3c3ccccc3c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c3ccc(OS(=O)(=O)C(F)(F)F)cc3c3ccccc3c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triphenylene-2,7-diol (314 mg, 1.2 mmol) was dissolved in DCM (13 mL) and pyridine (1 mL). The solution was cooled to 0° C. and Tf2O (0.48 mL, 2.65 mmol) was added dropwise. After stirring for 2 h, the reaction mixture was poured into HCl (1N) and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated. Taken on crude.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:34]([C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)=[O:35])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(NC2CCN(CC3CCCCC3)CC2)nc1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CC3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine (216 mg) prepared in Preparation Example 1A-1 and triethylamine (152 mg) in dichloromethane (3 mL) was added 2-furoyl chloride (0.11 mL) dropwise under ice cooling. The solution was stirred at room temperature for 18 hours. Silica gel (NH silica gel) was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound as a colorless crystal (271 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19]C(C)=O.C(P(C(C)(C)C)C1(C)CC=CC=C1C1C=CC=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:25]([O:24][C:18](=[O:23])[CH2:19][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[CH3:26]
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: CCOC(=O)CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC=CC=C1c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 90 °C

Procedure:
The title A compound, 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (5.00 g, 15.663 mmol), ethyl acetoacetate (2.97 mL, 23.495 mmol), 2-(di-tert-butylphosphino)-2-methyl biphenyl (98 mg, 0.313 mmol), palladium acetate (105 mg, 0.157 mmol) and potassium phosphate (9.97 g, 46.989 mmol) are charged to a flask. Toluene (60 mL) is added. The reaction is heated at 90° C. overnight, then cooled to RT. The reaction mixture is poured onto ethyl acetate and water. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown oil. This is chromatographed using 0→20% methanol in ethyl acetate to afford [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as a tan solid which contains ˜8% of the acylated material: LC/MS 327.1 (M+1); 1H NMR (400 MHz, DMSO-D6) δ 1.2 (t, J=7.1 Hz, 3 H) 2.1 (s, 3 H) 2.3 (m, 4 H) 2.9 (d, J=4.3 Hz, 4 H) 3.8 (s, 2 H) 4.1 (q, J=7.1 Hz, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.6 (d, 7.7 (m, 2 H). C. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic Acid Ethyl ester
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].C(=O)(O)[O-].[Na+]>CCOCC>[CH:7]1[C:6]([C:4]([CH2:3][Br:1])=[O:5])=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 1 h
Yield: 655.7 %

Procedure:
Bromine (1 7.6 g, 1 10 mmol) was added dropwise to a 0° C. solution of 4-hydroxyacetophenone (15 g, 110 mmol) in ether (200 mL) over 20 minutes. The mixture was stirred for 1 hour. and poured carefully into saturated sodium bicarbonate solution (500 mL). The organics were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was then recrystallized from ether to afford the title compound (14.1 g).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:24](=[O:37])[CH:23]=[CH:22]4)=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[N+](=[CH2:41])=[N-]>C(OCC)C>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:41][CH:18]3[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:24](=[O:37])[CH:23]=[CH:22]4)=[CH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: C=[N+]=[N-]
Reactant: C[Si](C)(C)CCOCn1c(=O)ccc2cc(/C=C/c3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc21
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(C3CC3c3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc21
Temperature: -10 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a stirred solution of (E)-6-(2-(2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (0.15 g, 0.280 mmol) in diethyl ether (10 mL) was added PdOAc2 (6.28 mg, 0.028 mmol). The reaction mixture was cooled to −10° C., and a cold solution of diazomethane in ether (generated from aqueous KOH (0.45 g) and NMU (0.6 g) at −15° C.) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through celite, diluted with diethyl ether, and washed with water and saturated NaCl solution. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel column using 15% ethyl acetate in hexane to give 6-(2-(2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one as a yellow gum (0.075 g, 49%). LCMS: RT 2.317 min, (M+H) 551.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[C:4](=[O:5])[O:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CS(C)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:20]/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[C:4](=[O:5])[O:3][CH:2]3[OH:1])=[CH:17][CH:16]=1
Reactant: O=C1OC(O)c2cc(Br)ccc21
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/c2ccc3c(c2)C(O)OC3=O)cc1
Reaction time: 5 h

