Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:10]=[CH:9][O:8][N:7]=1)[OH:5].[F:11][C:12]1[C:13]([CH3:21])=[CH:14][C:15](O)=[C:16]([CH:19]=1)[C:17]#[N:18]>>[Cl:1][CH2:2][CH2:3][C@@H:4]([O:5][C:15]1[CH:14]=[C:13]([CH3:21])[C:12]([F:11])=[CH:19][C:16]=1[C:17]#[N:18])[C:6]1[CH:10]=[CH:9][O:8][N:7]=1
Reactant: O[C@@H](CCCl)c1ccon1
Reactant: Cc1cc(O)c(C#N)cc1F
Product: Cc1cc(O[C@H](CCCl)c2ccon2)c(C#N)cc1F

Procedure:
The product of step (d) (0.47 g) was reacted with 5-fluoro-2-hydroxy-4-methylbenzonitrile using the procedure described for Example 5(a) to afford the product as a white solid (0.4 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:16])[CH:11]=[CH:12][NH:13]2)=[CH:8][C:7]=1[O:17][CH3:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[NH:13][CH:12]=[CH:11][C:10]2=[O:16]
Reactant: C1CCNC1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCCl
Solvent: CC#N
Product: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Yield: 95.1 %

Procedure:
Intermediate V (62 g, 0.232 mol) and tetrahydropyrrole (82.46 g, 1.16 mol) were added to acetonitrile (620 mL). The mixture was heated under reflux for 8 h. After completion of the reaction, a portion of solvent was evaporated off. The reaction vessel was placed in a cold trap. The reaction was filtered by suction. The filtered cake was washed with ethyl acetate to produce a yellow solid (66.74 g) in a yield of 95.3%.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:21])([CH3:20])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:23])[CH:7]=1.C(O)(=O)C>O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][CH:22]([C:8]2[CH:7]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[C:11]3[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:10]=3[CH:9]=2)[CH3:23])=[CH:32][CH:31]=1
Reactant: N#C[O-]
Reactant: CC(CCCc1ccc(F)cc1)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCc1ccc(F)cc1)c1cc(NC(N)=O)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanate (1.22 g., 0.015 mole) was added to a stirred solution of 1.95 g. (0.005 mole) of 10-amino-8-[5-(4-fluorophenyl)-2-pentyl]-5,5-dimethyl-5H-[1]benzopyrano [4,3-c]pyridine in 20 ml. of glacial acetic acid. The mixture was stirred at room temperature for 18 hours and was diluted with 80 ml. of water. After cooling in an ice bath, the aqueous acetic acid solution was decanted, the residue was triturated with water, cooled, filtered, and recrystallized from acetonitrile, m.p. 179°-181°.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[CH:59][CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45](B2OC(C)(C)C(C)(C)O2)[C:44]([CH3:57])=[N:43]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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]>[F:37][C:38]1[CH:39]=[C:40]([CH:58]=[CH:59][CH:60]=1)[CH2:41][N:42]1[C:46]([CH3:47])=[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:3]=2)[C:44]([CH3:57])=[N:43]1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cnc1NC(=O)OC(C)(C)C
Yield: 89.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (intermediate 66B) (200 mg, 0.322 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (160 mg, 0.483 mmol) using Pd(dppf)Cl2 (12 mg, 0.016 mol) and sodium carbonate (103 mg, 0.967 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 200 mg (89.2% yield) of the titled compound after column purification using 2% methanol in DCM as eluent. MS: m/z=597.5 (M-Boc+1).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[CH2:12][C:13](=[O:20])[CH2:14]2.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1.CCOCC>[O:20]([C:13]1[CH2:14][C:15]2[C:11]([CH:12]=1)=[C:10]([CH3:9])[CH:18]=[CH:17][C:16]=2[CH3:19])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(C)c2c1CC(=O)C2
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C=C(O[Si](C)(C)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyldimethylchlorosilane (2.85 g, 18.9 mmol) and 4,7-dimethyl-2-indanone (2.53 g, 15.8 mmol, obtained by oxidation of 4,7-dimethylindene) in benzene (30 mL) was added DBU (3.13 g, 20.5 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The mixture was diluted with Et2O (50 mL), washed with water (2×50 mL), 5% HCl (50 mL) water (2×50 mL) and dried over sodium sulphate. Evaporation of the solvents left a dark oil that was dissolved in pentane (30 mL). The unreacted starting materials were crystallized at −15° C. and removed by filtration. Evaporation of the solvent gave 3.03 g (69.9%) of fairly pure title compound as an orange oil. 1H NMR (CDCl3, δ): 6.94 (dq, 3J=7.7 Hz, 4J=0.3 Hz, 1H),; 6.78 (dq, 3J=7.7 Hz, 4J=0.3 Hz, 1H); 5.84 (t, 4J=1.1 Hz, 1H); 3.20 (m, 2H); 2.30 (s, 3H); 2.25 (s, 3H); 1.00 (s, 9H); 0.27 (s, 6H); 13C NMR (CDCl3, δ): 162.08; 143.39; 134.89; 129.45; 127.78; 125.49; 123.84; 105.28; 38.80; 25.65; 18.29; 18.21; −4.57.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CCCCCCC>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc2cc[nH]c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=C(Nc1cccc2cc[nH]c12)OCc1ccccc1
Temperature: 55 °C
Yield: 96.4 %

