Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[NH2:43][C:44]1[CH:45]=[CH:46][C:47](Br)=[N:48][CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([C:31]2[CH:32]=[CH:33][C:28]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:16](=[O:17])[C:15]4[N:14]=[CH:13][N:12]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=5)[C:11]=4[N:10]=3)=[CH:29][CH:30]=2)=[N:48][CH:49]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(S(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one (8, 0.21 g, 0.348 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 5-amino-2-bromopyridine (0.090 g, 0.52 mmol), cesium carbonate (0.227 g, 0.696 mmol), Pd(dppf)2Cl2 (0.025 g, 0.035 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 2 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford 2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-9-(3-methanesulfonyl-phenyl)-1,9-dihydro-purin-6-one. 1H NMR (CD3OD, 400 MHz) δ 8.63 (s, 1H), 8.56 (s, 1H), 8.23 (d, 1H), 8.09 (d, 1H), 7.95 (s, 1H), 7.86-7.90 (m, 2H), 7.68-7.71 (m, 2H), 7.59 (m, 3H), 7.39 (m, 2H), 7.34 (m, 2H), 3.21 (s, 3H); LC-MS calculated for C29H21ClN6O3S (M+H+) 569.1, found 569.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[C:14]([F:32])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[NH2:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15]2[C:14]([F:32])=[CH:13][N:12]=[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:9][CH:8]=3)[N:16]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Nc3ccc(C(N)=O)cc3)ncc2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2nc(Nc3ccc(C(N)=O)cc3)ncc2F)CC1
Yield: 63.1 %

Procedure:
A solution of tert-butyl (1-(2-(4-carbamoylphenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (10 mg, 0.023 mmol) in TFA (2 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give 4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)benzamide (5 mg) MS 345.3 (M+H); UV 210.0, 281.8 nm.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].CCN(C(C)C)C(C)C.[N:17]([C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23])=[N+:18]=[N-:19]>ClCCCl>[N:17]([C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])=[O:23])=[N+:18]=[N-:19]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CC(=O)NCC(F)(F)F)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred ice cold solution of 2,2,2-trifluoroethanamine hydrochloride (7.10 g, 1 equiv, 52.4 mmol) and DIEA (18.0 mL, 2.0 equiv, 0.103 mol) in anhydrous DCE (150 mL) was added 3-azido-3-methylbutanoyl chloride (8.46 g, 52.4 mmol) in small portions. The ice bath was removed and the reaction was stirred and left at room temperature for 3 h. Water (150 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with 1 M HCl (2×150 mL) and brine (150 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (10.9 g, 94.4). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.42 (s, 6H), 2.40 (s, 2H), (dq, J=2.4 & 8.8, 2H). LRMS (ESI+) for C7H11F3N4O (224.1); Found: 225 (MH+).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C#C>CN(C=O)C.C1(C)C=CC=CC=1.CCOCC>[C:1]1([C:7]2[N:12]([CH2:22][C:21]#[CH:20])[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)=N1
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CC(c2ccccc2)N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3.95 g (15.8 mmol) of 5,6-dihydro-2,6-diphenylpyrimidin-4-one in 15 mL of DMF was added 2.07 g (18.5 mmol) of solid potassium t-butoxide. The mixture was stirred for 10 rain and 2.60 g (17.5 mmol) of an 80% by weight solution of propargyl bromide in toluene was added. The mixture was stirred at room temperature for 4 days, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap left 2.47 g of crude product which was purified by flash chromatography on silica gel eluted with an ether-hexane gradient to afford 0.72 g of 5,6-dihydro-2,6-diphenyl-3-propargylpyrimidin-4-one (Compound 15) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[O:11])[CH2:7][C:6]2[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][C:26]3[N:27]=[C:28]4[N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31][CH2:30][N:29]4[CH:41]=3)=[CH:22][C:5]=2[CH2:4][N:3]1[CH2:42][C:43]([F:46])([F:45])[F:44].[ClH:47].O1CCOCC1>ClCCl>[ClH:47].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[O:11])[CH2:7][C:6]2[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][C:26]3[N:27]=[C:28]4[NH:33][CH2:32][CH2:31][CH2:30][N:29]4[CH:41]=3)=[CH:22][C:5]=2[CH2:4][N:3]1[CH2:42][C:43]([F:46])([F:45])[F:44]
Reactant: CN(C)C(=O)COC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)N(C(=O)OC(C)(C)C)CCC4)cc2CN(CC(F)(F)F)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)COC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
To 4 mL of a dichloromethane solution containing 125 mg (0.192 mmol) of (N,N-dimethylaminocarbonyl)methyl(4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate obtained in Example 12-(a) was added 864 μL (3.46 mmol) of 4N hydrogen chloride/1,4-dioxane solution, and the resulting mixture was stirred under under argon gas atmosphere at room temperature for 19.5 hours.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9]>O.CCO>[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][C:7]([CH3:14])([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of KOH (2.48 g, 44.2 mmol, 15 eq) in H2O (12 mL) was added a solution of ethyl 2-(2,4-dichlorophenoxy)-2-methylpropionate (compound 5; 0.80 g, 2.89 mmol) in EtOH (12 mL). The solution was stirred at room temperature for 4 hours, then excess EtOH was removed under vacuum. The remaining aqueous solution was washed with EtOAc (10 mL), then acidified with concentrated aqueous HCl. The aqueous mixture was then extracted with EtOAc (10 mL), and the organic extract dried over Na2SO4, filtered, and evaporated to yield a thick, colorless oil which was used without further purification: 1H NMR (CDCl3) δ 7.42-7.41 (d, 1H), 7.19-7.15 (dd, 1H), 7.04-7.01 (d, 1H), 1.64 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2[CH2:17][CH2:18][CH2:19][CH2:20][C:12]1=2>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.3 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 3,4,5,6-tetrahydrophthalic anhydride (6 g) were dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture was allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract was washed with a saturated sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:16]([C:13]1[CH:14]=[CH:15][C:9]2[CH:8]=[CH:7][C:6]3[CH:18]=[C:2]([OH:20])[CH:3]=[CH:4][C:5]=3[S:11][C:10]=2[CH:12]=1)#[N:17]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)Sc1ccc(O)cc1C=C2
Temperature: 3 °C
Reaction time: 2 h