Procedure:
A mixture of 9.9 gm 3-hydroxy-5-bromophthalide, 5.8 gm p-methoxystyrene, 0.09 gm palladium acetate, 0.47 gm tri-(o-tolyl)-phosphine, 7 ml triethylamine and 35 ml dimethylsulfoxide were heated with stirring at 95° for 5 hours. The reaction mixture was cooled and added to 400 ml water. The product was extracted into ethyl acetate, which solution was washed with water and dried over magnesium sulfate. Removal of solvent left 8.0 gm yellow solid melting at 140°-148°.
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:12])[NH:8][CH2:9][C:10]#[CH:11])[C:3]([O:5][CH3:6])=[O:4]>CC#N>[CH3:11][C:10]1[O:12][C:7]([CH:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[N:8][CH:9]=1
Reactant: C#CCNC(=O)C(C)C(=O)OC
Solvent: CC#N
Product: COC(=O)C(C)c1ncc(C)o1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To the intermediate from Step A (1.46 g, 8.63 mmol) in 20 mL of CH3CN at room temperature was added a solution of AuCl3 (0.262 g, 0.863 mmol) in 5 mL of CH3CN. The resulting mixture was stirred at 50° C. for 14 hours and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product (pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 6.78 (1H, s), 4.07 (1H, q, J=7.4 Hz), 3.79 (3H, s), 2.37 (3H, s), 1.67 (3H, d, J=7.5 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>C1COCC1.[C].[Pd]>[CH:20]([N:18]1[N:17]=[N:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:19]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1nnc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
To a solution of 5-(4-benzyloxyphenyl)-2-isopropyl-2H-tetrazole (521 mg) in THF (5 mL)-methanol (5 mL) was added 7.5% palladium-carbon (60 mg). The mixture was stirred at room temperature for 3.5 hours under hydrogen atmosphere. The catalyst was filtered off through a Celite pad. The filtrate was concentrated to give the title compound (352 mg).
Reaction SMILES: [Sn](Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2(O)[C:27]3[C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[S:24][C:23]=3[C:22]([C:33]#[C:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)(O)[C:21]3[C:20]4[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=4[S:18][C:17]2=3)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C(O)(=O)C.CC(C)=O>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:34]#[C:33][C:22]2[C:21]3[C:20]4[CH:45]=[CH:46][CH:47]=[CH:48][C:19]=4[S:18][C:17]=3[C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([C:4]([CH3:6])([CH3:5])[CH3:7])=[CH:9][CH:10]=3)=[C:27]3[C:23]=2[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=23)=[CH:36][CH:37]=1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1ccc(C#CC2(O)c3sc4ccccc4c3C(O)(C#Cc3ccc(C(C)(C)C)cc3)c3sc4ccccc4c32)cc1
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C#Cc2c3sc4ccccc4c3c(C#Cc3ccc(C(C)(C)C)cc3)c3sc4ccccc4c23)cc1
Temperature: 8 °C

Procedure:
A solution of tin(II)chloride dehydrate (1.82 g, 8.05 mmol) in glacial acetic acid (30 ml) is added within ten minutes to a solution of 6,12-bis-(4-tert-butyl-phenylethynyl)-6,12-dihydro-dibenzo[d,d′]benzo[1,2-b;4,5-b′]dithiophene-6,12-diol (educt 2) in acetone (30 ml). There is a slight temperature increase (8° C.), and formation of a yellow suspension takes place. This suspension is stirred over night at ambient temperature, and then the solid is filtered off. The solid is then washed with water/glacial acetic acid (twice, 30 ml 1:1 v:v), water (twice with 30 ml), and twice with acetone (30 ml). The residue is then dried to give crude product which is recrystallised from anisol (65 ml). The product is filtered off, washed with anisol (8 ml), toluene (2 times 8 ml) and hexane (twice ca. 10 ml) and dried to give the title product as yellow crystals. Mp. (DSC) 349-350° C., MS (m/z 602 (100%), correct isotopic pattern), elementary analysis: C, 84.61%; (calcd. 83.68%); H, 5.89%; (calcd. 5.68%). 1H-NMR (CDCl3, 300 MHz) δ 1.33 (s, 9H, C(CH3)3); 7.41-7.47 (m, 4H, 2 Ph H, 2 benzothiophene H); 7.66 (AA′BB′, 2H, 2 Ph H); 7.84 (m, 1H), 9.15 (m, 1H) (2 benzothiophene H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][C@@H:33]([OH:34])[C@H:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available acetyl chloride the title compound is obtained as colorless solid.