Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].Br[CH2:33][CH:34]1CC1>>[CH:29]1([CH2:28][O:27][C@H:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:18]2[NH:17][C:12]2[C:11]([CH2:30][CH3:31])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:34][CH2:33]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: BrCC1CC1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCC1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (bromomethyl)cyclopropane and making non-critical variations provided the title compound as a yellow amorphous solid. IR (liq.) 3442, 2971, 2935, 2874, 1565, 1552, 1498, 1471, 1393, 1206, 1184, 1101, 1077, 1021, 740 cm−1; OAMS supporting ions at: ESI+ 481.8; MS (EI) m/z 481 (M+); HRMS (FAB) calcd for C27H29CL2N3O +H1 482.1766, found 482.1775. [α]25D=−65 (c 0.73, methylene chloride); Anal. Calcd for C27H29Cl2N3O: C, 67.22; H, 6.06; N, 8.71. Found: C, 67.15; H, 6.08; N, 8.66.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:15]=[C:16]=[O:17])=[C:4]([F:18])[CH:3]=1.C[Si]([N:23]=[N+:24]=[N-:25])(C)C>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][C:5]([N:15]2[C:16](=[O:17])[NH:25][N:24]=[N:23]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=C=Nc1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: O=c1[nH]nnn1-c1cc(Oc2ncccn2)c(Cl)cc1F

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidyloxy)phenylisocyanate (0.96 g) and trimethylsilyl azide (5 ml) were heated at reflux overnight under nitrogen. The reaction mixture was processed and the resulting oil chromatographed on silica gel eluting with ethyl acetate: methylene chloride, 1:4, to give a yellow semi-solid (0.54 g). 1H NMR (CDCl3, TMS): 7.16(1H, dd, J=4.8 Hz), 7.49(1H, d, J=9.3 Hz), 7.64(1H, d, J=6.8 Hz), 8.59(2H, d, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17]OC3CCCCO3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)O.[SiH](CC)(CC)CC.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>CC(=O)OCC.O>[F:50][C:49]([F:52])([F:51])[C:47]([O:53][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[C:8]2[C:7]([CH2:28][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[C:6]([O:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:2]([Cl:1])[CH:3]=3)[S:27][C:9]=2[N:10]([CH3:26])[C:11]1=[O:25])=[O:48]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 6-(3-chlorophenoxy)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 mg, 0.076 mmol) in TFA (0.9 mL) was added Et3SiH (0.3 mL). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 89.5% yield) as an oil. LCMS: MH+ 587 and TR=2.308 min.
Reaction SMILES: Br.Br[CH2:3][CH:4]1[O:23][C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[C:14]([C:15](=[O:16])[C:6]=2[CH2:5]1)=[CH:13][CH:12]=[CH:11][N:10]=3.[OH2:24]>CO.[OH-].[Na+]>[OH:24][CH2:3][CH:4]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7](=[O:23])[C:6]=2[CH2:5]1
Reactant: O
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)OC(CBr)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)OC(CO)C2

Procedure:
A solution of 15.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one hydrobromide in 200 ml of methanol, 160 ml of 1.0N sodium hydroxide solution and 150 ml. of water is stirred and refluxed on a steam bath for 21 hours. The reaction is concentrated to a volume of 200 ml in vacuo and the solid filtered and washed with water. Recrystallization of the crude solid from methanol yields the title compound, m.p. 267°-268°.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[N:11]1>C(O)C.CO>[CH:15]1[CH:14]=[C:13]2[C:12]([NH:11][NH:10][C:18]2=[CH:17][CH:16]=1)=[C:19]([N:2]=[O:3])[NH2:20]
Reactant: NO
Reactant: N#Cc1n[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: NC(N=O)=C1NNc2ccccc21
Temperature: 25 °C
Yield: 36.6 %

Procedure:
Hydroxylamine hydrochloride (1.5 g) and potassium carbonate (3.83 g) were stirred together in absolute ethanol (100 ml) for 15 minutes. Indazole-3-carbonitrile (2 g) was added and the solution heated at reflux for 4 hours, cooled to room temperature and diluted with methanol (5 ml). The solution was filtered and the solvent evaporated. The residue was extraced with anhydrous either, the extracts were dried over MgSO4, filtered and the solvent removed to afford a white solid, which was recrystallised from acetone/dichloromethane to afford the title compound (900 mg), m.p. 155°-158° C. δH (360 MHz, CDCl3) 6.46 (1 H, brm, N--OH), 7.17 (1 H, t, J=1 Hz, H-6), 7.41 (1 H, t, J=2 Hz, H-5), 7.55 (1 H, d, J=2 Hz, H-4), 8.03 (1 H, t, J=2 Hz, H-7 ); m/z (M+, 100%), 176 (100), 144 (80), 119 (25), 92 (15).