Procedure:
Suspend 50 mg. of the 3-cyano-8-aminodibenzo[b,f]thiepine from Example 18, Step 1, in 2 ml. of 10% sulfuric acid and cool to 3° C. Add dropwise 0.2 ml. of 10% aqueous sodium nitrite solution. Stir at 3° C. for 2 hours and allow to warm to 15° C. for 1 hour. Add the solution dropwise to 50 ml. of boiling 10% sulfuric acid and continue heating for 15 minutes. Dilute with cold water and filter. Wash the solids with water and dry to obtain the title product (m.p., 224°-227° C.).
Reaction SMILES: [OH:1][CH:2]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)[C:3]([OH:5])=[O:4].[CH3:17][C:18]1C=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C>[CH3:17][C:18]1([CH3:23])[O:1][CH:2]([CH:6]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7]2)[C:3](=[O:5])[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(O)C1Sc2ccccc2NC1=O
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)C(C2Sc3ccccc3NC2=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid (0.13 mmol) and p-TSA (1 mg) in 1.5 mL of 2,2-dimethoxypropane is stirred at room temperature for 16 hours. Solvent is removed under vacuum and the residue is treated with a saturated aqueous solution of NaHCO3 (2 mL). The resulted mixture is extracted with EtOAc (3×5 mL). The organic layers are combined and concentrated to provide the crude 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-one which was used directly for next step without further purification. Yield: 31%
Reaction SMILES: CN(C)S(C1C=[C:10]2[C:11]([O:13][C:14](=[O:16])[NH:15][C:9]2=[CH:8]C=1)=O)(=O)=O.COC([N:23]1CCN[CH2:25][CH2:24]1)=O.C(=O)=O>O1CCOCC1>[CH2:11]([O:13][C:14]([N:15]1[CH2:9][CH2:8][NH:23][CH2:24][CH2:25]1)=[O:16])[CH3:10]
Reactant: COC(=O)N1CCNCC1
Reactant: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Agent: O=C=O
Solvent: C1COCCO1
Product: CCOC(=O)N1CCNCC1

