Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[CH3:20].O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:12]1[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Yield: 86.7 %

Procedure:
N-bromosuccinimide (590 mg, 3.30 mmol) was added to a solution of 1-methoxy-2-methyl-3-nitro-benzene (500 mg, 3.0 mmol) in carbon tetrachloride (5 mL) followed by a catalytic amount of dibenzoyl peroxide (25 mg). The reaction mixture was heated at reflux for 3 h then cooled to room temperature and poured into water. The organic phase was separated, washed with water (2×20 mL), dried over the anhydrous sodium sulfate and concentrated in vacuo to afford 2-(bromomethyl)-1-methoxy-3-nitro-benzene (640 mg, 86%) as a solid.
Reaction SMILES: [C:1]1(/[C:7](/[CH3:14])=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:14]/[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)/C=C(\C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(/CBr)c1ccccc1
Temperature: 75 °C

Procedure:
A mixture of 14 g (74 mmol) of ethyl (E)-3-phenylbut-2-enoate, 0.47 g of 2,2′-azobis(2-methylpropionitrile) and 330 ml of carbon tetrachloride is heated to 75° C. 19.8 g (111 mmol) of N-bromosuccinimide are added portionwise at this temperature. The mixture is then refluxed for five hours. The insoluble material is filtered off at 25° C. The filtrate is washed with water and dried over Na2SO4; the solvents are evaporated off (orange-coloured oil: 19.7 g; 99%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[C:20]2[S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1>[CH:18]1[C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][C:20]=2[C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1
Reactant: Ic1cccc2c1sc1ccccc12
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
Carbazole (0.62 g, 3.67 mmol) and 4-iododibenzothiophene (1.2 g, 3.87 mmol) were mixed in 70 mL of dry xylene. The solution was bubbled nitrogen while stirring for 15 minutes. Pdz(dba)3 (0.16 g, 0.17 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.24 g, 0.58 mmol) and sodium tert-butoxide (1.0 g, 10.4 mmol) were added in sequence. The mixture was heated to reflux for 3 days under nitrogen. After cooling, the reaction mixture was filtered through a Celite®/silica pad and the solvent was then evaporated. The residue was then purified by column chromatography using DCM:hexane (1:4, v/v) as the eluent to obtain 0.64 g of product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:21]([CH3:20])[C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CNC1CCCCC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Product: CN(c1cccc2nc(NC(=O)c3cccnc3)nn12)C1CCCCC1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 55 mg; 0.20 mmol; 1.0 eq.) and N-methylcyclohexylamine (1.0 mL) as an off white solid (30 mg, 43%). HPLC, Rt: 2.67 min. (purity 97.8%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[Br:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.CN(C)C=CC1NC(=O)C=CC=1C#N.CN(C)C=O>O.[OH-].[Na+].CN1CCCC1=O>[Br:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[CH:18]=1
Reactant: Brc1c[nH]cn1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Agent: CN(C)C=Cc1[nH]c(=O)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=c1ccc2c(-n3cnc(Br)c3)nccc2[nH]1
Yield: 70.8 %

Procedure:
A stirred mixture containing 11.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 16.6 g of 4-bromo-1H-imidazole and 100 ml of N-methylpyrrolidinone was heated in an oil bath at 135°-140° C. for 22 hours. The reaction mixture was cooled and diluted with 200 ml of water. The resulting precipitate was collected, washed with water, air-dried, combined with 1.5 g of 5-(4-bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one prepared in another run starting with 1 58 g of 5-bromo-1,6-naphthyridin-2(1H)-one, recrystallized twice from dimethylformamide and dried in an Abderhalden drying pistol at 90° for 22 hours, after which the sample still contained 0.2 mol of dimethylformamide per mol of product. The material was then dissolved in 100 ml of 5% aqueous sodium hydroxide solution, the solution filtered and the filtrate solidified with acetic acid. The cottony solid that crystallized out was collected, washed with distilled water and dried in an oven at 100° C. over the weekend to produce 10.3 g of 5-(4-bromo-1H-imidazol-1-yl)- 1,6-naphthyridin-2(1H)-one, m.p. 278°-280° C.
Reaction SMILES: O[CH:2]1[O:6][C:5](=[O:7])[CH:4]=[C:3]1[CH3:8].C(N(CC)CC)C.[CH3:16][C:17]([CH:39]=[CH:40][C:41]1[C:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][CH2:43][C:42]=1[CH3:49])=[CH:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Mg+2].[Cl-]>CCCCCCC.CN(C)C(=O)C>[CH3:49][C:42]1[CH2:43][CH2:44][CH2:45][C:46]([CH3:47])([CH3:48])[C:41]=1/[CH:40]=[CH:39]/[C:17](/[CH3:16])=[CH:18]/[CH:19]=[CH:2]/[C:3](/[CH3:8])=[CH:4]\[C:5]([OH:6])=[O:7]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=CC(=O)OC1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)CCC1
Temperature: 15 °C
Reaction time: 17 h

