Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][O:28]C(C3C=CC(C)=CC=3)=O)[C@@H:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40].C[O-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40]
Reactant: CC(=O)c1c(Br)n([C@H]2C[C@H](OC(=O)c3ccc(C)cc3)[C@@H](COC(=O)c3ccc(C)cc3)O2)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1c(Br)n([C@H]2C[C@H](O)[C@@H](CO)O2)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5,6-Dichloro-2-bromo-3-acetyl-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.142, 1.24 g, 1.7 mmol) was suspended in absolute MeOH (75 mL) to which was added sodium methoxide (250 mg, 4.6 mmol). The suspension was stirred at room temperature for 2 h, after which time the solution first clarified and then a precipitate formed. Water (100 mL) was added, and the suspension was evaporated until no more MeOH remained. The remaining solids were filtered and recrystallized twice from MeOH/H2O to yield 475 mg (68%) of 4.143 as a white crystalline solid: mp slow dec. >235° C.; Rf0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.37 (s, 1H), 6.56 (dd, 1H), 5.46 (s, 1H, D2O exch.), 5.31 (s, 1H, D2O exch.), 4.48 (d, 1H), 3.92 (d, 1H), 3.76 (s, 2H), 2.65 (s, 3H), 2.48 (m, 1H), 2.13 (ddd, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 192.59, 133.20, 126.74, 125.89, 125.77, 121.91, 121.80, 115.94, 115.32, 87.59, 87.30, 69.84, 60.66, 39.23 (under DMSO), 30.95. HRMS (EI) m/z calcd. for C15H14BrCl2NO4 420.9483, found 420.9493. Anal calcd for C15H14BrCl2NO4: C, 42.58; H, 3.34; N, 3.31. Found: C, 42.77; H, 3.25; N, 3.22.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9]1=[O:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([N:8]1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9]1=[O:20])=[O:7])[CH:32]=[CH2:31]
Reactant: C=CCBr
Reactant: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](CCCC)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of the compound of step G (1) (208 mg, 756 μmol) in THF (1.5 mL) at −78° C. was added 1 M NaHMDS (832 μL, 832 μmol) dropwise. After 10 minutes, allyl bromide (196 μL, 2.27 mmol) was added in one shot. The reaction was continued at −78° C. until TLC showed complete reaction (˜6 hours). The reaction was quenched with saturated ammonium chloride solution and allowed to come to room temperature. The mixture extracted 3 times with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (0% to 10% EtOAc/Hexane gradient) afforded pure product (137 mg, 58%). 1H NMR (500 MHz, CDCl3) δ ppm 0.93-0.81 (m, 6H) 1.35-1.21 (m, 4H) 1.53-1.44 (m, 1H) 1.75-1.66 (m, 1H) 2.34-2.22 (m, 1H) 2.47-2.36 (m, 1H) 3.98-3.86 (m, 1H) 4.82-4.74 (m, 1H) 5.08-4.94 (m, 2H) 5.63 (d, J=7.32 Hz, 1H) 5.87-5.75 (m, 1H) 7.46-7.24 (m, 5H). HPLC retention time: 1.92 min (method A). MS (ESI) (M+H)+ 316.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:41])=[C:5]([C:32]([O:39]C)=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:11]([CH:25]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:36][O:35][C:34]1[C:3](=[O:2])[C:4]([CH3:41])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[C:11]([CH:25]=2)[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[O:13])[C:32](=[O:39])[C:33]=1[O:37][CH3:38]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]-4-trifluoromethylaniline (140 mg, 0.2473 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (399 mg, 0.7416 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (60 mg, 0.1119 mmol, 45%).
Reaction SMILES: [NH:1]([C:3]1[CH2:4][N:5]=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]2[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:8]=2[N:9]=1)[NH2:2].[N:22]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:6]1[C:7]2[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:8]=2[N:9]2[N:22]=[N:2][N:1]=[C:3]2[CH2:4][N:5]=1
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(s1)-n1nnnc1CN=C2c1ccccc1Cl
Yield: 79.3 %