Procedure:
Equip a 12-L reaction flask with a cooling bath, air driven stirring apparatus, addition funnel, and thermometer probe. Thoroughly purge the flask with nitrogen, charge 7-aminoindole (352 g, 2.663 moles), CH2Cl2 (5.30 L, 15 volumes) and 2N NaOH (1.76 L, 3.515 moles). After cooling the biphasic solution to less than 10° C., benzyl chloroformate (500 g, 2.929 moles) add dropwise at such a rate so as to maintain the temperature at less than 10° C. over one hour. Stir the reaction vigorously for 1 hour until complete by TLC. Separate the layers and extract the aqueous layer with CH2Cl2 (1.7 L). Combine the organic layers, wash with 2N NaOH (2×2 L), and dry over Na2SO4. After filtering off the drying agent, concentrate the filtrate in vacuo to a volume of ˜1.5 L resulting in thin dark mixture. Gradually exchange the solvent using heptane (˜4 L) to form a thick sand-like slurry and increase the bath temperature to 50-60° C. Concentrate to a volume of ˜1.5 L, filter while hot (50-60° C.), wash with warm (45° C.) heptane (1 L) and RT heptane (1 L), and dry to yield 683.5 g (96.7%) of the title compound as light purple solid. 1H-NMR(DMSO-d6, 300 MHz), δ 10.79 (br s, 1H), 9.42 (br s, 1H), 7.20-7.56 (m, 8H), 6.92 (t, 1H), 6.41 (dd, 1H), 5.18(s, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)C>[CH3:26][O:25][C:19]1[CH:24]=[CH:23][C:22]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:21][CH:20]=1
Reactant: CCCCCCC(=O)O
Reactant: COc1ccccc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: CCCCCCC(=O)c1ccc(OC)cc1
Yield: 84 %

Procedure:
In 40 ml of dichloroethane were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 7.57 g (0.07 mole) of anisole and 0.9 g of boron trifluoride-acetic acid complex and the resulting mixture was then stirred at refluxing for 8 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure to obtain 9.25 g of 4-methoxy-1-heptanoyl-benzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+].CCOCC>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(C#N)ccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCc2cc(C(=N)NO)ccc2C1
Temperature: 55 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
1,1-Dimethylethyl 7-cyano-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 4) (350 mg, 1.285 mmol), hydroxylamine hydrochloride (223 mg, 3.21 mmol) and sodium bicarbonate (540 mg, 6.43 mmol) were suspended in ethanol (15 ml) and stirred at 55° C. for 5 hours. The reaction mixture was left standing overnight. LC/MS showed a single major product. Inorganics were removed by filtration, washing well with 10% MeOH/DCM to dissolve any precipitated product. Solvent evaporation yielded a white solid. Trituration with ether gave the title compound (320 mg). MS (ES) C16H23N3O3 requires 305; found 306.2 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:24])=[CH:26][CH:27]=2)=[CH2:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: C=C(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.527 g (3.302 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.74 g (3.30 mmol) of 4-(1-phenylethenyl)benzoic acid and 1.84 ml (13.2 mmol) of triethylamine in 15 ml of N,N-dimethylformamide, 0.60 ml (3.96 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield 6-[4-(1-phenylethenyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:37][CH:38]=1)[CH3:23]
Reactant: CN(C)Cc1ccccc1-c1ccc(N)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(-c2ccccc2CN(C)C)cc1

Procedure:
The titled compound was prepared analogously as describe in EXAMPLE 55, using 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 4-(2-dimethylaminomethyl-phenyl)phenylamine MS 527.7 and 529.6 (M+H, Cl pattern).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]([CH2:17]Br)=[CH2:16]>>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:17][C:15]([Br:14])=[CH2:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: C=C(Br)CC(C(=O)OCC)C(=O)OCC
Temperature: -22.5 °C
Yield: 137.9 %