Procedure:
13.5 g of 5-(dimethylsulphamoyl)-isatoic acid anhydride and 70 ml of absolute dioxane are gently warmed. As soon as the reaction mixture has reached 40°C, a solution of 8.3 g of N-methoxycarbonylpiperazine is added dropwise and the mixture is then heated further, an evolution of carbon dioxide setting in at about 70°C. The mixture is heated under reflux for a further hour and allowed to cool somewhat, insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The colourless crystals which are precipitated are filtered off with suction and recrystallised from 350 ml of methanol. 13.1 g of 1-[5-dimethylsulphamoyl)-anthraniloyl]-4-ethoxycarbonyl-piperazine, melting point 202°-204°C, are thus obtained.
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1
Reactant: CC(=O)c1cc(Br)ccc1Cl
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)ccc1Cl
Temperature: 170 °C
Yield: 61.5 %

Procedure:
Sodium hydroxide (0.39 g, 9.6 mmol) and hydrazine monohydrate (0.56 mL, 11.5 mmol) were added to a solution of 1-(5-Bromo-2-chloro-phenyl)-ethanone (0.9 g, 3.85 mmol) dissolved in triethylene glycol (5 mL). The reaction mixture was heated to 170° C. for 24 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound (0.52 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.23 (t, J=7.6 Hz, 3H), 2.72 (q, J=7.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 1H), 7.25 (dd, J=8.3, 2.3 Hz, 1H), 7.36 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][Cl:5].Cl.CN(CCCl)P(Cl)(Cl)=O.[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])(N(C)CCBr)=[O:25])[CH2:19][O:18]1>>[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])([N:2]([CH3:1])[CH2:3][CH2:4][Cl:5])=[O:25])[CH2:19][O:18]1
Reactant: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Reactant: CNCCCl
Agent: CN(CCCl)P(=O)(Cl)Cl
Agent: Cl
Product: CN(CCCl)P(=O)(Cl)CCC1COC(C)(C)O1
Yield: 61 %

Procedure:
This compound was prepared from N-methyl-N-chloroethylamine.HCl via N-methyl-N-(2-chloroethyl)phosphoramidic dichloride, as described for 16a (14 mmol scale). The crude residue was purified by chromatography (1:4 EtOAc:hexanes) to give 16b as an oil (2.72 g, 61%): Rf 0.75 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.22(m, 4H), 3.60(m, 3H), 3.42(m, 2H), 2.80(d, 3H, J=12.85 Hz), 1.99(dt, 2H, J=6.11 Hz), 1.36(d, 6H, J=15.82 Hz)ppm; -P NMR (CDCl3) -7.69, -7.92 ppm (1:1 ratio of diastereomers).
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].S([O:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])(C)(=O)=O.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CS(C)=O.[OH-].[Na+]>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)OC[C@H](O)CO
Agent: [CH2-]C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OC[C@H](O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of sodium hydroxide (39 g) in 200 ml water added to a rapidly stirred solution of (2R)-3-mesyloxy-1,2-propanediol acetonide (172.1 g) and 4-benzyloxyphenol (200 g) in 1.5 L dimethylsulfoxide, and the reaction was heated on a steam bath for 3 hours. The cooled solution was diluted with 1 L 1N sodium hydroxide solution and the resulting solids were washed with dilute sodium hydroxide solution with water. The air-dried solids were taken up in benzene (2 L) and the solution was dried over sodium sulfate, decolorized with charcoal and evaporated in vacuo. The product was dissolved in hot methanol (~1.5 L), cooled to ~40° and filtered free from some non-polar impurity. A small portion of the methanol solution was diluted with water to give (2S)-3-(4-benzyloxyphenoxy)-1,2-propanediol acetonide. Crystallization from hexane furnished the pure specimen, mp 69.5°-71°; [α]D25, +6.26° (c, 1.0, methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[N:3]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C=CC(=O)Nc1cccc(N)c1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3cc(OC)c(OC)c(OC)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (54.9 mg, 0.185 mmol) in IpOH (2.5 ml) was added DIEA (0.048 mL, 0.277 mmol) and N-(3-aminophenyl)acrylamide (33 mg, 0.203 mmol). The mix was heated at 100° C. for 18 h. The solution was cooled to RT and a precipitate formed. The precipitate was filtered off and dried under reduced pressure to give N-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl)-acrylamide: MS m/z=423[M+H]+. Calc'd for C2H22N6O4: 422.17.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH:16]([OH:19])[CH:17]([OH:18])[CH:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:17]=[O:18])[C:6]3[C:11]([C:12]=2[CH:16]=[O:19])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: OC1C2c3ccccc3C(c3cc(Br)ccc32)C1O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1c2ccccc2c(C=O)c2cc(Br)ccc12
Yield: 78.6 %

