Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([C:14]2(O)[CH:19]3[CH2:20][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:14]1([C:9]2[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:13][CH:12]=[CH:11][N:10]=2)[CH:19]2[CH2:20][N:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1nccnc1C1(O)CN2CCC1C2
Solvent: ClCCl
Product: CCCCCCOc1nccnc1C1(Cl)CN2CCC1C2

Procedure:
A mixture of 4.8 g of (26) (0.021 mol) and 125 ml of hexanol that had reacted with 1.5 g of Na (0.065 mol) was heated to 80° C. for 45 min. The reaction was cooled to ambient, 100 ml of 1N HCl was added, and the hexanol was azeotroped off with water. The residue was made basic with 1N NaOH and extracted 3× with 50 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark solid. Recrystallization of the solid from ether gave 3.83 g of 3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (26a) as a floculent yellow solid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.65 (7H, m), 1.85 (2H, m), 2.25-3.07 (6H, m), 3.1 (1H, d), 3.75 (2H, d), 4.45 (2H, t), 8.01 (1H, d), 8.07 (1H, d). A solution of 1.5 g of (26a) (0.0052 mol) in 75 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1.5 h the reaction was heated to reflux for 45 min. The reaction was cooled to ambient, water was added, and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2 the washed with brine, dried, and the solvent evaporated to give a yellow oil. Radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 gave 1.2 g 3-chloro-3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptane (26b) as a pinkish liquid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.95 (10H, m), 2.25-3.9 (7H, m), 4.4 (2H, t), 8.0-8.1 (2H, m). A mixture of 1.2 g of (26b) (0.0039 mol) and 0.5 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi H2. The catalyst was removed, the solvent evaporated, the residue suspended in water, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. Tlc shows two major spots, 10% ethanol-1% NH4OH-CHCl3. The less polar of the two component was not well separated. The more polar component was treated with HCl in isopropanol and thoroughly evaporated. The residue was recrystallized from ether to give 0.15 g of (27) as slightly hygroscopic colorless crystals, mp 117°-118° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.55 (8H, m), 1.85 (3H, m), 3.2-3.75 (6H, m), 4.05 (2H, m), 4.38 (2H, m), 8.05 (1H, d), 8.08 (1H, d). Anal. C16H25N3O-HCl-0.5H2O requires C: 59.89; H: 8.48; N: 13.10%. Found C: 59.83; H: 8.31; N: 12.95%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=S)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[CH3:15][C:14]1[N:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[NH:3][CH:2]([CH3:1])[CH2:8][C:7]2=[N:18][N:17]=1
Reactant: CC1CC(=S)Nc2ccccc2N1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1NC(C)C2
Temperature: 130 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A disposable tube was charged with 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (163 mg, 0.848 mmol) and a stirbar. nBuOH (5 mL) was added, followed by acetohydrazide (126 mg, 1.695 mmol), and the solution was stirred at 130° C. overnight. The solution was concentrated and purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) to yield 1,5-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white amorphous solid (0.126 g, 0.588 mmol, 69%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)O)=[C:29]([CH3:42])[CH:28]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[C:29]([CH3:42])[CH:28]=1
Reactant: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3C)c[nH]c12

Procedure:
The title compound was prepared starting from 380 mg (2.14 mmol) of the compound from Example 8 and 591 mg (2.36 mmol) of the compound from Example 83A in analogy to the synthesis of the compound from Example 101. 307 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[F:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]3[N:35]=[C:36]([CH2:38][O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:37]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1>CC#N>[F:21][C:37]1[C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:35][N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:47][CH:46]=3)=[O:28])[CH2:30][C:31]=12
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(F)c2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (56 mg, 0.16 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (50 mg, 0.14 mmol) in CH3CN (2 mL). The mixture was stirred at 80° C. for 16 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield (3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (11 mg, 20% yield). C20H17F2N3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.05 (br. s., 2H), 4.20 (br. s., 2H), 4.79 (br. s., 2H), 5.05 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 49 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 4-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 49% yield: mp 96-97° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=4.8 Hz, 2H), 7.31-7.19 (m, 7H), 6.52 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.35 (s, 2H), 4.02 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 157.5, 155.3, 153.7, 149.7, 147.7, 135.4, 128.9, 128.2, 128.0, 122.3, 116.7, 47.9, 42.6, 42.0, 41.6, 17.3: MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: Oc1cc(C(F)(F)F)nc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Hydroxy-2,6-bis(trifluoromethyl)quinoline (1.28 g) was dissolved in phosphorus oxychloride (5.0 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform and concentrated under reduced pressure to give 4-chloro-2,6-bis(trifluoromethyl)quinoline (1.17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)[CH3:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cn1
Product: CCOC(=O)C(=CNc1ccc(OCC)nc1)C(=O)OCC
Temperature: 130 °C
Yield: 93.7 %

