Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].[S:25]([O-:28])([O-:27])=[O:26].[Na+:29].[Na+].O.C(O)(C)C>C(#N)C>[CH:11]1([CH2:10][CH2:9][O:8][C:6]([C:5]2[CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:2]([S:25]([O-:28])(=[O:27])=[O:26])=[C:3]([N+:22]([O-:24])=[O:23])[CH:4]=2)=[O:7])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Na+:29]
Reactant: O=S([O-])[O-]
Reactant: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
50 parts of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate was dissolved in 157 parts of acetonitrile. To the solution was added dropwise the solution of 35.4 parts of sodium sulfite and 72 parts of water at room temperature. To the mixed solution 1965 parts of acetonitrile little by little, and then was added 500 parts of water to obtain uniform solution. The solution was heated to 80° C. and maintained the temperature with stirring for 3 hours. After checking the disapearance of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate by HPLC, the resulting solution was concentrated 80° C. under reduced pressure. To the concentrate was added 80 parts of methanol, and stirred for 30 minutes. The crystals precipitated were filtrated and washed with 40 parts of methanol, and the filtrate was concentrated at 80° C. to obtain yellow crystals. Further, to the crystals was added 400 ml of isopropanol and the mixture was subjected to azeotropic dehydration. The crystals were filtrated and washed with 200 ml of isopropanol, and dried to obtain 42.2 parts of sodium 4-(2-cyclohexylethoxycarbonyl)-2,6-dinitrobenzenesulfonate (Yield:90.7%, Yield:70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH2:20]([N:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1)[C:21]#[CH:22]>>[O:30]=[S:26]1(=[O:29])[CH2:27][CH2:28][N:23]([CH2:20][C:21]#[C:22][C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]3[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=3[F:1])[CH:16]=2)[CH2:24][CH2:25]1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCS(=O)(=O)CC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 80.2 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) and commercially available N-propargyl-S,S-dioxo-4-thiapiperidine (34 mg, 0.19 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 5 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a white powder (45 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 7.61 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.55 (m, 2H), 6.49 (m, 1H), 3.86 (br s, 2H), 3.72 (s, 2H), 3.17 (m, 8H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:9]=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH:4]12[O:37][CH:3]1[CH2:2][N:1]([C:6]1[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:9]=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=1)[CH2:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1cc(N2CC=CC2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: ClCCl
Product: NC(=O)c1cc(N2CC3OC3C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a suspension of the 6-(2,5-dihydro-1H-pyrrol-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (0.333 g, 0.885 mmol) in DCM (25 mL) was added mCPBA (0.201 g, 0.897 mmol, 77% solid). After 2 h, more mCPBA was added (0.198 g, 0.883 mmol, 77% solid). After stirring overnight, more mCPBA was added (0.202 g, 0.901 mmol, 77% solid) and the reaction was heated to reflux. After 5 h, more mCPBA was added (0.200 g, 0.892 mmol, 77% solid). After 2 h, more mCPBA was added (0.202 g, 0.901 mmol, 77% solid) and refluxing was continued overnight. When cooled, the reaction mixture was diluted with 100 mL DCM, washed twice with 25 mL saturated aqueous NaHCO3 solution, and once with 25 mL brine. The organic layers were dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 1 mL acetone, filtered, rinsed once with 0.5 mL acetone and dried under vacuum at 40° C. to give 6-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as an off-white powder (0.052 g, 0.13 mmol, 15% yield). LC/MS: m/z=393.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1ccncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2ccncn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