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and CuI (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: [CH2:1]1[CH2:24][O:23][C:3]2([CH2:8][CH2:7][C@H:6]3[C@H:9]4[C@H:19]([CH2:20][CH2:21][C@:4]23[CH3:5])[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH:15]=[CH:16]2)=[CH:11][CH2:10]4)[O:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:22][C@H:14]1[CH:15]=[CH:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]32[O:2][CH2:1][CH2:24][O:23]3)[CH2:13]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=C[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of crude 17,17-ethylenedioxyandrosta-1.5-dien-3β-ol (4, 1.2 g) in pyridine (10 ml) and acetic anhydride (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and the compound was extracted with ether. The organic layer was washed with ice-water several times followed by brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo below 35° C. gave 1.0 g of crude solid. Recrystallization from methanol gave 3β-acetoxy-17,17-ethylenedioxyandrosta-1,5-diene (5). Mp. 105-6° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:29][CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:5]1=[O:28])[CH:2]=C.I([O-])(=O)(=O)=[O:43].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C:5](=[O:28])[C:4]([CH2:1][CH:2]=[O:43])([CH2:29][CH2:30][O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:40])[CH3:41])[CH:36]([CH3:38])[CH3:37])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Reaction time: 0.42 h

Procedure:
To a solution of 1.28 g (2.08 mmol) of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one (Example 69, Step A, mixture of diastereomers) in THF (50 mL) and water (17.5 mL) was added a catalytic amount of osmium tetroxide. After 25 min, 1.34 g (6.25 mmol) of sodium periodate was added. The resulting light brown slurry was stirred for 19 h and then was filtered through a fitted funnel. The filtrate was partially concentrated under reduced pressure, then was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of C-3 epimers) was used directly in the next step.
Reaction SMILES: N[C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:23]>O1CCOCC1.O.[Cu]Br>[Br:23][C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Br
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Temperature: -5 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile (0.5136 g, 2.07 mmol) in hot 1,4dioxane (1 ml) was added 48% aqueous hydrobromic acid (7 ml) and the mixture was cooled to −5° C. before adding dropwise a solution of sodium nitrite (0.1657 g, 2.40 mmol) in water (0.5 ml) over 5 min so that the temperature did not rise above −4° C. The resulting mixture was stirred at −5 to 2° C. for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (0.4452 g, 3.10 mmol) in 48% hydrobromic acid (3 ml). The mixture was stirred for 5 min then heated to 46° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The combined organic extracts were washed with 10% aqueous ammonia (25 ml), then saturated aqueous NaCl (20 ml), dried (MgSO4), and evaporated in vacuo. Purification by chromatography (silica gel, 20% EtOAc/isohexane) gave 0.3790 g (59%) of 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCC(CO)CC1
Yield: 12.1 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and 4-piperidinemethanol (131 mg, 1.14 mmol) were reacted as described in Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea as a colorless solid (28 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (brs, 1H), 9.04 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.52 (m, 5H), 6.49 (s, 1H), 4.41 (m, 1H), 4.27 (m, 2H), 3.99 (s, 3H), 3.24 (m, 2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m, 2H), 1.99-2.06 (m, 2H), 1.61-1.65 (m, 2H), 1.27 (s, 9H), 1.00-1.15 (m, 2H); LC-MS (ESI) m/z 607 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([NH:9][C:10](=[O:20])[CH:11]([C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1)[CH3:12])[CH3:8].CCOC(C)=O>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:7]([NH:9][C:10](=[O:20])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:14]=1)[CH3:12])[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)C(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 4.90 g (49.9 mmol) trimethylsilylacetylene in 450 mL acetonitrile are added 12.1 g (39.9 mmol) N-ethyl-2-(4-iodo-phenyl)-propionamide (IV.1) under argon, followed by 1.68 g (2.40 mmol) Pd(PPh3)2Cl2 as catalyst, 0.23 g (1.20 mmol) copper(I)iodide and 11.1 mL (80 mmol) TEA as base. The mixture is stirred at rt for 2.5 h. After that time, EtOAc is added and the organic layer is washed with saturated ammonium chloride solution and brine. The organic layer is separated, dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silicia gel; EtOAc/heptane, gradient 50% to 80%) to yield the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: BrC1CCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 73.5 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and bromo cyclopentane (103 mg, 0.691 mmol) gave 7-cyclopentyl-2-[5-(4-cyclopentyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (85 mg, 71%). MS (ESI) m/z 503.3 (M+H)+