Procedure:
[f] 10 g of 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine prepared in the above example [d] is suspended in 54 ml of 2N hydrochloric acid. A solution of 2.4 g of sodium nitrite in 20 ml of water is added to the suspension at -5°C with stirring. The mixture is stirred at room temperature for 30 minutes, and then alkalified with sodium carbonate. The precipitated crystals are filtered off and dissolved in chloroform, and the solution is washed with water. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is distilled off under reduced pressure. The reddish brown jellylike residue thus obtained is crystallized from a mixture of ligroin and ethanol to give 8.2 g of 6-o-chlorophenyl-8-ethyl-4H-tetrazolo[5,1-c]thieno[2,3-e] [1,4]diazepine as white crystals. The product, when recrystallized from ethanol, melts at 135° - 136°C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C:24]([F:27])([F:25])[F:26])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: FC(F)(F)c1ccncc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (604 mg, 4.2 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.76 g, 12.8 mmol) and 3-(bromomethyl)-4-(trifluoromethyl)pyridine (5.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 6-methyl-2-({[4-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol (349 mg, 21% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.59 (s, 2H), 6.07 (bs, 1H), 7.75 (d, J=5.3 Hz, 1H), 8.76 (d, J=5.1 Hz, 1H), 9.02 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[C:40]#[CH:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>C1COCC1.[Cu]I>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:42])[C:40]#[C:41][C:8]3[CH:13]=[CH:12][C:11]([C:14]4([NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[CH:34][CH:33]=2)=[CH:30][CH:31]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.4 g (4.2 mmol) of cesium carbonate and 0.5 g (1.4 mmol) of tert-butyl [1-(4-iodophenyl)cyclopropyl]carbamate are placed in 20 mL of THF and cooled to −15° C. in the ice/methanol bath, rinsed with argon, and degassed. To this reaction mixture is added successively 160 mg (0.14 mmol) of tetrakistriphenylphosphine palladium and 30 mg (0.158 mmol) of copper (I) iodide and the mixture is again degassed. 0.5 g (1.4 mmol) of propynoic acid-(4′-chlorobiphenyl-4-yl)amide is finally added. The mixture is stirred for 24 hours at ambient temperature and the reaction mixture is then evaporated down. The residue is triturated with water and ethyl acetate, suction filtered, washed with ethyl acetate, and dried in the air. Yield: 0.4 g (59% of theory); C29H27ClN2O3 (M=486.99); calc.: molecular ion peak (M+H)+: 487/89 (Cl); found: molecular ion peak (M+H)+: 487/89 (Cl); Rf value: 0.62 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=1
Reactant: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Yield: 61.9 %

Procedure:
3-(4-Chlorophenyl)-5-methyl-1,2-benzisoxazole (12.2g.) and N-bromosuccinimide (9.6g.) were mixed in carbon tetrachloride (200ml.) and heated under reflux in the presence of UV light. (Hanovia medium pressure lamp 125 watts, emitting at 254,265,297,313,366 mp). On cooling, the mixture was filtered and the filtrate evaporated to dryness. The resulting solid was recrystallized from 33% toluene/60-80 petrol ether (150 ml.) to give the title compound as a white crystalline solid (10.0g) m.p. 142°C
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O>[CH3:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=[C:20]1[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c2n1CC(C)C)CCCC3
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)Cc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Temperature: 25 °C
Yield: 65.6 %