Into an appropriate sized reaction vessel, a mixture of (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.24 mmol), 4-bromopyrimidine (77.3 mg, 0.49 mmol), sodium carbonate (77.3 mg, 0.73 mmol) and Pd(PPh3)4 (14.04 mg, 0.01 mmol) was added Dioxane (8 ml), water (1 ml). The reaction mixture was stirred and heated at 120° C. for 3 h. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 45.0 mg (50.9%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyrimidin-4-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 9.211 (d, J=1.2 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.19 (dd, J=2.4, 0.9 Hz, 2H), 8.11 (s, 1H), 7.719 (s, 1H). 7.603 (s, 1H), 4.91-4.83 (m, 1H), 3.77-3.70 (m, 1H), 3.41 (t, J=9.2 Hz, 1H), 3.21 (dd, J=6.6, 6.9 Hz, 1H), 2.87-2.82 (m, 1H), 2.41-2.24 (m, 2H), 1.34 (d, J=6 Hz, 3H), 1.20-1.01 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C20H21N5O2: 363.17; found 364.04.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][N:5]=[CH:4][CH2:3]1.C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Na+]>CCOCC.O>[C:14]([N:6]1[CH:2]([CH3:1])[CH2:3][CH:4]=[N:5]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC1CC=NN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1N=CCC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a stirred solution of 6.5 g (0.0773 mole) of 5-methyl-2-pyrazoline and 8.08 g (0.08 mole) of triethylamine in 350 mls of ether was added in a rapid dropwise manner, a solution of 6.06 g (0.0773 mole) of acetylchloride in 100 mls of ether. After the addition was complete, the mixture was stirred at room temperature for 30 minutes then 50 mls of water was added. This mixture was stirred for 10 minutes. Sufficient sodium chloride was added to saturate the water present and the aqueous and ether phases were allowed to separate. The ether phase was removed and dried. The ether was evaporated off to yield 7 g of the crude product. This material was distilled at 68°-70° C. at 2 millimeters of mercury to give 4.5 g of the desired product as a colorless liquid. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 56.76, 7.79 and 22.26 percent, respectively, as compared with the theoretical contents of 57.12, 7.99 and 22.21 percent, respectively, calculated for the above-named compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.CN([CH:31]=[O:32])C>C(OCC)C>[CH2:12]([N:11]([CH2:15][CH2:16][CH3:17])[CH:7]1[CH2:8][C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:31]=[O:32])[CH:10]=2)[CH2:6]1)[CH2:13][CH3:14]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C1Cc2ccc(Br)cc2C1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCN(CCC)C1Cc2ccc(C=O)cc2C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Distilled (6-bromo-indan-2-yl)-dipropyl-amine (Example 11, 270 mg, 0.91 mmol) was dissolved in dry diethyl ether (20 mL). The solution was kept under argon and cooled to -78° C. A solution of t-BuLi in pentane 1.7M (0.7 mL, 1.20 mmol) was added and the mixture was stired at -78° C. for 1 h. Freshly distilled DMF (0.12 mL, 1.55 mmol) was added at -78° C. and the mixture was stirred at this temperature for 30 min. The reaction mixture was allowed to reach room temperature and stirred for additional 1 h. The organic layer was washed with aq. Na2CO3 (5%), the layers separated, dried (Na2CO3) and evaporated to dryness. MS m/e 245 (11, M+), 216 (100), 145 (17), 117 (22), 72 (21).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:21]1[CH:22]=[C:23]2[C:28](=[N:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:21]1[CH:30]=[N:29][C:28]2[NH:27][C:26](=[O:31])[CH2:25][CH2:24][C:23]=2[CH:22]=1
Reactant: C=CC(=O)N(C)Cc1c(C)n(C)c2c(C)cccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cccc2c(CN(C)C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)c(C)n(C)c12
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide (256 mg, 1 mmole) and 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (227 mg, 1 mmole) in propionitrile (20 mL) was treated with DIEA (0.3 mL), Pd(OAc)2 (29 mg, 0.13 mmole), and tri-o-tolylphosphine (50 mg, 0.16 mmole). The reaction was heated at reflux under argon for 10 h, then was cooled to RT and filtered through supercel. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel to afford the title compound (100 mg, 25%) as an off-white solid: MS (ES) m/e 403.2 (M+H)+. Anal. Calcd for C24H26N4O2.2.75H2O: C, 63.77; H, 7.02; N, 12.39. Found: C, 63.81; H, 7.25; N, 11.90.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.O.[Cu]I>[CH3:1][C:2]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc[nH]c1C
