Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20]Cl)=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3cc(Br)ccc3c21
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A solution of 7-bromo-2-(chloromethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.65 g, 20.8 mmol) in DMF (20 mL) was added dropwise via addition funnel to a solution of N-hydroxyphthalimide (4.07 g, 25.0 mmol) and triethylamine (4.3 mL, 31.2 mmol) in DMF (20 mL). The addition funnel was rinsed with DMF (20 mL) and the rinse was added to the reaction solution, which was stirred at room temperature. After 30 minutes, a precipitate formed. The viscous mixture was stirred at room temperature overnight, then diethyl ether (150 mL) was added. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 7.44 g of 2-{[4-amino-7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione, which contained some triethylamine hydrochloride. The filtrate was concentrated to yield 8.5 g of a brown oil, which was found to contain product and was combined with the material from above and used in the next step.
Reaction SMILES: [Cl:1]C(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](CO)=[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:19]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[ClH:1].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:7][O:6][C:5](=[O:11])[N:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:18]=2[CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2CO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cl
Product: O=C1OCc2ccc(Cl)cc2N1C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triphosgene (1.6 g) was added to a stirred solution of the product from step (i) (5 g), N,N-diisopropylethylamine (5.2 ml) in tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at room temperature for 16 h, the precipitate filtered and the filtrate evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate/toluene. The product was dissolved in dichloromethane then a solution of hydrogen chloride in 1,4-dioxane added. After 2 h the solvent was removed under reduced pressure to yield a solid. Used directly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[N:7][CH:6]=[CH:5]2.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH:21]1[C:22](=[O:23])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nccc2cc(Br)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1nccc2cc(Br)ccc12
Reaction time: 6 h
Yield: 115.4 %

Procedure:
To a mixture of 6-Bromo-isoquinolin-1-ylamine (0.80 g), Boc-L-proline (0.803 g), and 4-methylmorpholine (0.83 mL) in DMF (10 mL) was added HATU (1.39 g). Reaction mixture was stirred for 6 hours. Additional Boc-L-proline (0.803 g), 4-methylmorpholine (0.83 mL) and HATU (1.39 g) were added and reaction stirred overnight at ambient temperature and then concentrated. The residue was dissolved in ethyl acetate and washed with 10:1 H2O/saturated sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-(6-Bromo-isoquinolin-1-yl carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g): LCMS-ESIF: calc'd for C19H23BrN3O3: 421.31 (M+H+). Found: 419.8, 421.8 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>CC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nc(C2CCN(CCCO)CC2)c2ccc(F)cc21
Yield: 36 %

Procedure:
A mixture of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine (5.0 g; 0.02 mol), potassium carbonate (8.28 g; 0.06 mol), 3-bromopropanol (2.98 g; 0.02 mol) and acetone (100 ml) was stirred and refluxed for 20 h. The reaction mixture was filtered, concentrated in vacuo and purified by chromatography on silica gel 60 with ethyl acetate:methanol (8:2, v/v) as eluent. Concentration of the appropriate fractions afforded 2.1 g (34%) of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-(3-hydroxypropyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.O.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)nc(Cl)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of 2,6-dichloro-4-nitropyridine (14.82 g, 76.79 mmol) in 350 mL ethanol were sequentially added iron powder (19.91 g, 356.58 mmol), water (65.8 mL, 3.6 mol) and concentrated hydrochloric acid (14.1 mL, 464.1 mmol). After the reaction was performed by stirring for 16 h at 95° C., the reaction solution was cooled to room temperature, adjusted to neutral pH, and subjected to suction filtration. After the filtrate was concentrated, it was extracted with ethyl acetate. The organic phase was combined, dried with anhydrous MgSO4, and subjected to rotary evaporation to afford 11.9 g titled product with a yield of 95.1%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)OCC1.C1COCC1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:13][CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][CH2:7]1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25° C. for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification.
Reaction SMILES: [ClH:1].[C:2](=O)(O)[O-].[Na+].Cl.C[CH:9]1[C:14](O)([CH:15]([SH:17])[CH3:16])[C:13]([CH2:19][OH:20])=[CH:12][CH:11]=[N:10]1.[OH2:21]>>[ClH:1].[CH3:2][C:11]1[C:12]([OH:21])=[C:13]([CH2:19][OH:20])[C:14]([CH:15]([SH:17])[CH3:16])=[CH:9][N:10]=1
Reactant: O=C([O-])O
Reactant: CC(S)C1(O)C(CO)=CC=NC1C
Reactant: O
Agent: Cl
Agent: [Na+]
Product: Cc1ncc(C(C)S)c(CO)c1O
Temperature: 0 °C

