Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:44])[NH:33][C:34]4[C:39]([CH2:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:28][C:27]=3[CH3:45])[N:20]=2)[N:16]([CH3:46])[CH:15]=1)=[O:13])[CH3:2].C1C(=O)N([Br:54])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24]([Br:54])=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:44])[NH:33][C:34]4[C:39]([CH2:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42][CH3:43])=[CH:28][C:27]=3[CH3:45])[N:20]=2)[N:16]([CH3:46])[CH:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1ccc(Nc2nccc(-c3cc(C(=O)Nc4c(CC)cccc4CC)cn3C)n2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1NC(=O)c1ccc(Nc2ncc(Br)c(-c3cc(C(=O)Nc4c(CC)cccc4CC)cn3C)n2)c(C)c1

Procedure:
A solution of 5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (100 mg, 0.1626 mmol) and NBS (29 mg, 0.1626 mmol) in 7.5 mL of DMF was stirred at room temperature for 1 h. The mixture was then diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4 and the solvent removed under reduced pressure. The target product was purified by preparative HPLC (39.8 mg, 35%, Exact Mass: calculated 693.2547, found 693.2548) as well as 2-bromo-5-{2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (24.7 mg, 22%, Exact Mass: calculated 693.2547, found 693.2556.) and 2-bromo-5-{5-bromo-2-[4-(2,6-diethyl-phenylcarbamoyl)-2-methyl-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (8.1 mg, 6.5%, Exact Mass: calculated 771.1652, found 771.1653).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH:26]N(C)C)[C:21](OCC)=[O:22])=[CH:16][CH:15]=1)#[N:13].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:21]=2[OH:22])=[CH:16][CH:15]=1)#[N:13]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
Combined 6-hydrazinylnicotinic acid (6.00 g, 39.2 mmol) and ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (10.05 g, 41.1 mmol) and 2-propanol (80 mL) and treated with 1.85% hydrochloric acid (77 mL, 39.2 mmol). The reaction was stirred at room temperature for 16 h, then Hunig's base (34.1 mL, 196 mmol) was add to the suspension which became homogeneous. The mixture was stirred for 3 h. The reaction mixture was washed with isopropyl acetate (2×150 mL). The combined organic layers were extracted with water (40 mL) and the combined aqueous layers were concentrated in vacuo to give a solid. The solid was triturated with 1N HCl (300 mL), filtered and washed with water (20 mL), then slurried in ethanol (350 mL) and granulated overnight. The solid was collected by filtration and dried in vacuum to give the title compound (9.20 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=8.34 Hz, 2H) 8.14 (br. s., 2H) 8.47 (d, J=7.07 Hz, 1H) 8.71 (br. s., 2H) 8.97 (s, 1H) 13.44 (br. s., 1H) 13.60 (br. s., 1H). MS [M+H]307.
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[C:15]2[C:10](=[C:11](OC)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.C[OH:19]>ClCCl>[BrH:2].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc2c(Cl)ccnc12
Reactant: CO
Solvent: ClCCl
Product: Br
Product: Oc1ccc2nccc(Cl)c2c1
Reaction time: 8 h
Yield: 86 %

Procedure:
In a flame dried three-neck 50 mL round bottom flask equipped with a rubber septum and a mechanical stirrer, and under a nitrogen atmosphere at room temperature, 4.0 mL of 1.0M boron tribromide in dichloromethane (Aldrich Chemical Co.) was added portionwise through gas tight syringe to a solution of 727 mg (3.75 mmol) of 4-chloro-8-methoxyquinoline and 5.0 mL of dichloromethane. A thick solid formed immediately and after 0.5 hour of stirring another 4.0 mL portion of boron tribromide solution was added and stirring was continued overnight. The reaction mixture was treated dropwise with methanol. The solution was evaporated under reduced pressure, and the residue titurated with dichloromethane and filtered to afford 844 mg (86%) of the title compound: m.p. 243°-244° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:42](Cl)Cl.CO.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:42][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1
