Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][N:23]=1)CCC>COCCOC.[Cu]I.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>[CH3:13][C:12]1[C:2]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccc(C)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C)c1-c1ncco1
Temperature: 150 °C
Yield: 2057.2 %

Procedure:
In a microwave vial was dissolved ethyl 2-iodo-3-methylbenzoate (627 mg, 2.16 mmol) and 2-(tributylstannyl)oxazole (0.54 mL, 0.07 mmol) in DME (2.59 mL). The solution was degassed with N2 for 5 minutes then CuI (21 mg, 0.11 mmol) and Pd(PPh3)4 (125 mg, 0.11 mmol) were added. The reaction was purged with N2 and heated at 150° C. for 1 h. The reaction was cooled to room temperature, filtered through a pad of Celite and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). MS (ESI) mass calcd. for C13H13NO3, 231.1. m/z found 232.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 7.89-7.82 (m, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.30 (d, J=0.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 25.6 g of 19-acetoxyandrost-4-ene- 3,17 -dione in 4 liters of methanol cooled to 0° C is added 3.1 g of sodium borohydride, and the mixture is stirred at 0° C for 1 hour after which 30 ml of acetic acid is added and the methanol removed under reduced pressure. The resulting residue is taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed. The solid residue is dissolved in 2 liters of chloroform treated with 125 g of manganese dioxide and stirred for 2 hours. The reaction mixture is filtered, and the solvent removed under reduced pressure. The residue is chromatographed on alumina using benzene-ether (1:1) as the eluant. The product is recrystallized from acetone-hexane to give 19-acetoxy-17β-hydroxyandrost-4-en-3-one, M.P. 125°-127° C.
Reaction SMILES: [CH2:1]([O:14][C:15](Cl)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH:18]1[CH:23]=[C:22]2[NH:24][C:25]([C:27]3[NH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[N:26][C:21]2=[CH:20][CH:19]=1>>[CH2:1]([O:14][C:15]([N:35]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=[C:27]1[C:25]1[N:24]([C:15]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:16])[C:22]2[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=2[N:26]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: c1ccc2[nH]c(-c3nc4ccccc4[nH]3)nc2c1
Reactant: CCCCCCCCCCCCCOC(=O)Cl
Product: CCCCCCCCCCCCCOC(=O)n1c(-c2nc3ccccc3n2C(=O)OCCCCCCCCCCCCC)nc2ccccc21

Procedure:
Following the procedure of Example 2, tridecylchloroformate was reacted with 2,2'-bibenzimidazole to give 1,1'-bis(tridecyloxycarbonyl)-2,2'- bibenzimidazole in 86% purity.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1OS(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[PH3:37]=[O:38]>[Pd]>[PH2:37]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][S:3]([C:2]([F:1])([F:36])[F:35])(=[O:4])=[O:5])=[O:38]
Reactant: O=[PH3]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)C(F)(F)F
Agent: [Pd]
Product: O=[PH2]c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12

Procedure:
More specifically, following Tetrahedron Letters, 31, 6321-6324 (1990), trifluoromethanesulfonic anhydride (4) is reacted with 1,1-bi-2-naphthol (3) to form 2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (5). This compound (5) is reacted with phosphine oxide (6) in the presence of a palladium catalyst to form 2-phosphinyl-2'-trifluoromethanesulfonyloxy-1,1'-binaphthyl (7). Compound (7) is then reduced in the presence of triethylamine, followed by hydrolysis of the reduction product to form 2-phosphino-2'-hydroxy-1,1'-binaphthyl (8). Further, this compound (8) is reacted with chlorophosphine (9) in the presence of triethylamine, whereby the phosphine compound (I) of the present invention is prepared.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[SH:29].N1C2C(=CC=CC=2O)CCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([S:29][C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1cccc(C)c1S
Agent: O=C([O-])[O-]
Agent: Oc1cccc2c1NCCC2
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Sc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 130 °C
Yield: 68.2 %