Procedure:
A mixture of 2.0 g. of the mercaptoethyl compound from Step B, 6.0 ml. of 2.5 N hydrochloric acid and 10 ml. of water was heated at 50° C. for 45 minutes. The mixture was made alkaline with solid sodium bicarbonate and concentrated to dryness. The residue was extracted with 50 ml. of hot isopropanol. The extract was cooled to 0° C., saturated with dry hydrogen chloride and concentrated to dryness. The solid residue was isolated by trituration with ether and filtration and dried to give 1.26 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-3-(1-mercaptoethyl)pyridine hydrochloride. After recrystallization from isopropanol-ether, it had m.p. >200° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[CH:11]([O:13]COCCOC)[CH3:12].O>CO>[Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:8])=[O:9])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: COCCOCOC(C)c1cc(S(N)(=O)=O)sc1Br
Solvent: O
Solvent: CO
Product: CC(O)c1cc(S(N)(=O)=O)sc1Br
Temperature: 25 °C
Yield: 48.9 %

Procedure:
5-Bromo-4-[l-(methoxyethoxymethoxy)ethyl]thiophene-2-sulfonamide (5.3 g, 0.014 mol) was dissolved in methanol (25 ml) and water (25 ml) was added. Some oil separated. To this stirred mixture was added sulfuric acid (25 ml) dropwise with cooling over 20 minutes. The resulting solution was stirred at room temperature over night. The methanol was removed in vacuo and the residual suspension was diluted with two volumes of water. The product was extracted into ethyl acetate. The extract was washed with saturated NaHCO3, water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This gave 4.0 g of a viscous amber oil. The crude oil was chromatographed on silica gel (150 ml) eluting with 5% methanol/chloroform to give 1.96 g of colorless oil which showed a single spot by TLC. Trituration of the oil in n-butyl chloride gave a white solid (1.69 g, 49%), m.p. 126-128.5° C. NMR supported the structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](Cl)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNOC
Reactant: O=C(Cl)C=Cc1ccc(F)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
The unpurified 3-(3-bromo-4-fluoro-phenyl)-acryloyl chloride (3.5 g, 13.3 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.0 mmol), and pyridine (2.4 mL, 29.4 mmol) were added at 0° C. to dichloromethane (20.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 3.2 g of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:6][CH:7]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(Br)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (2.00 g, 5.00 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.025 mL, 0.13 mmol) were combined in THF (7 mL). The mixture was cooled to 0° C. and sodium hydride (210 mg, 60% dispersion in mineral oil, 5.25 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.25 mmol) in THF (4 mL) was added and the reaction was warmed to room temperature. After 16 h, an additional amount of sodium hydride (spatula tip) was added and the mixture was stirred an additional 6 h. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil. This material was crystallized from hot isopropyl ether/heptane. The supernatant was decanted and the solid was washed with heptane and dried in vacuo to afford the title compound (1.37 g, 62% yield) as an off-white solid. MS (APCI) M−100=345.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.44-2.50 (m, 2H) 3.38-3.44 (m, 2H) 3.48-3.54 (m, 2H) 6.35 (s, 1H) 6.85 (dd, J=8.77, 0.58 Hz, 1H) 6.94-7.00 (m, 2H) 7.03-7.07 (m, 1H) 7.35 (t, J=7.80 Hz, 1H) 7.78 (dd, J=8.67, 2.63 Hz, 1H) 8.23 (dd, J=2.53, 0.58 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[C:4]([N+:14]([O-])=O)[CH:3]=1.CC1C=CC=C([N+]([O-])=O)C=1C(OCC=C)=O>>[NH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=1[C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7]
Reactant: C=CCOC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Product: C=CCOC(=O)c1ccc(Cl)cc1N