Reactant: OB(O)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncn(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Part A: A magnetically stirred mixture of ethyl 5-methyl-1H-imidazole-4-carboxylate (13.875 g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and CuI (0.85 g, 0.0045 mol) in ethanol/water (900 ml, 1/1 (v/v)) was divided in 12 equal portions and reacted in parallel at 85° C. for 60 hours. After cooling to room temperature the 12 portions were combined and concentrated in vacuo. The residue was purified by flash chromatography (Ethylacetate/petroleum ether 40-65=1/1 (v/v)) to give ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (5.88 g, 26% yield). 1H-NMR (400 MHz, CDCl3): 1.42 (t, J=7 Hz, 3H), 2.47 (s, 3H), 4.40 (q, J=7 Hz, 2H), 7.26-7.31 (m 7.56 (m, 3H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:27](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:27][C:19]([C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)O)c2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(N)=O)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
3-{2-[1-(Tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (17.8 g) was dissolved in DMF (200 ml), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (15.4 g) and 1-hydroxybenzotriazole (10.8 g) were added thereto, followed by stirring at room temperature for 2 hours. Ammonium chloride (8.57 g) and TEA (22.3 ml) were added to the reaction liquid, followed by stirring overnight at room temperature. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and the precipitated crystal was collected by filtration and dried to obtain tert-butyl 4-{2-[3-(aminocarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (10.8 g).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34]>C1(C)C=CC=CC=1>[S:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:31]([CH2:32][CH:33]([OH:35])[CH3:34])[C:5]=32)=[CH:10][CH:9]=1)([CH3:17])(=[O:16])=[O:15]
Reactant: CC(O)CN
Reactant: CS(=O)(=O)Oc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(OS(C)(=O)=O)ccc1C2
Reaction time: 0.75 h
Yield: 28 %

Procedure:
A solution of 2.31 g of (RS)-2-(2-oxoethyl)-6-mesyloxy-1-indanone and 110 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.58 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 2:3). 0.74 g (28%) of (RS)-1-(7-mesyloxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a light brown solid which was used directly in the next reaction.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:45]([C:46](=[O:49])[NH:47][CH3:48])=[C:44]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[O:43][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:42])[C:19]([O:21][CH2:22][O:23][P:24]([O:34]CC2C=CC=CC=2)([O:26]CC2C=CC=CC=2)=[O:25])=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>CCOC(C)=O.[Pd]>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:45]([C:46](=[O:49])[NH:47][CH3:48])=[C:44]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[O:43][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:42])[C:19]([O:21][CH2:22][O:23][P:24]([OH:26])([OH:34])=[O:25])=[O:20])[S:11]([CH3:14])(=[O:12])=[O:13])[CH2:2][CH2:3]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)OCOP(=O)(OCc3ccccc3)OCc3ccccc3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)OCOP(=O)(O)O)S(C)(=O)=O)c(C3CC3)cc12

Procedure:
(S)-((bis(benzyloxy)phosphoryl)oxy)methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoate (10 mg, 0.012 mmol) and Pd—C (10% wt) (1.3 mg) in EtOAc (250 μL) with NaHCO3 (1.045 mg, 0.012 mmol) was placed under N2 and then evacuated and backfilled with H2 and kept under an H2 balloon at RT for 2 hrs (trace COOH side prod.) Filtered through 0.45μ PTFE filter to give (S)-(phosphonooxy)methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[CH2:19]([NH:23][CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]>O>[CH2:19]([N:23]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCCO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: CCCCN(CCO)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.62 ml (0.02 mol) of 2-butylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.9 g of yellow powder are obtained, ie a yield of 70%.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)[C:6]([N:17]=NC2C=CC(Cl)=CC=2)=[C:5]([Cl:26])[N:4]=1.[C:27](O)(=O)C.O>O1CCCC1.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]2[C:6]([N:17]=[CH:27][N:9]2[C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[CH:12]=[CH:11]2)=[C:5]([Cl:26])[N:4]=1