Procedure:
N,N-Bis(phenylmethyl)-6,7,8,9-tetrahydro-1,2-di(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.61 g, 3.3 mmole), palladium hydroxide on carbon (0.50 g, Pearlman's catalyst) and formic acid (10 mL) were combined and heated at reflux for 20 hours. The reaction mixture was cooled to ambient temperature, filtered through a layer of celite and diluted with water (about 20 mL). The resulting mixture was cooled to 0° C., made basic by the addition of 28% ammonium hydroxide then extracted with methylene chloride (3×50 mL). The extracts were combined, dried over magnesium sulfate and concentrated to provide a white solid. The solid was purified by silica gel chromatography eluting with methylene chloride:methanol 90:10 to provide 0.65 g of the desired product as a white solid, m.p.160°-161° C. Analysis: Calculated for C18H28N4 : %C, 71.96; %H, 9.39; %N, 18.65; Found: %C, 71.66; %H, 9.37; %N, 18.46.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=O)=[C:21]([CH3:29])[C:20]([Br:30])=[CH:19][N:18]=2)=[CH:11][CH:10]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)[C:17]3=[N:18][CH:19]=[C:20]([Br:30])[C:21]([CH3:29])=[C:22]3[N:23]=2)[CH2:28][CH2:27]1
Reactant: Cc1c(Br)cnc(NCc2ccc(-c3ccccc3C#N)cc2)c1NC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Toluene (20 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methylpyridine, p-toluenesulfonic acid monohydrate (200 mg) and Molecular Sieves 4A (500 mg) followed by heating under reflux with stirring for 3 hours. The reaction solution was brought to room temperature and filtered through Celite to remove insolubles. Chloroform (100 ml) and an aqueous solution (100 ml) of sodium hydrogencarbonate were added to the flitrate and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate an(subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.7 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine (yield 88%).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:1][CH2:5][CH2:4][CH:3]=[CH2:2])(=[O:8])[CH3:7]
Reactant: C1=CCCC1
Reactant: C=CCCCOC(C)=O
Product: C=CCCCC=CCCCOC(C)=O

Procedure:
A process according to claim 17 wherein cyclopentene is reacted with 4-penten-1-yl acetate to produce 4,9-decadien-1-yl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C=C(C#N)CCC#N
Reactant: Cc1ccc(S)cc1C
Solvent: CCO
Product: Cc1ccc(SCC(C#N)CCC#N)cc1C

Procedure:
A mixture of 3,4-dimethylbenzenethiol (0.59 ml), 2-methyleneglutaronitrile (0.48 ml), ethanol (10 ml), and triton B (40% ethanol solution, 5 drops) was refluxed for 5 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by flash column chromatography on silica by eluting with benzene/ethyl acetate (7:1) to give 1.18 g of 2-(3,4-dimethylphenylthiomethyl)glutaronitrile as an oil.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.IC>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of LDA (8.66 mL, 2M in heptane/THF/ethylbenzene, 17.3 mmol) in 30 mL THF at −78° C., was added a solution of ethyl 4-bromophenylacetate (4.00 g, 16.5 mmol) in 20 mL THF. The mixture was stirred at −78° C. for 30 min, then a solution of iodomethane (10.7 mL, 2M in methyl tert-butyl ether, 21.5 mmol) was added. The mixture was stirred for 10 min at −78° C., then was removed from the cooling bath and stirred for 30 min. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc. The organic phase washed with water, sat. Na2SO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 3.07 g of 73A as a colorless oil. MS (ESI) m/z 257.1, 259.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:47][CH3:48])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[C:14]3[C:15](=[O:38])[C:16]4[C:21]([C:8]([C:9]=23)=[N:7]1)=[C:20]([O:22]CC1C=CC=CC=1)[CH:19]=[CH:18][C:17]=4[O:30]CC1C=CC=CC=1)[CH3:2].ClCCl.B(Cl)(Cl)Cl>CO>[OH:30][C:17]1[CH:18]=[CH:19][C:20]([OH:22])=[C:21]2[C:16]=1[C:15](=[O:38])[C:14]1[C:9]3[C:8]2=[N:7][N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:47][CH3:48])[C:10]=3[CH:11]=[CH:12][C:13]=1[NH:39][CH2:40][CH2:41][N:42]([CH2:43][CH3:44])[CH2:45][CH3:46]
Reactant: CCN(CC)CCNc1ccc2c3c(nn2CCN(CC)CC)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCNc1ccc2c3c(nn2CCN(CC)CC)-c2c(O)ccc(O)c2C(=O)c13
Temperature: 25 °C
Yield: 87.1 %