Procedure:
The oil was removed from 21.70 g (0.542 mol) of 60% sodium hydride in oil by washing with hexanes. To the residue suspended in 200 ml tetrahydrofuran, 84.38 ml (0.556 mol) diethyl malonate was added slowly via addition funnel. While the reaction was cooled to −35 to −10° C., 100 g (0.400 mol) of 2,3-dibromopropene was added slowly via addition funnel. After heating to reflux for 1 hour, the reaction was cooled to room temperature and concentrated ill vacuo. Hexanes and water were added to the residue and the resulting mixture was transferred to a separatory funnel where the-phases were separated. The isolated organic layer was washed with IN hydrochloric acid then dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 154 g of 2-(2-bromo-allyl)-malonic acid diethyl ester as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]>ClCCl>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]1[NH:28][C:27](=[O:29])[N:26]2[C:30]([CH3:36])=[N:31][C:32]([CH2:33][CH2:34][CH3:35])=[C:25]2[N:24]=1)[CH3:11]
Reactant: OCCN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CCO)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
86 mg (0.66 mmol) of hydroxylethylpiperazine are added to a solution of 90 mg (0.22 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 16 hours. After chromatographic purification (dichloromethane/methanol=95:5), 63 mg (57%) of 2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-phenyl}-6-methyl-8-propyl-3H-imidazo[1,5-α][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.Cl.C([O-])(O)=[O:29].[Na+]>C1COCC1>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:29])[C:13]=3[C:4]=2[CH:3]=1
Reactant: Fc1cc(F)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(F)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c(Nc3c(F)cc(F)cc3F)nc3ccc(Br)cc3c12
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (800 mg, 2.4 mmol) in THF (10 mL) were added 2,4,6 trifluoroaniline (359 mg, 2.4 mmol) and sodium tert-butoxide (703 mg, 7.32 mmol) and the reaction mixture was heated to 85° C. for 45 min. The solution was cooled to room temperature, quenched with methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% hexane to 100% EtOAc, gradient elution) to afford 9-bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine. 9-Bromo-1-chloro-N-(2,4,6-trifluorophenyl)benzo[c]-2,6-naphthyridin-5-amine was taken up in THF (10 mL) and 6 N HCl (10 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].Br[C:28]1[C:29]([CH3:35])=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1.C(Cl)Cl>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]>[NH2:34][C:31]1[N:30]=[C:29]([CH3:35])[C:28]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:4]=2)=[CH:33][N:32]=1
Reactant: CC1(C)OB(c2ccc(Cl)c(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: Cc1nc(N)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
N-[2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide (Intermediate B) (50 mg, 0.13 mmol), 5-Bromo-4-methyl-pyrimidin-2-ylamine (Intermediate C) (26 mg, 0.14 mmol) and PdCl2(dppf).DCM (10 mg, 0.013 mmol) are placed in a microwave vial containing degassed DME (3 ml) and 2M Na2CO3 (1 ml). The resulting mixture is heated using microwave radiation at 100° C. for 45 minutes. The reaction mixture is diluted with DCM, MgSO4 is added and the mixture is filtered through Celite® (filter agent). The filtrate is absorbed onto silica and purification by flash chromatography on silica eluting with MeOH:DCM (1% to 2% MeOH) affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([S:30](Cl)(=[O:32])=[O:31])=[C:25]([F:34])[CH:24]=1>>[Br:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([S:30]([NH:21][C:18]2[S:19][CH:20]=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=4)=[CH:7][C:2]=3[Cl:1])[N:17]=2)(=[O:31])=[O:32])=[C:25]([F:34])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1cc(F)c(Br)cc1F

Procedure:
The title compound was prepared 4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (46.9 mg) with purity >90%: MS (neg) m/z 589.5, 591.5, 593.5; HRMS m/z 589.8745 (calc. of monoisotopic mass for C21 H11 Br Cl2 F2N2 O3 S2 gives 589.8740).
Reaction SMILES: C([NH:8][C:9]([C:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC3C=CC=CC=3)[CH:20]=2)[CH:15]=1)([CH2:12][OH:13])[CH2:10][OH:11])C1C=CC=CC=1.C(O)C.C(OCC)(=O)C.C(O)(=O)C>[Pd]>[NH2:8][C:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH2:15]1)([CH2:12][OH:13])[CH2:10][OH:11]
Reactant: OCC(CO)(NCc1ccccc1)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(CO)(CO)C1CCc2cc(O)ccc2C1
Reaction time: 6 h