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:53])[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42]2>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:53]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)c1cc2cc(C(=N)NO)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 15 min. Ethyl 5-[(hydroxyamino)(imino)methyl]-1H-indole-2-carboxylate (D22) (173 mg) was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was heated to 80° C. and stirred at that temperature for 5 hours. Most of the DMF was evaporated. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. Trituration with ethanol provided ethyl 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-2-carboxylate (D23) (85 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.37 (9H, m), 4.38 (2H, q), 4.89 (1H, m), 7.35 (1H, d), 7.45 (1H, d), 7.62 (1H, d), 7.98 (1H, dd), 8.12 (1H, dd), 8.20 (1H, d), 8.49 (1H, d), 12.27 (1H, s). MS (ES): C22H20ClN3O4 requires 425; found 426.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.[CH3:38][N:39]1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:39][CH3:38])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: CN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(C)COC(=O)Cl
Product: CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.16 g, 0.00034 mol, obtained from Step 5) at 0° C. is added isobutylchloroformate (0.063 g, 0.00046 mol) followed by the addition of N-methylmorpholine (0.064 g, 0.00064 mol). The resulting reaction mixture is stirred for 5 minutes under an argon atmosphere. The ice bath is then removed, the reaction mixture is stirred at room temperature for 20 minutes, then the reaction mixture is recooled to 0° C., and N-methylamine (0.5 mL of 2.0 M soln in THF) is added. The resulting mixture is stirred at room temperature for 10 min, concentrated in vacuo, and the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=478) are combined, concentrated to a small volume (˜20 mL), cooled, 5% NaHCO3 solution (10 mL) is added and then the combined fractions are extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.16 g, 96%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.87 (dd 1H, J=8.0 Hz), 7.64 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (m, 2H), 2.89 (s, 3H), 2.16 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 478.0586 (M+H calcd for C21H19N2O4F2 requires 478.0572). 19F NMR(CD3OD/400 MHz) −111.84(m) and −115.91 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH:40]1([CH2:43][O:44][C:45]2[CH:50]=[C:49]([CH2:51]O)[CH:48]=[CH:47][C:46]=2[N:53]([S:61]([CH3:64])(=[O:63])=[O:62])C(=O)OC(C)(C)C)[CH2:42][CH2:41]1.Cl.O1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13][CH2:51][C:49]1[CH:48]=[CH:47][C:46]([NH:53][S:61]([CH3:64])(=[O:63])=[O:62])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:50]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(COC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner as described in Scheme 3, Step 1) (0.150 g, 0.256 mmol) in DCM (10 ml), DMAP (0.0156 g, 0.128 mmol) was added followed by tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl(methylsulfonyl)carbamate (0.124 g, 0.333 mmol), and the resulting mixture was stirred at RT for 3 hours. HCl 4M in dioxane (3 ml, 12 mmol) was added and the reaction was stirred at RT for additional 5 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.15). A further purification by flash chromatography on silica gel column (DCM:acetone=10:1) was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzyloxy)carbonyloxy)ethyl)pyridine 1-oxide as a white solid (0.073 g, 0.102 mmol, 39.7% yield, MS/ESI+ 716.93 [MH]+, [αD]=−11.84, c=0.495, DCM).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7].S([N:23]=[N+:24]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C1C=CC=CC=1.O1CCCC1>[CH3:3][O:4][P:5]([C:9](=[N+:23]=[N-:24])[C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To sodium hydride (188 mg of a 60% solution in mineral oil, 113 mg clean, 4.70 mmol) in 14 mL of benzene and 2.5 mL of tetrahydrofuran, add the (2-Oxo-propyl)-phosphonic acid dimethyl ester (743 mg, 618 μL, 4.48 mmol) as a solution in 5 mL of benzene at 0° C. dropwise. The mix remains white and produces some gas. After 1 h at 0° C., add tosyl azide (940 mg, 4.70 mmol) as a solution in 2.5 mL of benzene and remove the bath. After 2.3 hours, pour the mix through a plug of Celite® with tetrahydrofuran, benzene and ether. Concentrate and apply to a 4 mm chromatotron plate and elute with 100 mL of Hexanes, and then 200 mL of 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc, 85:15 EtOAc/Hexanes and 250 ml of EtOAc to provide 794 mg of (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester as a yellow solid. This material may be used directly. Exact Mass 192.03: mass spectrum (aspci): m/z=165.0 (M+1 (—N2).