Reactant: ClCCl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6ccccc6)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-{3-[2-(1,2,3,4-tetrahydro-7-isoquinolinylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)benzamide (107 mg, 0.199 mmol) in 2:1 DCM/MeOH (1.5 mL) was added 37% aq. formaldehyde (50 μL, 0.67 mmol), glacial acetic acid (13 μL) and sodium triacetoxyborohydride (64 mg, 0.30 mmol). The mixture was stirred at rt for 1 h. The mixture was worked up by removal of solvent with a totary evaporator and partitioning the residue between saturated aq. NaHCO3 and 5:1 CHCl3/isopropanol. The organic layer was separated, dried and concentrated to give 67 mg of crude material. Purification by silica gel chromatography (0 to 30% methanol in DCM) afforded 60.4 mg of the title compound as a cream-colored solid. LCMS (ES)+ 552.3. 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 2.57 (bs, 2H), 2.72 (m, 2H), 3.39 (s, 2H), 6.49 (d, 1H, J=5.6), 6.95 (d, 1H, J=8.0, 7.10 (t, 1H, J=6.8), 7.28 (d, 1H, J=8.0), 7.37 (d, 1H, J=8.0), 7.42-7.56 (m, 5H), 7.93 (d, 2H, J=7.2), 8.11 (s, 1H), 8.22 (d, 1H, J=5.6), 8.45 (d, 1H, J=8.8), 8.81 (d, 1H, J=7.2, 9.41 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[CH3:30][C:24]1[C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:20]([CH3:19])[C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Solvent: CCO
Product: Cc1cc(C)c(C)c(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1C
Product: Cl
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,3,5,6-tetramethylbenzyl chloride (287 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 177 mg of the product 236. 1H NMR (DMSO-d6) δ 11.33 (s, 2H), 7.25-6.95 (m, 11H), 5.86 (s, 2H), 4.84 (s, 2H), 2.35 (s, 6H), 2.21 (s, 6H); MS: m/z 401 (M++1).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:22][F:23])[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:5]=2[O:4]1.[OH-].[K+].Cl>C(O)C>[F:23][CH2:22][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:5]=2[O:4]1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 0.51 g of ethyl 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylate, 0.13 g of potassium hydroxide and 10 ml of ethyl alcohol was stirred at room temperature for 2 hours. Ice water and hydrochloric acid were added to the reaction mixture, and the precipitated crystals were separated by filtration to obtain 0.43 g of 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][NH:5]C(=O)C1C=C(CC)C(OC)=NC=1C)(=[O:3])[CH3:2].S(Cl)([C:22]1[CH:28]=[CH:27][C:25](C)=[CH:24][CH:23]=1)(=O)=O.C([N:34]=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[CH3:2][C:1]1[O:3][C:22]([C:28]2[CH:27]=[CH:25][CH:24]=[CH:23][N:34]=2)=[N:5][N:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(C(=O)NNC(C)=O)c(C)nc1OC
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccccn2)o1
Temperature: 145 °C
Reaction time: 0.05 h
Yield: 73 %

Procedure:
Into each of two microwave vials is added 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-acetyl-hydrazide (100 mg), tosyl chloride (64 mg, 0.336 mmol), and 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol/g, 634 mg, 1.39 mmol) and anhydrous tetrahydrofuran (6 mL). Each vial is flushed with nitrogen, sealed and heated in the CEM Discover microwave at 145° C. holding at that temperature for 3 min, with a maximum pressure of 6.5 bar. LC/MS shows the reaction is complete. The product from both the vials are combined and evaporated, and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined and the solvent evaporated and further purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined again and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl-pyridine (95 mg, 73% yield, 2 steps). MS: m/e=234 (M+H); 1H NMR (CDCl3, δ, ppm): 7.86 (1H, s), 4.00 (3H, s), 2.79 (3H, s), 2.55-2.65 (5H, m), 1.21 (3H, t).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[H-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.[OH-].[Na+]>CN1C(=O)CCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])=[N:14][CH:15]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCCN1CCO
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCN1CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
2.45 g (19 mmol) of 1-(2-hydroxyethyl)-pyrrolidin-2-one and 0.83 g (19 mmol) of sodium hydride (55% in mineral oil) in 10 ml of NMP were stirred at room temperature for 1 h. 3.0 g (12.7 mmol) of 2,5-dibromopyridine were added, and the mixture was heated to 80° C. for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and concentrated. The remaining oil was taken up in 200 ml of tert-butyl methyl ether and treated with a solution of hydrogen chloride in diethyl ether. The resulting greasy solid was isolated by decantation of the solvent and treated with a 25% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Yield: 2.75 g.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11](Br)([F:13])[F:12].O>CN(C=O)C>[Br:10][C:11]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:13])[F:12]