Procedure:
N,N-dimethylacetamide (300 milliliters (mL)) , 5-hydroxy-4-methyl-2[5H]-furanone (26.81 grams (g)), 235 millimoles (mmol), 1.2 equivalents), and triethylamine (164 mL,1.2 moles, 6 equivalents) were added to 107.26 g (197 mmol) of [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl] triphenyl phosphonium salt. The resulting mixture was cooled to 15° C. prior to addition of magnesium chloride (30.03 g, 315 mmol, 1.6 equivalents). The reaction mixture was allowed to stir at room temperature for 17 hours. The reaction solution was washed with 200 mL of heptane. Toluene (100 mL) was added and the solution was acidified with 280 mL of 20% by volume HCl . The aqueous layer was back-extracted three times, each time with 200 mL of a 9:1 heptane:toluene mixture. The combined organic layers were washed with aqueous methanol, water, and then concentrated to give an orange solid. Heptane (250 mL) was added to the crude solid and the slurry was cooled to 0° C. and then filtered. Acetone (200 mL) and heptane (800 mL) were added to the solid and the resulting mixture was stirred at 25° C. Filtration of this slurry provided isotretinoin with >98% purity as a solid. 1H NMR: (300 MHz, CDCl3):δ 1.03(s,6; H), 1.44-1.68(m,4H), 1.72(s,3H), 1.88-2.05(m,2H), 2.0(s,3H), 2.11 (d,3H), 5.67(s,1H), 6.15-6.32(m,3H), 7.03 (dd,1H), 7.76 (d,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>O1CCCC1.CO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:13]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of the 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) was stirred at 0 degrees Centigrade while a solution of 7N ammonia in methanol (23 mL) was added. The reaction turned deep red and was stirred overnight in a sealed tube. The mixture was filtered to remove NH4F and the solvent removed to give a red-orange solid which was purified by silica gel chromatography using 2:1 hexanes/ethyl acetate to give 6.27 g of 3,5-difluoro-2-nitroaniline.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>ClCCl>[F:1][C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: [F-]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C#CCl)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CF)cc2)CC1
Reaction time: 24 h