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate, to give allyl 2-amino-4-chlorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:40])=[C:10]([CH3:39])[C:11]=2[C:12]([C:14]2[CH:33]=[CH:32][C:17]([O:18][S:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=3)(=[O:21])=[O:20])=[C:16]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:31][C:24]1[CH:23]=[C:22]([S:19]([O:18][C:17]2[CH:32]=[CH:33][C:14]([C:12]([C:11]3[C:10]([CH3:39])=[C:9]([CH3:40])[S:8][C:7]=3[CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:42][CH:41]=3)=[O:13])=[CH:15][C:16]=2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)(=[O:21])=[O:20])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccc(Br)cc4)sc(C)c3C)cc2C2CCCC2)ccc1C(=O)O

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-{4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.211 g, 0.315 mmol), magnesium iodide (0.0876 g, 0.315 mmol) and acetic anhydride (2.5 mL) in ether. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.185 g (57%) of the tide compound as a white solid, mp 113-114° C. 1H NMR (DMSO-d6) δ1.27-1.34 (m, 2 H), 1.51-1.58 (m, 2 H), 1.63-1.78 (m, 4 H), 1.80 (s, 3 H), 2.25 (s, 3 H), 2.28 (s,3 H), 2.95 (quintet, 1 H), 3.86 (s, 2 H), 6.97 (d, 2 H), 7.24 (d, 1 H), 7.38 (d, 2 H) 7.52 (dd, 1 H), 7.57 (d, 1 H), 7.86 (d, 1 H), 7.92 (dd, 1 H), 8.16 (d, 1 H) 13.8 (br,s 1 H). mass spectrum (−ESI) m/z 709 (M−H). Anal. Calcd. for C34H31BrO8S2: C, 57.38; H, 4.39; N, 0.00. Found: C, 56.99; H, 4.38; N, 0.02.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=N[C:20]2N(O)N=[N:25][C:19]=2[CH:18]=1.CN1CC[O:31][CH2:30]C1.CCN=C=NCCCN(C)C.[ClH:45]>C(Cl)Cl.O>[ClH:45].[ClH:45].[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]=[C:20]([C@@H:19]([NH2:25])[CH2:18][O:31][CH3:30])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=2[C:2]=1[F:1]
Reactant: CN1CCOCC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccccc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC[C@H](N)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4-difluoro-N2-phenylbenzene-1,2-diamine (400 mg, 1.8 mmol), Boc-ser(OMe)-OH (800 mg, 2.0 mmol), HOAT (340 mg, 2.0 mmol) and N-methylmorpholine (500 μL, 4.0 mmol) in DCM (5 mL) was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (480 mg, 2.0 mmol) and the reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (10 mL, 4 M) and the reaction mixture heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in EtOAc (10 mL). The solution was washed with sat. aq. NaHCO3 and the product extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to give the title compound as an off white solid (207 mg, 38%). LCMS (Method C): RT=2.27 min, [M+H]+=304.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:21][C:22]([F:40])([F:39])[C:23]1[N:28]=[C:27]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.CS(C)=O>[C:11]([C:10]1[N:6]2[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]2)=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30]([NH:29][C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:39])([F:21])[F:40])[N:28]=3)=[O:31])=[CH:16][CH:15]=2)[CH:9]=1)(=[O:13])[CH3:12]
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Reactant: CC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A mixture of 1-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanone (50.0 mg, 0.19 mmol), phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate (105.6 mg, 0.37 mmol,), and triethylamine (0.10 mL, 0.75 mmol) in DMF (2 mL) was stirred overnight resulting in formation of a precipitate. The mixture was diluted with DMSO (1 mL) and then the solid was collected by filtration, washed with MeOH, and air-dried to give 53.0 mg (62%) of the title compound. 1H-NMR (DMSO-d6) δ 9.87 (s, 1H), 9.71 (s, 1H), 9.60 (d, J=3.2 Hz, 1H), 8.34 (d, J=3.3, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 4H), 7.76 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.52-7.50 (m, 1H), 2.64 (s, 3H); MS [M+H]+=456.1; LCMS RT=3.25 min.
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[N+]=[N-].C(N(CC)CC)C.[I:32][C:33]1[CH:40]=[CH:39][C:36](CBr)=[CH:35][CH:34]=1>Cl.CO.C(Cl)Cl>[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([C@H:4]([NH2:1])[C:5](=[O:11])[N:6]3[CH2:10][CH2:9][S:8][CH2:7]3)[CH2:17][CH2:16]2)=[CH:35][CH:34]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N=[N+]=[N-])C(=O)N2CCSC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCSC1)C1CCN(Cc2ccc(I)cc2)CC1
Reaction time: 4 h