Reactant: FC(F)(Br)Br
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(Br)Sc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a three-necked round-bottomed flask placed under a nitrogen atmosphere, topped with a dry-ice condenser and a dropping funnel, thiophenol (10.2 ml, 100 mmol) was added dropwise, over 40 min at 0° C., to a suspension of NaH (6 g, 150 mmol) in anhydrous DMF (100 ml). The mixture was then stirred at 0° C. for 30 min then cooled to −50° C. Dibromodifluoromethane (27 ml, 300 mmol) was then added at −50° C. The mixture was then stirred for 3 h at this temperature, then 30 min at ambient temperature. Water (100 ml) was added to the reaction mixture, then the product was extracted with ethyl ether (3×100 ml). The organic phases were washed with water (3×100 ml) and dried over MgSO4. After evaporation of the solvent, the residue was purified by distillation under reduced pressure (97° C./34 mmHg) to give the product [(bromodifluoromethyl)sulfanyl]benzene in the form of a colorless liquid (15.3 g, 60%).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14]Br)[C:10]=2[CH:16]=1>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[C:11]([CH2:14][C:1]#[N:2])[C:10]=2[CH:16]=1
Reactant: BrCc1csc2ccc(Br)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1csc2ccc(Br)cc12
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 0.115 gm (2.34 mMol) sodium cyanide, 2 mL ethanol and 1 mL water was heated to reflux. To this refluxing mixture was added a solution of 0.356 gm (1.16 mMol) 5-bromo-3-(bromomethyl)benzothiophene in 4 mL ethanol. The resulting mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 10% dichloromethane and 5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.214 gm (73%) of the desired nitrile as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:55]([NH:57][CH2:58][CH3:59])[CH3:56].C1C[O:63]CC1>>[CH:46]([OH:47])=[O:63].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:46][N:57]([CH2:58][CH3:59])[CH2:55][CH3:56])[CH:42]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCNCC
Reactant: C1CCOC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: CCN(CC)CCOc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and diethylamine (34 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional diethylamine (102 μL, 0.99 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (22 mg, 45%). LCMS (Method 5): Rt 3.74 min, m/z 734.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.89-0.96 (WA, m), 1.28 (9H, s), 1.46-1.56 (2H, m), 1.62-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.18 (2H, m), 2.52 (4H, m, obscured by solvent), 2.76 (2H, t, J=8.0 Hz), 2.87-2.94 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.30 (1H, m, obscured by water), 4.05 (2H, t, J=8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.05-7.13 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.19 (1H, s).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[CH2:13]([CH:15]([CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].IC(C)C.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH2:13]([C:15]([CH:5]([CH3:6])[CH3:7])([CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C(CC)C(CC)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)I
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC)C(CC)(C(=O)OCC)C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 10 mL (72 mmol) of diisopropylamine in 250 mL of tetrahydrofuran (THF) was added 28.6 mL (72 mmol) of BuLi (2.5 molar in cyclohexanes) at −20° C. After 20 minutes stirring, 9.2 g (83% pure) (28.3 mmol) of diethyl 2,3-diethylsuccinate was added at −40° C. and after addition the mixture was stirred for 2 h at room temperature. Then this mixture was cooled to −70° C. and a mixture of 4.3 mL (43 mmol) of 2-iodopropane and 7.4 mL (43 mmol) of hexamethylphosphoramide (HMPA) was added. After addition the cooling was removed and the mixture was stirred for four days. The volatiles were removed and 250 mL of ether was added. The organic layer was washed twice with 100 mL of water. The organic layer was isolated, dried over MgSO4, filtered and concentrated in vacuo yielding an orange oil. This oil was chromatographed over silica with CH2Cl2 yielding 2.3 g (30%) of a 96% pure product. According to gaschromatography (GC) only one isomer was present.