Procedure:
110 ml of 1 molar solution of tetrabutylammonium fluoride in dichloromethane are added at 0° C. to a solution of 28.85 g (0.1 mol) of 1-(2-chloroethynyl)-4-(trans-4-pentylcyclohexyl)benzene in 150 ml of dichloromethane. The reaction mixture is boiled for 24 hours and evaporated in vacuo, and the residue is then extracted with 3×150 ml of petroleum ether (30°-50° C.). The combined petroleum ether phases are dried over magnesium sulphate and evaporated. The product is obtained from the resultant residue by chromatography using petroleum ether as eluent.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>ClCCl>[C:41]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:30][CH3:31])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:25][CH2:26]1)(=[O:43])[CH3:42]
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
4-[(4-Fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-ylmethoxy)quinazoline (210 mg, 0.50 mmol) was suspended in dichloromethane (7 ml) and diisopropylethylamine (104 μl, 0.60 mmol) and acetyl chloride (42 μl, 0.60 mmol) were added. All solid material went into solution. The mixture was stirred at ambient temperature overnight. The mixture was washed with brine, followed by saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 6-[(1-acetylpiperdin-4-yl)methoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (146 mg, 63%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH:30](O)[CH3:31])=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:30]([CH3:31])[CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:33])[F:34])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: CC(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OC(C)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 d], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) was reacted with [rac]-6-(4-trifluoromethoxy-phenyl)-hex-5-yn-2-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]([O:21]CC)=O)=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[C:8]1[C:16]([CH:17]=2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1.[NH2:24][NH2:25]>>[CH3:1][C:2]1[C:3]([C:19]([NH:24][NH2:25])=[O:21])=[N:4][C:5]2[C:6]=1[C:7]([CH3:18])=[CH:8][C:16]1[C:17]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: NN
Reactant: CCOC(=O)C1=Nc2cc3c(c(C)c2=C1C)N=c1ccccc1=3
Product: CC1=c2c(C)cc3c(c2N=C1C(=O)NN)N=c1ccccc1=3
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethyl 3,4-dimethylpyrrolo[3,2-b]carbazole-2-carboxylate (500 mg) and 95% hydrazine (5 cm3) were stirred and heated at 120° C. for 6 h in a Readi-Vial. The mixture was allowed to stand overnight, cooled in ice and filtered. The resulting yellow solid was washed carefully with water and dried. Yield of title compound 350 mg (73%), no sharp m.p. but decomposes at 285° C. (Found: C, 69;19; H, 5.57; N, 19.38. Calc. for C17H16N4O. 0.1H2O requires C, 69.42; H, 5.55; N, 19.05%); δH [2H6 ]-DMSO) 10.80 (1H, s, exchangeable, NH), 10.55 (1H, s, exchangeable, NH), 9.20 (1H, s, exchangeable, NH), 8.06 (1H, d, J7.5 9-H), 7.81 (1H, s, 10-H), 7.42-7.28 (2H, m, 6-H and 7-H) 7.12-7.01 (1H, m, 8-H, 4.5 (2H, br, s, exchangeable, NH2), and 2.4 and 2.3 (2×s, 4-CH3 and 3-CH3), m/z 293 (M+1)+, FAB)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1.C([O:29][C:30](=O)[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32])(=O)C>>[OH:32][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30]([N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@@H:5]2[OH:12])[CH2:22][CH2:21][C:18]1[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1)=[O:29]
Reactant: Nc1ccc2c(c1)C(O)CCO2
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: O=C([C@@H](O)c1ccccc1)N(CCc1ccc(C(F)(F)F)nc1)c1ccc2c(c1)[C@@H](O)CCO2

Procedure:
In analogy to example 55, 6-Amino-chroman-4-ol (WO 2003063794), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give after silica gel chromatography the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:19])([CH3:18])[CH2:10][C@:11]1([C:14]([F:17])([F:16])[F:15])[CH2:13][O:12]1.C(=O)(O)[O-:21].[Na+]>CS(C)=O.[Cl-].[NH4+]>[CH3:18][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[O:21])([CH3:19])[CH2:10][C@:11]1([C:14]([F:17])([F:16])[F:15])[CH2:13][O:12]1
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1CBr
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a stirred solution of (R)-2-[2-(2-bromomethylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (46.6 g, 0.138 mol) in 300 mL of DMSO was added sodium bicarbonate (24 g, 0.285 mol) and the reaction mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to normal room temperature, diluted with 1200 mL of saturated aqueous ammonium chloride solution and extracted with four 250 mL portions of diethyl ether. The combined diethyl ether extracts were washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo. The crude material was purified by column chromatography over silica gel (400 g) eluting with 0-15% ethyl acetate in hexanes and fractions corresponding to the major peak were pooled and solvent removed in vacuo to give 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzaldehyde as a light yellow oil (20 g, 62%).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26](Br)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C1(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)C=CC=CC=1>[CH2:1]([C@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](Cc2ccccc2)NC(=O)c2cc(C)cc(Br)c2)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C)cc(-c3ccco3)c2)c1
Temperature: 100 °C