Procedure:
To a solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (2.00 g; 6.02 mmol) and 2,6-dimethylthiophenol (0.88 mL; 6.62 mmol) in DMF (15 mL) was added CuBr (0.43 g; 3.01 mmol), 1,2,3,4-tetrahydro-quinolin-8-ol (0.45 g; 3.01 mmol) and Cs2CO3 (2.45 g; 7.52 mmol; 1.25 eq.). The resulting mixture was heated, in a closed vessel, at 130° C., for 2 days. After cooling to RT, water was added and the mixture extracted with Et2O. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (Et2O/hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dimethyl-phenylsulfanyl)-phenyl]-morpholine (1.60 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH2:15][CH2:16][CH2:17][C:4]=2[N:3]=1.[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21].CCOCC>C(O)CCC>[CH3:18][O:19][C:20]([C:22]1([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[N:7]=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]4[CH2:15][CH2:16][CH2:17][C:4]=4[N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH2:25]1)=[O:21]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Reactant: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Solvent: CCOCC
Solvent: CCCCO
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(Oc5ccccc5)n3)CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 2-chloro-4-phenoxy-6,7-dihydro-5H-cyclopentapyrimidine (0.28 g, 1.1 mmol) and 1-(4-amino-phenyl)cyclobutanecarboxylic acid methyl ester (0.23 g, 1.11 mmol) in 1-butanol (3.0 mL) was stirred at a temperature in the range of 20° C. to 100° C. for 8 to 16 hours. Thereafter, the reaction was cooled to about 20 to 35° C. Anhydrous ether was added and the mixture was stirred for 1 hour at about 20 to 35° C. The separated solid was filtered, washed with ether, and dried in vacuum to afford the title compound as a white solid (0.38 g, 81% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]1[CH2:15][NH2:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NCc1ccccn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCC1C=CC=CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 2-nitrobenzenesulfonylchloride (16.62 g, 0.075 mol) in dry CH2Cl2 (120 mL) was added dropwise via cannula to a stirred solution of 2-(aminomethyl)pyridine (5.41 g, 0.05 mol) and Et3N (13.9 mL, 0.10 mol) in dry CH2Cl2 (150 mL) under nitrogen. The reaction mixture was stirred for three hours at room temperature, and then quenched with water (20 mL). The aqueous layer was separated and extracted with EtOAc (5×80 mL). The combined organic extracts were dried (MgSO4) and evaporated to small volume to give a white precipitate which was collected by filtration and washed with cold CH2Cl2 to give the desired product (11.37 g, 78%) as a white solid: 1H NMR (Acetone-d6) δ 4.46 (s, 2H), 7.19 (dd, 1H, J=7.4, 4.5 Hz), 7.25-7.35 (br s, 1H), 7.39 (d, 1H, J=7.7 Hz), 7.68 (ddd, 1H, J=7.7, 7.5, 1.8 Hz), 7.76-7.88 (m, 2H), 7.94 (dd, 1H, J=7.7, 1.5 Hz), 8.04 (dd, 1H, J=7.5, 1.8 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:28])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:31][NH:28][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)=[CH:20][C:19]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.1 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-N1-phenylbenzene-1,2-diamine (0.2 g, 0.54 mmol), paraformaldehyde (0.025 g, 1.01 mmol), and 6 drops of acetic acid in 10 ml 1,2-dichloroethane was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (0.45 g, 2.2 mmol) was added and stirred overnight before quenching with 10 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. ((4-(4-(Methylamino)-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.021 g, 10%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) 8 (ppm) 2.86 (s, 3H), 2.97 (s, br, 4H), 3.58 (s, br, 2H), 3.94 (s, br, 3H), 5.18 (s, 1H), 6.88 (m, 6H), 7.25 (m, 2H), 7.47 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
107 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 2A; 300 mmol, 1 equivalent) were dissolved in 2.8 l of THF/methanol (1:1), 1.5 of 1 N aqueous lithium hydroxide solution (1.5 mol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The organic solvents were removed under reduced pressure and the resulting aqueous solution was adjusted in an ice bath to pH 3-4 using 1 N aqueous hydrochloric acid. The resulting solid was filtered off, washed with water and isopropanol and dried under reduced pressure. This gave 92 g (95% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[CH3:26][S:27](Cl)(=[O:29])=[O:28].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(S(C)(=O)=O)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a 0° C. solution of 2-[1-(1-methylpiperazine-2-yl)-ethylamino]-4[-benzimidazol-1-yl]-pyrimidine (EXAMPLE 20; 6 mg) in 1 mL of CH2Cl2 and 0.5 mL of pyridine was added methanesulfonyl chloride (2.5 mg). The mixture was allowed to warm to room temperature and stirred overnight, then poured into 10 mL of 1M NaHSO4, extracted with 2×5 mL of CH2Cl2, basified (pH>10) with 5N NaOH, and extracted with 5×5 mL of EtOAc. The combined EtOAc extracts were washed with 5 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2—2M NH3 in MeOH to provide 1.0 mg of the title compound. Mass spectrum (ESI) 416.3 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17])(=O)=O.[Cl-:20].[Li+]>CN1CCCC1=O.O>[Cl:20][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[CH3:17]
Reactant: [Cl-]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reaction time: 10 h

