Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H:2]1[C@@H:29]([OH:30])[C@@:28]2([CH3:31])[C@@H:13]([CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH:21]4[Br:27])[C@@H:17]([CH3:18])[C@@H:16]32)[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][C@@H:7]([OH:32])[CH2:6][CH2:5]1.BrC1C[C@@H](C)CO[C@@]21[C@@H](C)[C@@H]1[C@]3(C)[C@@H](C[C@@H]1O2)[C@H]1[C@@H]([C@]2(C)[C@@H](CC1)C[C@@H](O)CC2)CC3=O>N1C=CC=CC=1.[Ag]=O>[Br:27][CH:21]1[CH2:22][C@@H:23]([CH3:24])[CH2:25][O:26][C@@:19]21[C@@H:17]([CH3:18])[C@@H:16]1[C@:28]3([CH3:31])[C@@H:13]([CH2:14][C@@H:15]1[O:20]2)[C@H:12]1[C@@H:3]([C@:4]2([CH3:33])[C@@H:9]([CH2:10][CH2:11]1)[CH2:8][C@@H:7]([OH:32])[CH2:6][CH2:5]2)[C@H:2]1[O:30][C@@H:29]31
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H](Br)[C@@H](O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: O=[Ag]
Agent: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC(=O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Solvent: c1ccncc1
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H]5O[C@H]5[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Reaction time: 71 h

Procedure:
The following procedure is a variation of that described in Helv. Act. Chim., 1953, 36, 1241. (3β,5α,11α,12β,25R)-11,23-dibromospirostan-3,12-diol (18.08 g) was dissolved in pyridine (500 mL) at room temperature and treated with silver oxide (70.0 g). The resulting mixture was stirred in the dark for 71 hours. The mixture was filtered and the solid washed with ether and then chloroform. These washes were combined with the flitrate and concentrated. The resulting solid was purified by flash chromatography (1:1 hexane:ethyl acetate) to give 12.2 g of a 1:1 mixture of the title compound and (3β,5α,25R)-23-bromospirostan-3-ol-12-one. Further chromatography (7:3 hexane:ethyl acetate) provides pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH:26]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC[C@H]2C(c2ccccc2)c2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, (2S)-2-benzhydrylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 5.18 minutes; C34H30Cl2N4O2 (597.54); mass spectrum: (M−H)−=597/599/601 (chlorine isotope).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][C:8]([CH3:20])([CH3:19])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[OH:21][C:22]1[CH:31]=[C:30](I)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>>[OH:21][C:22]1[CH:31]=[C:30]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([O:15][CH3:16])=[CH:13][C:12]3[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][C:8]([CH3:20])([CH3:19])[C:7]=3[CH:6]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: C#CC(O)c1cc2c(cc1OC)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(C#CC(O)c2cc3c(cc2OC)C(C)(C)CCC3(C)C)cc1O
Yield: 76.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.15 g (4.2 mmol) of α-ethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.21 g (4.64 mmol) of methyl 2-hydroxy-4-iodobenzoate, 1.36 g (76%) of the expected product, with a melting point of 125°-126° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1C(=O)N([Br:19])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1>[Br:19][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1ccc(CBr)cc1Cl

Procedure:
A solution of 3-chloro-4-nitrotoluene (2.0 g, 12 mmol), NBS (2.62 g, 14.6 mmol) and 2,2′-azo-bis-isobutyronitrile (0.195 g, 1.16 mmol) in α,α,α-trifluorotoluene (200 mL) was heated at 80° C. under an atmosphere of nitrogen for 3 h. Solvent was removed in vacuo and the residue was partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was taken to the next step without purification.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[O:16][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A cooled (0° C.) solution of (S)-4-benzyl-3-((S)-2-cyclopropyl-2-hydroxy-acetyl)-oxazolidin-2-one (4.137 g, 15.026 mmol) in dichloromethane (60 mL) was subsequently treated with 2,6-lutidine (3.5 mL, 30.052 mmol) and triisopropylsilyl trifluoromethanesulfonate (6.1 mL, 22.539 mmol). After stirring at room temperature for 1 h, the reaction was quenched with pH 4 buffer (phthalate). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (5.28 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.40-0.49 (m, 2H), 0.53-0.62 (m, 1H), 0.63-0.71 (m, 1H), 1.02-1.18 (m, 21H), 1.20-1.34 (m, 1H), 2.66 (dd, J=13.1, 10.5 Hz, 1H), 3.49 (dd, J=13.1, 3.4 Hz, 1H), 4.17-4.27 (m, 2H), 4.63-4.73 (m, 1H), 5.58 (d, J=5.1 Hz, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:19]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([CH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[CH:24]=[CH:23][CH:22]=1)#[N:19]
Reactant: Cc1cc(C#N)c(F)cc1Br
Reactant: N#CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(F)cc1-c1cccc(CC#N)c1
Temperature: 150 °C
Yield: 91.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (10 mg, 0.1 mmol) was added into the solution of 4-bromo-2-fluoro-5-methylbenzonitrile (110 mg, 0.5 mmol), K2CO3 70% aqueous solution (1 mL) and 3-(cyanomethyl)phenylboronic acid (96 mg, 0.6 mmol) in 10 ml N,N-dimethyl formamide, the solution was heated at 150° C. under microwave condition for 20 minutes, and the reaction mixture was partitioned with 20 mL water and 50 mL ethyl acetate, the aqueous layer was extracted with ethyl acetate (100 mL×2), and the combined organic layer was washed by saturated solution of sodium bicarbonate, sodium chloride, and dried by sodium sulfate, and concentrated by give quantitative products 3′-(cyanomethyl)-5-fluoro-2-methylbiphenyl-4-carbonitrile 3 (114 mg, 88% yield, confirmed by LCMS: 251.10) without purification for next steps.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (1 g, 2.15 mmol) and (6-formylpyridin-3-yl)boronic acid (0.539 g, 2.31 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.82 g, 7.74 mmol) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.288 g, 0.25 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 80° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound (0.60 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Clc1cnnc2ccc(Br)cc12
Solvent: CO
Product: Brc1ccc2nncc(Nc3ccccc3)c2c1
Yield: 62 %