Procedure:
N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide (X, EXAMLE 761, 295 mg, 0.59 mmol), 2-furanylboronic acid (133 mg, 1.19 mmol) and sodium carbonate (366 mg, 2.95 mmol) are combined in dimethylformamide (5 ml) and sparged under a flow of nitrogen for 15 minutes. Tetrakis(triphenylphosphino)palladium (136 mg, 0.12 mmol) is added and the mixture heated to 100 degrees C. overnight. The mixture is cooled to 20-25 degrees C., diluted with chloroform (50 ml) and extracted with water (3×100 ml). The organic phase is separated and washed with saturated sodium bicarbonate (2×100 ml) and saline (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressue. The residue is chouromatographed (silica gel; methanol/methylene chloride, 8/92) to give the title compound, MS [M+H]+=485.3.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1I)=[C:8]([OH:14])[CH:7]=[CH:6][CH:5]=2.[CH3:16][CH:17]([OH:20])[C:18]#[CH:19]>N1C=CC=CC=1.[Cu]=O.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>[OH:20][CH:17]([C:18]1[O:1][C:2]2[C:3](=[O:15])[C:4]3[C:9]([C:10](=[O:13])[C:11]=2[CH:19]=1)=[C:8]([OH:14])[CH:7]=[CH:6][CH:5]=3)[CH3:16]
Reactant: C#CC(C)O
Reactant: O=C1C(O)=C(I)C(=O)c2c(O)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: c1ccncc1
Product: CC(O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of 2,5-dihydroxy-3-iodonaphthalene-1,4-dione (30 mg, 0.095 mmol) in pyridine (3.5 ml) were added copper oxide (1) (13.5 mg, 0.095 mmol), 3-butyn-2-ol (75 μl, 0.949 mmol) and dichlorobis(triphenylphosphine)palladium (2 mg, 3 mol %), and the mixture was stirred at 80° C. of the reaction temperature for 30 minutes. The reaction solution was cooled to room temperature, and then the reaction was quenched by the addition of 2M hydrochloric acid. The reaction solution was extracted with chloroform. The organic layer was washed with ice water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (17.2 mg, 70%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=O)[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]1[C:8](=[S:29])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1nc(-c2ccccn2)c2cccnc2c1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1nc(-c2ccccn2)c2cccnc2c1=S
Temperature: 25 °C

Procedure:
A mixture of 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazin-8(7H)-one RL-8 (90 mg, 0.36 mmol), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (145 mg, 0.36 mmol), and toluene (8 mL) was heated to 115° C. for 3.5 h. After cooling to ambient temperature, the reaction mixture was diluted with 20 mL of ethyl acetate and washed with a 1:1 solution of saturated brine/1 N NaOH. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by normal phase flash chromatography eluting with 0-10% methanol in dichloromethane over 22 minutes. Like fractions containing the desired product were pooled, concentrated under reduced pressure, and dried overnight at 60° C. under vacuum to give 7-ethyl-5-(pyridin-2-yl)pyrido[2,3-d]pyridazine-8(7H)-thione RL-9 (52 mg, 0.20 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.98 (dd, J=8.3, 1.7 Hz, 1H), 8.77 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 8.08-7.97 (m, 2H), 7.91 (dd, J=8.3, 4.3 Hz, 1H), 7.59 (ddd, J=7.3, 4.8, 1.5 Hz, 1H), 4.86 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O:26][O:27][CH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH:29](Br)[CH2:30][CH3:31])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:37][N:38](C)C=O.C(N)CN>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O:26][O:27][CH:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]([C:37]#[N:38])[CH2:30][CH3:31])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: CCCCC(OOC(=O)c1ccccc1)C(Br)CC
Agent: CCCCCc1ccc(-c2ccccc2)cc1
Solvent: NCCN
Solvent: O
Product: CCCCC(OOC(=O)c1ccccc1)C(C#N)CC

Procedure:
2.75 g (5.10-3 moles) of p-pentyl biphenyl-3-bromo-4-octyloxy benzoate and 0.6 g (6.7.10-3 moles) of cuprous cyanide are introduced into 10 ml of dimethyl formamide. After system had been heated under reflux for 6 hours, it is cooled and poured into a mixture of 60 ml of deionized water and 5.5 ml of ethylene diamine. The solution is stirred and then extracted with ether. 2.3 g of crude product are obtained and then purified chromatographically on a column of silica, followed by recrystallization in ethanol. 1.8 g of pure product are obtained.
Reaction SMILES: [C:1]12([CH2:11][N:12]3[CH:16]=[CH:15][CH:14]=[N:13]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:17]([Li])CCC.IC.O>O1CCCC1>[C:1]12([CH2:11][N:12]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: [Li]CCCC
Reactant: c1cnn(CC23CC4CC(CC(C4)C2)C3)c1
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3CC(CC(C3)C1)C2
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A solution of EXAMPLE 3A (869 mg) in tetrahydrofuran (10 mL) was chilled to −45° C. n-Butyllithium (2.3 M solution in hexanes, 2.10 mL) was added dropwise over 5 minutes. The reaction was stirred for 1.5 hours, during which time the temperature increased to −20° C. Iodomethane (0.305 mL) was added dropwise over 3 minutes. The reaction was stirred for 30 minutes between −20 and −15° C. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The extracts were dried (Na2SO4), filtered, and concentrated to provide the title compound.