Procedure:
tert-Butyl 4-[(1S)-1-azido-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]piperidine-1-carboxylate (Example 96, step B, 215 mg, 0.6 mmol) was dissolved in a freshly prepared HCl in methanol (1 mL acetyl chloride in 9 mL of methanol) and stirred for 4 h and concentrated to remove the Boc group. A portion of this material (29 mg, 0.1 mmol) was dissolved in methylene chloride (1 mL) and triethylamine (0.041 mL, 0.3 mmol) and 4-iodobenzylbromide (44 mg, 0.15 mmol) was added. The reaction mixture was stirred for 8 h, concentrated and purified by flash chromatography (silica gel, eluent: 20% acetone in CH2Cl2) to give the 4-iodobenzylamine. This material was dissolved in wet THF (10% water) and triphenyl phosphine (26 mg, 0.1 mmol) was added. The reaction mixture was heated in an oil bath at 60° C. for 3 h, concentrated and subjected to preparative TLC on silica gel (eluent: 10% MeOH in CH2Cl2) to afford 32 mg of the title compound. 1H NMR (500 MHz, CD3OD) δ 7.85 (d, 2H, J=6 Hz), 7.34 (d, 2H, J=6 Hz), 4.75–4.46 (m, 2H), 4.38–4.28 (m, 1H), 4.47 (s, 2H), 3.92–3.64 (m, 2H), 4.53 (bs, 2H), 3.16–3.02 (m, 4H), 2.19 (m, 1H), 1.98 (m, 2H), 1.83 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=O)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:33][NH:34][O:35][CH3:36]>CN(C=O)C>[CH3:36][O:35][N:34]([CH3:33])[C:19]([C:11]1[O:13][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:16][CH:15]=2)=[N:9][C:10]=1[CH3:14])=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNOC
Reactant: CC(NC(=O)c1ccc(C(F)(F)F)cc1)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-Trifluoromethyl-benzoylamino)-propionic acid (5.0 g, 19.14 mmol) is added oxalyl chloride (16.7 mL, 191.4 mmol) and 2 drops of DMF and the solution stirred overnight. The volatiles are removed in vacuo and toluene (20 mL) is added. The toluene is then removed in vacuo. To the resultant crude oil is dissolve in dichloromethane (100 mL), cooled to 0° C. and triethylamine (13.4 mL, 96 mmol) is added followed by N,O-dimethyl hydroxylamine hydrochloride (9.4 g, 96 mmol). After 1 hr the mixture is partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The product is purified over silica eluting with 8:2 hexanes:ethyl acetate to afford 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid methoxy-methyl-amide as a white crystalline solid, 2.4 g, 40%. MS (M++1)315.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred suspension of 4-(5-bromo-2-chlorobenzyl)phenol (5.0 g, 16.8 mmol) in N,N-dimethylformamide (20 mL) and cesium carbonate (11.0 g, 33.6 mmol) was added ethyl 2-bromoacetate (2.8 mL, 25.2 mmol). The mixture was stirred overnight at 80° C. The solution was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 5.0 g of white solid (78% yield).