Procedure:
A solution of Example 34D (500 mg; 2.5 mmol) and aniline (1.5 mL) in MeOH (11 mL) was stirred at r.t. for 2.5 hrs, the resulting precipitate was collected, rinsed with water and dried under vacuum to provide the desired product (400 mg; 62%).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4Br)[C:6]=23)[CH2:4][CH2:3][CH2:2]1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)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>[N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4[C:27]4[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=4)[C:6]=23)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1-c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(Azetidin-1-yl)-3-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C28) (345 mg, 0.991 mmol), (4-formylphenyl)boronic acid (163 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.0100 mmol), and sodium carbonate (210 mg, 1.98 mmol) were combined in ethanol (10 mL). Water (2 mL) was added, and the reaction mixture was allowed to stir for 18 hours at 100° C. The reaction mixture was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography [Gradient: 0% to 100% (90:5:5 ethyl acetate/methanol/triethylamine) in heptane]. The product was obtained as a mixture with some impurities, and was used in the next step without additional purification. Yield: 270 mg, 0.723 mmol, 73%. APCI m/z 374.0 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 2.25-2.34 (m, 2H), 3.8-4.0 (br m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 7.61 (br d, J=8.2 Hz, 2H), 7.76 (s, 1H), 7.92 (br d, J=8.4 Hz, 2H), 8.16 (s, 1H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH3:17])[C:13]([CH3:18])=[C:12]2[C:4]=1[C:5](=O)[CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].Cl.[CH3:21][O:22][NH2:23]>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[C:5]1[C:4]2[C:12](=[C:13]([CH3:18])[C:14]([CH3:17])=[C:15]([OH:16])[C:3]=2[CH2:1][CH3:2])[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: CCc1c(O)c(C)c(C)c2c1C(=O)CC1(CCC1)O2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCc1c(O)c(C)c(C)c2c1C(=NOC)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (0.51 g) in 9 mL of pyridine was added methoxyamine hydrochloride (0.82 g). The reaction mixture was allowed to stir at room temperature overnight. The mixture was extracted with ethyl acetate, washed with 1N HCl, and concentrated in vacuo to give 5-ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one O-methyloxime, 1H-NMR (300 MHz, CDCl3) δ=4.58 (s, 1H, 4.01 (s, 3H), 3.05 (m, 2H), 3.02 (s, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10-1.60 (m, 6H), 1.24 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=151.0, 147.4, 146.3, 125.8, 124.6, 124.3, 115.3, 76.9, 61.9, 33.9, 33.4, 21.2, 13.6, 12.7, 12.3, 12.1 ppm. MS: (m/z)=290.1 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1.Cl>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]=[C:11]([CH3:14])[S:12][CH:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)cnnc2cc1OCc1csc(C)n1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 47.9 %

Procedure:
The starting material 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline was obtained by adding potassium carbonate (786 mg, 5.7 mmol) followed by 4-chloromethyl-2-methylthiazole (308 mg, 2 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared as described for the starting material in Example 10), in DMF (10 ml). After stirring for 4.5 hours at 60° C., the reaction mixture was diluted with water and acidified to pH4 with 2M hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ethyl acetate (2/8) as eluent to give 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline as a solid (293 mg, 48%).
Reaction SMILES: ClCl.[C:3]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])=[CH:14][CH:13]=[C:12]([Cl:29])[C:10]=2[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:30]N(Cl)C(OCC)=O>>[C:3]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[C:20]([Cl:30])=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]([CH3:27])[C:17]3=[O:28])=[CH:14][CH:13]=[C:12]([Cl:29])[C:10]=2[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Reactant: CCOC(=O)N(Cl)Cl
Agent: ClCl
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O