Procedure:
Diol intermediate 12a (1.58 g, 5.0 mmol, 1 equiv.) was dissolved in anhydrous acetonitrile (100 mL) and heated to reflux with stirring and formed a transparent, light-tan solution. Lead tetraacetate (4.42 g, 10.0 mmol, 2 equiv.) was added portion-wise to the solution over a period of 5 minutes quickly turning the solution opaque and brown in color. The solution was then stirred at reflux for 4 hours, resulting in the formation of a dark-orange precipitate within the brown solution. The consumption of the diol intermediates were monitored through thin-layer chromatography (80% CH2Cl2/ethyl acetate, Rf=0.50 & Rf=0.33). After the reaction was complete, the reaction mixture was concentrated via rotary evaporation and gave a burgundy residue. 10% aqueous sodium carbonate (300 mL) was added to the residue, allowing the residue to be suspended in the aqueous solution. The organic contents were extracted from the aqueous layer using dichloromethane. The opaque, yellow organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow-orange solid residue. The residue was purified by column chromatography (20% ethyl acetate/hexane, Rf=0.29), providing 2-bromo-9,10-anthracenedialdehyde 13 as an orange solid (1.23 g, 80%). 1H NMR (CDCl3): 11.43 (s, 1H), 11.42 (s, 1H), 9.03 (s, 1H), 8.72 (m, 2H), 8.66 (d, 1H), 7.75 (m, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:32][C:33](=[O:35])[CH3:34])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CS(C)=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:32][C:33](=[O:35])[CH3:34])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCCCCC(CCCC(COc1cccc(C(F)(F)F)c1)OC(C)=O)S(C)(=O)=O
Temperature: 185 °C
Yield: 190 %

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-acetoxy-13-(3-trifluoromethylphenoxy)tridecanoate (5.82 g., 0.01 mole), sodium chloride (0.59 g., 0.01 mole), dimethylsulfoxide (8 ml.), and water (0.2 ml.) is heated in an oil bath at 185° C. for 10 hours under nitrogen. The reaction mixture is then concentrated in vacuo on a steam bath. The dark-colored residue is diluted with water, acidified with 6N hydrochloric acid, and extracted with ether. The ether extracts are washed with water, dried with anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (9.90 g., 0.019 mole, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C=O)C.CCOCC>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCc1cc(O)cc(C(=O)OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCOc1cc(CCOC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-hydroxy-5-(2-methoxyethyl)benzoate (1 eq.) from the previous step in DMF (0.2 M) was added Cs2CO3 (2 eq.) and 1-bromo-2-methoxy-ethane (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether and washed extensively with water and brine. The organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].Cl>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][O:11][S:46]([CH3:45])(=[O:48])=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCO)C(=O)OC(C)(C)C)[nH]c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (424 mg, 0.830 mmol) and triethylamine (0.14 ml, 1.0 mmol) in chloroform (5.0 ml) was added dropwise methanesulfonyl chloride (0.07 ml, 0.90 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 5 without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][C:7]=1[CH3:8].C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][CH2:8][C:7]1[N:6]=[C:5]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c(CBr)n1
Yield: 116.1 %

Procedure:
Following the procedure of Example 2, the product from Example 25 (6.07 g, 22 mmol) was reacted with NBS (3.96 g, 22 mmol) in CH2Cl2 (150 mL). The crude title product (8.98 g, >100%) was obtained and used without further purification.