Procedure:
4-Nitro-2,6-dimethylphenyl trifluoromethanesulfonate (4.06 kg, 13.6 mol) is dissolved in anhydrous N-methylpyrrolidinone (42 L) and to this solution is added anhydrous lithium chloride (900 g) all at once. The internal temperature is raised to 120° at which time the color changes to a dark golden brown. After 10 hours at this temperature the color of the solution is dark brown. The reaction is then cooled to 5° and diluted with cold water (5°, 21 L) at such a rate as to keep the temperature below 15°. Afte the addition is complete the mixture is stirred for 1 hour at 5°. The product is collected by filtration and washed with water (4×1 L). This dark brown solid is dissolved in t-butyl methyl ether (42 L) and stirred first with charcoal and then anhydrous magnesium sulfate (10 pounds). After filtration the solvents are removed in vacuo (40°, 3 Torr) to obtain tan solid which is dried in vacuo (25°, 3 Torr) for 2 days to obtain 4-chloro-3,5-dimethylnitrobenzene, m.p. 101°-105°.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[NH:19][C:18](=O)[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[N:6]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH:8]=2)[N:19]=1
Reactant: Cc1nc(-c2cccc(Nc3nccc(=O)[nH]3)c2)cs1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(-c2cccc(Nc3nccc(Cl)n3)c2)cs1
Temperature: 25 °C
Yield: 47 %

Procedure:
To 2-(3-(2-methylthiazol-4-yl)phenylamino)pyrimidin-4(3H)-one, 11, (1.0 g, 3.5 mmol) and N,N-dimethyl-aniline (1 mL) is added phosphorus oxychloride (9.5 mL). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue is neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 0.50 g (47% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 2.73 (s, 3H), 6.98 (d, J=5.1 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 8.25 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 10.08 (s, 1H). MS (ESI, pos. ion) m/z: 303 (M+1).
Reaction SMILES: C([Mg]Br)C.C1C[O:8][CH2:7][CH2:6]1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C(Cl)(=O)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:7]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)(=[O:8])[CH3:6]
Reactant: CSc1nc(I)n2ccsc12
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CSc1nc(C(C)=O)n2ccsc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (4.78 ml) was added in an argon atmosphere at −40° C. to a solution of 963 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 30 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Acetyl chloride (0.35ml) was added thereto. The temperature of the system was raised to −5° C. over a period of 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=2:1:1) to give 384 mg of 5-acetyl-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:33])[C@H:15]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=1[CH3:32])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[Li].[Li+].[O-:36][O-]>C1COCC1.O>[CH2:18]([O:17][CH2:16][C@@H:15]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=1[CH3:32])[C:14]([OH:33])=[O:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: [O-][O-]
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of 16D (11.2 g, 22.03 mmol) in THF (70 ml) and water (20 ml) at 0° C. was added a solution of lithium peroxide [prepared by adding hydrogen peroxide (11.25 ml, 110 mmol) to lithium hydroxide (1.387 g, 33.0 mmol) in water (20 ml)] dropwise. The mixture was stirred at 0° C. for 1 h, then quenched with sat. sodium sulfite, and organic solvent was removed under reduced pressure. The remaining solution was diluted by 50 ml of water and extracted with dichloromethane (2×20 ml). The aqueous layer was acidified using conc. HCl. The solution was then extracted with ethyl acetate (3×). The organic extracts was combined and washed with brine and dried over sodium sulfate. The solution was filtered, concentrated and dried in vacuo to give 16E (8 g, 22.91 mmol, 104% yield) as an oil. MS (ESI) (m/z): 347, 349.4 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[O:5])[CH2:23][CH2:22]1
Reactant: CC1CCNCC1
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2Cl)CC1

