Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([C:7]([NH2:9])=[NH:8])[CH:6]=[CH:5]C=N1.NCC[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CC#N>[ClH:1].[C:7]([NH:2][CH2:6][CH2:5][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[NH:8])[NH2:9]
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=N)N
Reaction time: 24 h
Yield: 100 %

Procedure:
Portions of solid 1H -pyrazole-1-carboxamidine hydrochloride (91.10 g, 624 mmol)) are added to a stirred solution of N-(2-aminoethyl)(tert-butoxy)carboxamide (0.62 M) in CH3CN (1 L) at 80° C. After 24 hours, the reaction was stripped of solvent under reduced pressure. The residue was triturated with ether (3×100 ml), and dried in vacuo. The N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride was obtained in over 100% yield containing a small amount of pyrazole. The N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride was used without further purification.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:25](#[N:30])/[CH:26]=[CH:27]/[C:28]#[N:29]>>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][CH:19]=3)=[C:27]([C:28]#[N:29])[C:26]=2[C:25]#[N:30])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: N#C/C=C/C#N
Reactant: CCCCOc1ccc(C=CC=C[C@H]2CC[C@H](CCC)CC2)cc1
Product: CCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC)CC3)c(C#N)c2C#N)cc1

Procedure:
Using 1-(Trans-4'-n-propylcyclohexyl)-4-(p-n-butoxyphenyl)-1,3-butadiene and fumaronitrile, 3-(trans-4'-n-propylcyclohexyl)-6-(p-n-butoxyphenyl)phthalonitrile was obtained by the same method as in Example 1. m.p. was 115° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[NH:17][C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=2)[C:7]=1[Br:30].[CH3:32]C([O-])(C)C.[K+].[H-].[Na+]>C1COCC1>[Br:30][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:16]3[N:17]([CH3:32])[C:18]4[C:23]([C:24]=3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][CH2:4][C:3]([OH:2])=[O:31]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OC)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)O)ccc3c2)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetic acid methyl ester (0.410 g, 0.853 mmol) in THF (20 mL) at 0° C. was added KOt-Bu (0.105 g, 0.938 mmol) followed by Mel (0.064 mL, 1.02 mmol). The reaction was warmed to rt and let stir for 1 h. It appeared by TLC and MS that all the starting material was gone; however, two polar acids (one N-Me and one N—H) had been generated due to hydrolysis in these basic conditions. After concentration, the residue was taken up in DMF (20 mL). Added NaH (0.075 g, 60% by wt., 1.88 mmol) followed by excess Mel to convert all intermediate to one acid (N-Me). After 1 h, the reaction mixture was concentrated and then diluted with EtOAc (200 mL) and 1 N HCl (20 mL). The organic layer was washed with H2O (20 mL) and brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by preparatory plate chromatography (10% MeOH:CHCl3) to afford the product (0.232 g, 57%) as a yellowish-orange foamy solid, mp >73° C. (decomp.); 1H NMR (DMSO-d6) δ 0.73 (t, J=7.0 Hz, 3H), 1.11-1.20 (m, 4H), 1.50-1.58 (m, 2H), 2.66 (t, J=7.3 Hz, 2H), 3.58 (s, 3H), 4.93 (s, 2H), 7.07 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.42-7.48 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.68 (dd, J=1.7, 8.7 Hz, 1H), 7.99 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 11.95-14.75 (bs, 1H); IR (neat) 3050, 2955, 2925, 2850, 1725, 1670, 1600, 1480, 1470, 1430, 1370, 1325, 1275, 1220, 1190, 1145, 1095, 1015, 980, 925, 895, 830, 800, 765, 735, 700, and 665 cm−1; mass spectrum [(+) ESI], m/z 480/482 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][CH2:45][CH2:46][CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:47][CH2:46][CH2:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: OCCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2011/154734A1, which is incorporated herein by reference in it is entirety; 500 mg, 1.88 mmol), and Ph3P (986 mg, 3.76 mmol) in dry THF (10 mL) was added 3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (Can. J. Chem. Vol. 73, 1195, pp 1682, which is incorporated herein by reference in it is entirety; 452 mg, 2.82 mmol). The resulting mixture was cooled to 0° C. using an ice bath and diethylazodicarboxylate (0.69 mL, 3.76 mmol) was added to the chilled mixture which was allowed to warm up to RT. The volatiles were removed under reduced pressure. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (739 mg, 96%). LCMS (Method 1): Rt 3.63 min, m/z 408 [MH+].
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[CH:20][C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](=O)=O.C([O-])(O)=O.[Na+]>C(O)=O>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([CH:20]=1)[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: O=C(Nc1cccnc1)c1cc(OC[C@@H]2CCCN2)ccc1OCc1ccccc1
Reactant: O=C=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
2-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2S)-2-pyrrolidinylmethyl]oxy}benzamide (may be prepared as described in Example 46; 80 mg, 0.20 mmol) was added to formic acid (4 ml) at 5° C., followed by aqueous formaldehyde (40%, 2.0 ml). When the initial evolution of carbon dioxide had subsided, the mixture was refluxed for 2 h. After the solution was cooled, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7.2 min, 40%-50%; 7.2-7.5 min, 50%-95%; 7.5-11.5 min, 95%, RT=4.0 min) to yield the title compound as a white solid. 68 mg.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH2:22][OH:23])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25](OC(=O)C)(=[O:27])[CH3:26].CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:23][CH2:22][C@@:21]12[C@@H:11]3[C@H:12]([C@H:7]4[C@:8]([CH3:24])([CH2:9][CH2:10]3)[C@@H:4]([C:2](=[O:3])[CH3:1])[CH2:5][CH2:6]4)[CH2:13][CH2:14][C:15]1=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.5 g of 19-hydroxyprogesterone and 0.25 g of 4-dimethylaminopyridine in 8 ml of pyridine is treated with 4 ml of acetic anhydride and stirred for 18 hours at room temperature. The solution is chilled to 0° C. and treated with 4 ml of methanol to consume excess acetic anhydride. After stirring for 15 minutes, the solution is concentrated to a small volume at reduced pressure and the residue is taken up in ether. The ether solution is washed three times with dilute hydrochloric acid, once with sodium bicarbonate solution and finally with brine. Drying and concentration gives 19-acetoxypregn-4-ene-3,20-dione which is obtained as a colorless solid upon crystallization from aqueous ethanol.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of benzyl alcohol (5.27 g, 48.7 mmol) in N,N-dimethylformamide (12 mL) was cooled to 0° C. prior to the portion-wise addition of sodium hydride (60% dispersion in mineral oil, 1.95 g, 48.7 mmol). This mixture was warmed to room temperature and stirred for 30 min before being cooled to 0° C. followed by the addition of a solution of the product from Step 1 (2.0 g, 12 mmol) in N,N-dimethylformamide (12 mL). After the addition, the reaction was warmed to 95° C. for 16 h. After cooling to room temperature, the reaction was partitioned between EtOAc and H2O. The layers were separated and the precipitated solids in the organic layer were collected by filtration, washed with EtOAc and air dried. A second crop of solids was collected and the filtrate washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to provide a third crop of solids. Combination of the solids and drying to constant weight afforded 2.82 g (93%) of 7-(benzyloxy)quinazolin-4(3H)-one as a tan solid. MS 253.3 (ES+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].I[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][N:12]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:6][C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: CCCCI
Reactant: COC(=O)c1ccc(CONCc2cc(F)cc(F)c2)cc1-c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(Cc1cc(F)cc(F)c1)OCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution at ambient temperature under N2 of 4-(N-(3,5-difluorobenzyl)aminooxymethyl)-2-(2-methylphenyl)benzoic acid methyl ester (254 mg, 0.640 mmol), prepared as in Example 1176 C, in DMF (2 mL) was added potassium carbonate (265 mg, 1.92 mmol) and 1-iodobutane (0.146 mL, 1.28 mmol). Reaction stirred vigorously at 80° C. overnight. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue was purified by flash chromatography on silica gel eluting with 7% EtOAc/Hexanes to 30% EtOAc/Hexanes to afford the desired product. (44 mg, 15%). m/e (ESI) 454 (MH+)
Reaction SMILES: [C:1](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH3:16])[N:6]=[C:5]([CH3:17])[C:4]=1I.[Cl-].[Li+].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>O1CCOCC1.C(Cl)(Cl)Cl.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>[C:1](=[O:24])([O:2][C:3]1[C:4]([CH:27]=[CH2:28])=[C:5]([CH3:17])[N:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=Cc1c(C)nc(C)c(CCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 10 %