Procedure:
A mixture of 2-ethoxy-5-aminopyridine (2.89 g, 20.9 mmol) and diethyl ethoxymethylenemalonate (4.23 mL, 20.9 mmol) was heated at 130° C. for 4.5 hours. While warm, the mixture was evacuated. After cooling, the product was triturated with 2:1 hexanes:ether and collected to afford 6.04 g of diethyl (2-ethoxy-5-pyridylaminomethylene)malonate as a beige solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1cc(F)ccc1-3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1cc(F)ccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of foregoing crude ketone (from Step 4) in DCE (0.06 M) was added N,N-dimethylethane-1,2-diamine (1.0 eq) and HOAc (1.5 eq.), followed by solid sodium triacetoxyborohydride (1.5 eq). NaOH (20 eq., 1 N) was added after 16 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over Na2SO4 and concentration i. vac. gave the crude product, which was used without further purification; MS (ES+) m/z 494 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C@@H:25]1[C@@H:29]([CH2:30][NH2:31])[O:28][C@@H:27]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:26]1)(=O)C.C(Cl)Cl.CO>N1C=CC=CC=1>[C:1]([NH:31][CH2:30][C@H:29]1[O:28][C@@H:27]([N:32]2[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[CH2:26][C@@H:25]1[OH:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CN
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 35 %

Procedure:
557 mg of trityl chloride were added to a solution of 560 mg (2 mmol) of 3'-O-acetyl-5'-amino-5'-deoxythymidine [which had been prepared by the procedure reported by J. P. Horwitz et al. in J. Org. Chem., 27, 3045 (1962)] in 20 ml of dry pyridine, and the resulting mixture was heated under reflux for 1 hour whilst excluding moisture. After the disappearance of the starting compound had been ascertained by thin layer chromatography (using methylene chloride containing 5% by volume methanol as the developing solvent), the solvent was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was mixed with 10 ml each of methanol and water, and then the mixture was concentrated by distillation under reduced pressure. This operation was repeated three times, after which the residue was dissolved in 30 ml of ethyl acetate, and the resulting solution was washed with 20 ml each of a saturated aqueous solution of sodium chloride, 0.2N aqueous hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate. The organic solution was then dried over anhydrous magnesium sulfate, and the solution was then evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of methanol saturated with ammonia gas and the flask holding the solution was tightly closed. It was then allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was dissolved in 10 ml of methylene chloride. The solution was purified by column chromatography through silica gel, using methylene chloride containing 5% by volume of methanol as the eluent. Fractions containing the desired compound were combined and evaporated to dryness under reduced pressure. By lyophilizing the residue from benzene, 338 mg of the title compound were obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([OH:21])=[O:20])=[CH:5]2.[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2
Reactant: CCO
Reactant: Cc1ccc2nc(-c3ccccc3)c(CC(=O)O)cc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc2cc(C)ccc2nc1-c1ccccc1