Procedure:
0.100 g (0.148 mmol) 2-[2-(diethylamino)-ethyl]-5-[[2-(diethylamino)ethyl]amino]-7,10-bis(phenylmethoxy)-anthra[1,9-cd]pyrazol- 6(2H)-one is dissolved in cold, dry dichloromethane (4 ml) and boron trichloride (4 ml, 1M solution in dichloromethane) is added dropwise over 30 minutes under argon. The reaction mixture is maintained at 0°-5° C. for 1 hour and then treated dropwise with cold methanol under argon. The mixture is then maintained at room temperature for 2 hours and then evaporated to dryness in vacuo. The resulting crude hydrochloride salt is dissolved in a minimum volume of methanol and then chromatographed on a column of silica gel (60A) using an eluting solvent of dichloromethane:methanol (80:20 v/v) and then dichloromethane:methanol:triethylamine (80:20:1 v/v). The major red band is collected and evaporated in vacuo to yield 0.060 g of the title compound as an orange-red solid, m.p. 152° C.; λmax (methanol) (E/cm/M) 520 nm (22000).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:6][C:5]=1[N:23]1[C:32](=[O:33])[C:31]2[C:26](=[N:27][C:28]([S:34][CH3:35])=[N:29][CH:30]=2)[NH:25][C:24]1=[O:36].I[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:6][C:5]=1[N:23]1[C:32](=[O:33])[C:31]2[C:26](=[N:27][C:28]([S:34][CH3:35])=[N:29][CH:30]=2)[N:25]([CH3:38])[C:24]1=[O:36]
Reactant: CI
Reactant: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 19.7 mg, 0.49 mmol) in DMF is added N-[4-Methyl-3-(7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (218 mg, 0.45 mmol) at 0° C. When H2 evolution has ceased, iodomethane (84 μl, 1.35 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is crystallized from MeOH to give N-[4-Methyl-3-(1-methyl-7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (184 mg, 82%) as a white solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=1
Reactant: CCOC(=O)COc1ccc(OC)c2occc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc(O)c2occc12
Reaction time: 3 h

Procedure:
A solution of boron tribromide (5.50 g, 22 mmol) in dichloromethane (20 mL) was added dropwise to a solution of the above ester (2.77 g, 11.1 mmol) in dichloromethane (30 mL) at −40° C. and the mixture was stirred for 3 h without cooling while the temperature reached 0° C. Water (3 mL) was added to the mixture the organic layer was evaporated in vacuo. The obtained residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording ethyl (7-hydroxybenzo[b]furan-4-yloxy)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=[O:7].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOC(C)=O>[Cl:16][CH2:17][C:18]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NNC(=O)CCl)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To 3-(methyloxy)-4-nitrobenzohydrazide (3.65 g, 17.3 mmol) in EtOAc (150 mL) was added chloroacetyl chloride (1.50 mL, 18.8 mmol). The reaction was stirred open to air overnight. The solid was filtered and washed with diethyl ether to provide the title compound (3.17 g, 11.0 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.98 (s, 3H), 4.21 (s, 2H), 7.56 (dd, J=8.2, 1.6 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 10.48-10.54 (m, 1H), 10.82 (d, J=1.5 Hz, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].N1C=CC=CC=1>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][NH:19][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: COCCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 33 %

Procedure:
A solution of 5-chlorosulfonyl-2-oxindole (5 g), 2-methoxyethylamine (2.25 mL) and pyridine (7 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The reaction was concentrated and dichloromethane (15 mL) was added. The precipitate was filtered, washed with dichloromethane and dried to give 1.9 g (33%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (2-methoxy-ethyl)-amide.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]=[CH:12][C:11]=2[OH:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]=[CH:12][C:11]=2[O:28][C:31](=[O:32])[N:30]([CH3:29])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1O
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (68%, white crystals). HPLC-MS m/z=563.1 (M+1), Rt: 5.3 min.