Procedure:
A 1 L pressure vessel was charged 10% Pd—C, dry Engelhard (10:90, palladium:carbon black, 0.966 g, 0.000908 mol) under an atmosphere of nitrogen. The solution of 2-benzylamino-2-(6-benzyloxy-3,4-dihydro-naphthalen-2-yl)-propane-1,3-diol (23.75 g, 0.05716 mol) in ethanol (300 mL, 5 mol) and ethyl acetate (300 mL, 3 mol) was added under an atmosphere of nitrogen. The mixture was connected to a H2 line, flashed with 50 psi of H2 three times, then stirred under 50 psi of H2 for 6 hours. The mixture was continuously stirred under 50 psi of H2 overnight. Acetic acid (18.0 mL, 0.316 mol) was added and the mixture was stirred under 50 psi of H2 for 30 hours. 10% Pd—C, dry Engelhard (10:90, palladium:carbon black, 1.01 g, 0.000949 mol) suspended in 10 mL of EtOAc was added and the mixture was continuously stirred under 50 psi of H2 for 45 hours. The mixture was filtered through Celite, concentrated to 54 g. The material was dissolved in ethanol (300 mL, 5 mol) and acetic acid (10.0 mL, 0.176 mol). The resulted solution was added to a pressure hydrogenation flask charged with 10% Pd—C, dry Engelhard(10:90, palladium:carbon black, 2.10 g, 0.00197 mol) under an atmosphere of Nitrogen. The mixture was flashed with 50 psi of H2 three times then stirred under 50 psi of H2 for 3 days. Acetic acid (10.0 mL, 0.176 mol) was added and the mixture was continuously stirred under 50 psi of H2 for 24 more hours. The reaction mixture was released from the H2 pressure, filtered through Celite, concentrated and dried in high vacuum to give a crude product. The material was used for next step without further purification. 1H NMR (MeOD) δ: 6.84-6.99 (m, 1H), 6.43-6.61 (m, 2H), 3.62-3.88 (m, 4H), 2.55-2.94 (m, 4H), 2.17-2.35 (m, 1H), 1.91-2.11 (m, 1H), 1.68-1.82 (m, 1H). MS (M+1): 238.0.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:26])[N:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl.CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:27].[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:26])[N:4]=1
Reactant: Cc1cc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)nc(N)n1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)c2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of amine B3 (205 mg, 0.55 mmol) in EtOH (20 mL) and H2O (10 mL) was added 4-chloro-6-nitroquinoline (135 mg, 0.64 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 5 h, diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc to give Cpd. RRR2 (217 mg 68%); m.p. (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 13.00 (br, 2 H, 2×N+H), 10.99 (br, 1 H, NH), 10.75 (br s, 1 H, NH), 10.53 (s, 1 H, NH), 9.75 (d, J=1.9 Hz, 1 H, ArH), 8.64 (br d, J=7.4 Hz, 1 H, ArH), 8.60 (d, J=6.7 Hz, 1 H, ArH), 8.17 (d, J=9.3 Hz, 1 H, ArH), 8.15 (br, 1 H, NH), 8.07 (br s, 1 H, NH), 7.99 (d, J=8.8 Hz, 2 H, ArH), 7.79 (br d, J=7.5 Hz, 3 H, ArH), 7.57 (t, J=7.9 Hz, 1 H, ArH), 7.48 (d, J=8.8 Hz, 2 H, ArH), 6.91 (d, J=6.7 Hz, 1 H, ArH), 6.22 (d, J=0.6 Hz, 1 H, ArH), 2.30 (s, 3 H. CH3); HRMS (FAB+) calc. for C27H23N8O3 (M+1) m/z 507.1893, found 507.1888.
Reaction SMILES: C[O:2][Si:3]([O:11]C)([O:9]C)[C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[C-:13]1([Si:18]([O:23]C)([O:21]C)[O:19]C)[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:25].C(O)(=O)C>CCOCC>[OH:2][Si:3]([OH:11])([OH:9])[C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[C-:13]1([Si:18]([OH:23])([OH:21])[OH:19])[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:25]
Reactant: CO[Si](OC)(OC)[c-]1cccc1
Agent: [Fe+2]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O[Si](O)(O)[c-]1cccc1

Procedure:
A solution of 1,1′ bis-(trimethoxysilyl)ferrocene (1.25 g, 2.93 mmol) in 3 ml of ether was stirred vigorously with 1.37 ml of 0.5% acetic acid solution for 75 days. The final orange suspension was filtered and the solid was washed three times with ethanol, acetone and ether.