Procedure:
0.50 g (1.80 mmol) of 13 was dissolved in 10 ml of EtOH, one drop of conc. sulfuric acid was added, and the mixture was heated under reflux for 2 h. The solvent was removed, the residue was taken up in ethyl acetate and washed 2× with water. The organic phase was dried and evaporated. The colourless oily residue is compound 16.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.CO.[C].[Pd]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(O)CCc1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 180 mg of (2E)-3-[1-(phenylsulfonyl)-1H-indol-2-yl]acrylic acid in 3 mL of ethanol and 5 mL of methanol, 50 mg of 10% palladium-carbon (wet, water content 53%) was added, and the resulting mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 2 hours. The catalyst was removed from the solution, the solvent was evaporated under reduced pressure, and the residue was washed with ether to obtain 90 mg of 3-[1-(phenylsulfonyl)-1H-indol-2-yl]propanoic acid as a white solid. FAB−: 328
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=O.[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[C:16](=[NH:19])OC)[CH3:13]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:10])[NH:19][C:16]([CH:15]([O:20][CH2:21][CH3:22])[O:14][CH2:12][CH3:13])=[N:11]2
Reactant: CCOC(OCC)C(=N)OC
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: CCO
Product: CCOC(OCC)c1nc2cccc(Cl)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 6-chloro anthranilic acid (6 g, 34.97 mmol) in EtOH (60 mL) under nitrogen atmosphere was added 1.5 equivalent of TEA (14 mL, 104.9 mmol). Upon completion of addition, the mixture was heated to 50° C. where it stirred for 30 min. After this time, a methyl 2,2-diethoxyacetimidate (6 g, 41.96 mmol) in ethanol solution was added through syringe and the resulting mixture was heated to reflux where it stirred for 24 h. At the conclusion of this period, the reaction mixture was cooled to RT and the volatiles were evaporated. The resulting residue was diluted with water, extracted with DCM and washed with brine solution. The crude product was purified by column chromatography (25% ethyl acetate in hexane) to provide 5-chloro-2-(diethoxymethyl)quinazolin-4(3H)-one (7 g, 60% yield). LCMS Method W: retention time 1.5 min; [M+1]=283.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[BH4-].[Na+].Cl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6]
Reactant: O=C(CCCCl)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCCl)c1cccs1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
4-Chloro-1-(2-thienyl)-1-butanone (9.37 g, 50 mmol) was dissolved in ethanol (100 ml) and the solution cooled to 0° C. Sodium borohydride (1.88 g, 50 mmol) was added in one portion and the reaction allowed to warm to room temperature, then stirred for 18 hours. Aqueous 2M hydrochloric acid was added dropwise until the reaction ceased to effervesce. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The layers were separated and the aqueous portion extracted with ethyl acetate (2×100 ml). The combined organic portions were washed with water (50 ml), dried (magnesium sulphate), filtered and evaporated. The residue was passed down a flash silica chromatography column, eluting with hexane: ethyl acetate (4:1) to afford the title compound as a pale straw coloured oil (7.58 g, 79%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.Cl[C:42]1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)([O-])[O-])=CC=2OC)[N:43]=1.NC1C=CC(C#N)=CC=1C(NC)=O>>[C:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1)#[N:43]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: COc1cc(CP(=O)([O-])[O-])ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: CNC(=O)c1cc(C#N)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-amino-5-cyano-N-methylbenzamide (Compound 150A). MS (ES+): m/z 593.19 (100) [MH+]; HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)C(Br)C(N)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)C(NCc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 41.60 g of p-nitrobenzylamine in 660 ml of dry ethanol was added 49.34 g of α-bromomalonamide and 38.2 ml of triethylamine. After being stirred for two hours under refluxing, the reaction mixture was cooled to room temperature. And then separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 53.36 g of α-(4-nitrobenzyl)aminomalonamide. And a mixture of 50.45 g of α-(4-nitrobenzyl)aminomalonamide, 177.8 g of triethyl orthoformate and 0.76 g of p-toluenesulfonic acid monohydrate in 1.3 liters of dry ethanol was stirred for three hours under refluxing in an argon atmosphere. The reaction mixture was cooled on an ice-bath and separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 50.78 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH2:18][OH:19])[C:5](Cl)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3[N:10]=[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]4[C:17]=3[CH2:18][O:19][C:5]2=[N:6][CH:7]=1
Reactant: OCc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)-c1nc3ccccn3c1CO2
Yield: 38.6 %

Procedure:
To a solution of (2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol (20 mg, 0.06 mmol) in DMF (2 mL), K2CO3 (20 mg, 0.14 mmol) was stirred at 100° C. overnight. The reaction mixture was concentrated in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using PTLC (eluted with dichloromethane:MeOH=50:1) to provide 2-bromo-4-aza-6H-chromeno[4′,3′:4,5]imidazo[1,2-a]pyridine (7 mg, yield: 39%). 1H-NMR (CDCl3, 400 MHz) δ 8.23 (d, J=2.4 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.75 (d, J=6.8 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.27˜7.30 (m, 1H), 6.90˜6.95 (m, 1H), 5.93 (s, 2H). MS (M+H)+: 302/304.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:42]C1C=CC2C3N(CCOC4C=CC=CC=4)C(CCCCNC(=O)OC(C)(C)C)=NC=3C=NC=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:42])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 2.5 h

Procedure:
A modification of the general method described in Part B of Example 49 was followed using N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.71 g, 3.55 mmol) in lieu of tert-butyl {4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate. The reaction was complete in 2.5 hours and provided 1.75 g of N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a light-brown solid.