Procedure:
A mixture of 0.012 mole (3.6 g) of 2,2'-dichloro-5-nitrobenzophenone, of 0.018 mole (1.8 g ) of 4-methylpiperidine and of 0.012 mole (1.7 g) of potassium carbonate in 100 cm3 of anhydrous ethanol is heated for 1 hour to reflux.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]([CH2:13][C:14](OC)=[O:15])[C:10](=[O:18])[N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pd]>[O:18]=[C:10]1[N:11]2[CH2:13][C:14](=[O:15])[NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:12]=32)[N:9]1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reaction time: 2 h

Procedure:
A mixture of dimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate from Step B (270 mg, 0.84 mmol) and 10% Pd/C (50 mg) in MeOH (100 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 2 h, the reaction was filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in toluene (3 mL) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) was added. The mixture was heated at reflux for 30 min and then concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[O:29][C:7]2[CH:8]=[CH:9][C:10]3[C:23](=[O:24])[C@@H:22]4[C@@H:13]([CH2:14][O:15][C:16]5[C:21]4=[CH:20][C:19]([O:25][CH3:26])=[C:18]([O:27][CH3:28])[CH:17]=5)[O:12][C:11]=3[C:6]=2[CH2:5]1)=[CH2:3].[BH4-].[Na+].O>CO>[CH3:3][C:2]([C@@H:4]1[O:29][C:7]2[CH:8]=[CH:9][C:10]([C:23]([CH:22]3[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=4)[O:15][CH2:14][CH2:13]3)=[O:24])=[C:11]([OH:12])[C:6]=2[CH2:5]1)=[CH2:1]
Reactant: C=C(C)[C@H]1Cc2c(ccc3c2O[C@@H]2COc4cc(OC)c(OC)cc4[C@@H]2C3=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(C)[C@H]1Cc2c(ccc(C(=O)C3CCOc4cc(OC)c(OC)cc43)c2O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
12-Rotenol Synthesis: Rotenone (2 g, 5 mmol) was suspended in methanol (50 mL) and was cooled to 0° C. in an ice bath. Added solid NaBH4 (770 mg, 20 mmol) in one portion and the mixture was stirred for 1 h at 0° C. The reaction mixture was allowed to come to room temperature. Water (100 mL) was added, extracted with dichloromethane (3×50 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to obtain a fluffy solid, which was purified by flash column chromatography on silica gel using EtOAc:Hexane (1:3) to afford rotenol as colorless fluffy solid (1.98 g, 98%). m. p.: 80-82° C.; 1H NMR (CDCl3): δ 7.03 (d, 1H, J=7.96 Hz, 11-H); 6.68 (s, 1H, 1-H); 6.45 (s, 1H, 4-H), 6.44 (d, 1H, J=7.96 Hz, 10-H); 5.19 (t, 1H, J=8.89 Hz, 5′H); 5.07 (s, 1H, 7′H); 4.90 (br s, 2H, 7′-H and 12-H); 4.8-4.9 (ddd, 1H, J=5.14, 5.28, 10.68 Hz, 6a-H); 4.60 (dd, 1H, J=10.08, 10.68 Hz, 6′-Hβ); 4.22 (dd, 1H, J=5.14, 10.08 Hz, 6′-Hα); 3.84 (s, 3H, 3-OCH3); 3.83 (s, 3H, 2-OCH3); 3.37 (dd, 1H, J=4.97, 5.28 Hz, 12a-H); 3.28 (dd, 1H, J=8.89, 15.67 Hz, 4′-Hβ); 2.94 (dd, 1H, J=8.89, 15.67 Hz, 4′-Hα); 1.79 (s, 3H, 8′-CH3); 13C NMR (CDCl3): δ 188.73 (C-12); 167.14 (C-9); 157.73 (C-7a); 149.23 (C-3); 147.19 (C-4a); 143.61 (C-2); 142.83 (C-6′); 129.77 (C-11); 113.14 (C-11a); 112.80 (C-8); 112.40 (C-7′); 110.09 (C-1); 104.68 (C-10); 104.63 (C-12b); 100.70 (C-4); 87.66 (C-5′); 72.04 (C-6a); 66.10 (C-6); 56.13 (OCH3); 55.69 (OCH3); 44.41 (C-12a); 31.12 (C-4′); 17.00 (C-8′).