Reaction SMILES: [CH2:1]1[CH:14]2[CH:5]([C:6](=[O:16])[C:7]3[C:12]([C:13]2=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH:3]=[CH:2]1>[Pd].C1(C)C=CC=CC=1>[CH2:4]1[C:5]2[C:14](=[C:13]([OH:15])[C:12]3[C:7]([C:6]=2[OH:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1.[CH2:4]1[CH:5]2[CH:14]([C:13](=[O:15])[C:12]3[C:7]([C:6]2=[O:16])=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:1][CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)C2CC=CCC12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)C2CCCCC12
Product: Oc1c2c(c(O)c3ccccc13)CCCC2

Procedure:
The operation is as in Example 1, except for using 63.6 g of 1,4,4a,9a-tetrahydro-anthraquinone, 150 cc of toluene and 0.4 g of palladium catalyst. After 3 hours at 80° C. under 100 bars pressure, 7 g of 1,2,3,4-tetrahydro-9,10-anthracene-diol and 57 g of 1,2,3,4,4a,9a-hexahydro-9,10-anthracene-dione are obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[NH:8][C:7](=[O:9])[C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:5]=1.[NH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25](O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]([N:12]1[CH2:13][CH2:14][C:6]2([N:5]=[C:4]([CH2:3][S:2][CH3:1])[NH:8][C:7]2=[O:9])[CH2:10][CH2:11]1)=[O:26]
Reactant: Nc1sc2ccccc2c1C(=O)O
Reactant: CSCC1=NC2(CCNCC2)C(=O)N1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CSCC1=NC2(CCN(C(=O)c3c(N)sc4ccccc34)CC2)C(=O)N1

Procedure:
A solution of 3A (1.0 equivalent) in DMF (0.12 M) along with a 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 equivalent) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with brine and dried over Na2SO4, and volatiles removed under reduced pressure. Residue purified by LCMS to afford 8-(2-aminobenzo[b]thiophene-3-carbonyl)-2-(methylthiomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2B).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(=O)O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A solution of 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.4 g) in glacial acetic acid (20 mL) is treated with sulfamic acid (0.82 g) at room temperature and stirred for 10 minutes. The resulting yellow solution is cooled to 0° C. and treated with a solution of sodium chlorite (0.69 g of an 80% pure sample) in water (20 mL) during 10 minutes. The resulting yellow suspension is stirred at room temperature for 3 hours, poured into water (100 mL) and filtered to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g), in the form of a white solid. [NMR (CDCl3):—7.46 (d, 1H, J=8 Hz), 6.65 (d, 1H, J=12 Hz), 4.80-0.76 (m, 1H), 3.90 (s, 3H), 2.01-1.58 (m, 8H)].
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]#[N:16].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.C[OH:37]>C(#N)C.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>[F:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[C:5]1[O:6][C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[C:3]([C:15]([NH2:16])=[O:37])[N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CO
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccccn1
Temperature: 150 °C
Yield: 58 %

Procedure:
A mixture of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.050 g, 0.16 mmol), tri-n-butyl(2-pyridyl)tin (0.120 g, 0.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.008 mmol) in acetonitrile (2.5 mL) was heated in the microwave for 15 minutes at 150° C. The reaction was diluted with MeOH and passed through a MP-SH resin cartridge (0.5 g), then purified by SPE using a MP-TsOH resin (500 mg) cartridge and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(pyridin-2-yl)oxazole-4-carboxamide (0.029 g, 0.10 mmol, 58%) as a white solid. 1H NMR (DMSO) 7.41 (2H, t), 7.55 (1H, ddd), 7.76 (1H, m), 7.88 (1H, br. s), 8.06 (1H, ddd), 8.32 (1H, dt), 8.77 (1H, ddd), 9.10 (1H, br. s). LCMS (2) Rt: 2.23 min; m/z (ES+) 302.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.C1COCC1>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4′-Nitro-biphenyl-4-sulfonic acid (1.12 g, 4 mmol) was mixed with tin (II) chloride (5.2 g, 32 mmol) and 40 ml of THF. The mixture was refluxed overnight. The reaction mixture was poured into 80 ml of water and stirred at room temperature for 8 h. The mixture was filtered and the solid was dried under vacuum to provide 0.73 g (73%) of 4′-amino-biphenyl-4-sulfonic acid, obtained as an off-white solid.