Procedure:
At this point additional substituents may be optionally added to the pyrimidinedione ring. For example, a chlorine moiety was added to the 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione molecule (I) by treating it with N,N-dichlorourethane under acidic conditions, affording 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (III). In addition, the 3-[2-(substituted-methoxyalkyl)-substituted-benzoxazol-7-yl]-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (I), for example 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, can be hydrogenated under basic conditions, yielding the targeted 3-[2-(substituted-hydroxyalkyl)-substituted-benzoxazol-7-yl)-1-alkyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (IV), for example 3-[2-(1-hydroxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. Examples 3 and 15 provide the detailed procedures for these methods.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)CC)C>C(Cl)Cl>[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:4](=[O:6])[CH2:3][C:2]([CH3:1])([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:7])[CH2:50][CH2:49]1
Reactant: CC(C)(CC(=O)O)SCc1ccccc1
Reactant: OCCN1CCNCC1
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCN(CCO)CC1)SCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methyl-3-(phenylmethylthio)butanoic acid (1 g, 4.6 mmol) and hexachloroacetone were dissolved in CH2Cl2 (20 mL) and cooled to −78° C. Triphenyl phosphine was added and the mixture was stirred for 30 minutes. Hydroxyethyl piperazine (550 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. Triethylamine (630 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. The cold bath was removed and the solution was stirred for 24 hours. The solvent was evaporated. The crude mixture was poured into 1N HCl (100 mL) and washed with Et2O (2×50 mL). The aqueous layer was made basic with 10% K2CO3 in a brine solution. The product was extracted with EtOAc (3×100 mL), dried over Na2SO4, and concentrated. This gave the title compound which was used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ 7.18-7.37 (mult, 5H), 3.8 (s, 2H), 3.6 (t, J=5 Hz, 4H), 3.4 (t, J=5 Hz, 2H), 2.45-2.65 (mult, 8H), 1.5 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=C1NC(=O)c2c1c(-c1cccc(Cl)c1Cl)cc1[nH]c3ccc(O)cc3c21
Yield: 27 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2,3-dichlorobenzeneboronic acid according to the procedure described in example 8 gave 4-(2,3-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (18) (I, Ar=2,3-dichlorophenyl) in a yield 27%; mp 233–235° C. 1H NMR δ [(CD3)2SO] 11.87 (br, 1H), 11.05 (br, 1H), 9.29 (br, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.74–7.70 (m, 1H), 7.55 (s, 1H), 7.48–7.45 (m, 3H), 7.09 (dd, J=8.7, 2.5 Hz, 1H). Found: C, 59.19; H, 3.04; N, 6.56, C20H10Cl2N2O3.1/2H2O requires C, 59.13; H, 2.73; N, 6.89.
Reaction SMILES: O=[C:2]([CH:18]([C:20](OCC)=O)C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Cl.[OH2:26]>>[O:26]=[C:18]([CH3:20])[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CCOC(=O)C(C)C(=O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O
Agent: Cl
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 14.2 g of 3-(2'-oxo-3'-ethoxycarbonyl-butyl)-benzophenone and 142 ml of 6N hydrochloric acid was refluxed with stirring of 17 hours and after cooling to 20°C, the mixture was diluted with 140 ml of water and extracted 3 times with 50 ml of methylene chloride. The organic phase was washed with 50 ml of an aqueous saturated sodium bicarbonate solution and twice with 50 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 10.76 g of 3-(3'-oxo-butyl)-benzophenone which was utilized as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])=[C:4]([CH:25]=[CH2:26])[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:8]([C:7]1[C:2]([NH:1][C:27](=[O:29])[CH3:28])=[N:3][C:4]([CH:25]=[CH2:26])=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[CH:23]=[CH2:24])[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(NC(C)=O)nc1C=C
Temperature: 60 °C

Procedure:
Under an argon atmosphere, to a solution of 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (100 mg, 292 μmol) in anhydrous pyridine (20 mL) were successively added 4-(dimethylamino)pyridine (DMAP) (3.0 mg, 25 μmol) and acetyl chloride (65.0 μL, 911 μmol) at room temperature. The mixture was heated at 60° C. and stirred for an hour. After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][O:16][CH2:22][C:23]([F:26])([F:25])[F:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COC[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.314 g, 7.84 mmol) in THF (20 mL) was added (S)-(1-benzyl-pyrrolidin-2-yl)-methanol (1.0 g, 5.23 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 2,2,2-trifluoroethyl methanesulfonate (1.4 g, 7.84 mmol) was added and stirring was continued at room temperature over night. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.706 g, 37%) as a light yellow liquid. MS: 274.3 (M+H+).