Reactant: CC(=O)O
Reactant: Nc1nc(Cl)c(N=Nc2ccc(Cl)cc2)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A suspension of (1 S,4R)-4-((2-Amino-6-chloro-5-((4chlorophenyl)azo)-4-pyrimidinyl)amino)-2-cyclopentene-1-methanol hydrate (1.96 g, 5 mmol) in tetrahydrofuran (15 mL) was treated with acetic acid/water (1:1, 5 mL), then with zinc dust (1.63g, 25 mmol) in portions so as to keep the pot temperature below 35° C. The deep yellow color faded after 10 min, and after an additional 50 min the solution was filtered to remove precipitated zinc salts. The filter cake was rinsed with tetrahydrofuran and the filtrate was refiltered to remove additional zinc salts, then concentrated in vacuo with addition of toluene to facilitate removal of water and acetic acid. The residue was rinsed with toluene/hexane to separate some of the 4-chloroaniline byproduct, taken up in triethyl orthoformate (40 mL), cooled on an ice bath (5° C.), and treated dropwise with concentrated hydrochloric acid (1.9 mL). The mixture was stirred at 5° C. for 5 h (tan suspension soon formed), slowly warmed to room temperature, and stirred for an additional 18 h, then cooled on an ice bath and filtered. The filter cake was rinsed with ether (save filtrate), and this solid was taken up in water (30 mL), filtered, and the solids washed with water. The aqueous filtrate was basified with sodium carbonate to pH-9, then extracted with 5% isopropanol-hloroform (3×25 mL) The combined extracts were dried (Na2SO4) and concentrated in vacuo to a residual tan foam (0.85 g). The organic filtrate from above was concentrated in vacuo and the residue taken up in 1N hydrochloric acid (30 mL), stirred for 1h, filtered, and the filtrate adjusted to pH-6 with 5 N sodium hydroxide (6 mL, then basified with sodium carbonate. This aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a tan foam (0.55 g ). The two batches were combined, dissolved in warm chloroform, and loaded onto a silica gel column, which was eluted with 7% methanol-chloroform to afford pure fractions containing the subject compounds. These were concentrated in vacuo and the residual foam crystallized from ethyl acetate(2 crops) to afford 0.86 g (65%) of the title compound as a pale tan solid; mp 160°-162° C. 1H-NMR (DMSO-d6)δ: 8.04(s,1H); 6.91(s,2H); 6.15(m,1H); 5.90 (m,1H); 5.45 (m,1H); 4.73 (t, 1H,J =5 Hz); 3.45 (t,2H,J=5 Hz); 2.80-2.95(m, 1H); 2.55-2.70(m,1H); 1.60-1.70(m,1H). Ms(Cl): m/z 170 (m-C5ring, 100); 230 (m-Cl, 50); 266 (m+H+, 100). [α]20589 -104°, [α]20436 -267°(c=0.29, methanol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:15]2[C:16]([Br:26])=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[N:21]=[CH:20][CH:19]=[CH:18]3)[OH:14])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:26][C:16]1[C:15]([C@@H:13]2[CH2:12][O:14]2)=[C:24]([CH3:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2c(C)cc3ncccc3c2Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2ncccc2c(Br)c1[C@@H]1CO1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(5-bromo-7-methylquinolin-6-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (299 mg, 0.69 mmol) in THF (7.5 mL) at 0° C. was added potassium tert-butoxide (0.76 mL of 1.0 M solution in THF, 0.76 mmol). After stirring for 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl, and then diluted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-5-bromo-7-methyl-6-(oxiran-2-yl)quinoline. LCMS-ESI+ (m/z): [M+H]+ calc'd for C12H11BrNO: 264.00; Found: 264.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>C(N(CC)CC)C.[Cu]I>[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3([O:3][CH2:1][CH3:2])[CH2:6][CH2:5]3)=[C:8]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:9]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(ibriphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.