Procedure:
To a solution of 7 (60 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-heptyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (9) (30 mg, 64%). 1H NMR (CDCl3) δ 0.85-0.88 (m, 3H), 1.27-1.32 (m, 10H), 1.47 (s, 9H), 2.40 (s, 3H), 2.43 (s, 3H), 2.47-2.50 (m, 2H), 5.50 (dd, 2H, J=18 Hz, 11.2 Hz) and 6.45 (dd, 1H, J=11.6 Hz, 11.6 Hz).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]1[C@H:25]2[C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13]([N:17]3[CH:16]4[CH:25]([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(-c2ccc(F)nc2)c1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(-c2ccc(F)nc2)c1)N1CCCC2CCCCC21
Yield: 19.8 %

Procedure:
5-(6-Fluoro-pyridin-3-yl)-thiophene-3-carboxylic acid (0.05 g, 0.22 mmol) was dissolved in acetonitrile (1 mL) together with cis, trans-decahydroisoquinoline (0.134 mL, 0.90 mmol), triethylamine (80 μL, 0.60 mmol) and HATU (0.085 g, 0.22 mmol) and the resulting mixture was stirred over the weekend. The crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were evaporated to give the title compound as a pink oil (0.015 g). LCMS m/z 345.23 [M+H]+ R.T.=11.76 min (Analytical Method 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[Br:17]Br.BrBr.C(O)(=O)C>C(O)(=O)C.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:16])[CH2:15][Br:17])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccccc1-c1ccc(C)cc1
Reactant: BrBr
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Temperature: 30 °C
Yield: 943.7 %

Procedure:
A solution of 4'-methyl-2-acetyl-1,1'-biphenyl (2.06 g, 9.79 mmol) in 10 mL of glacial acetic acid was treated dropwise with a solution of bromine (1.722 g, 1.07 mmol) dissolved in 3.0 mL of glacial acetic acid. After initiating the reaction with the first few drops of the bromine/acetic acid reagent by heating the reaction mixture at 30° C., the remainder of the bromine solution was added dropwise at 25°-30° C. The reaction mixture was stirred at room temperature until the consumption of bromine was complete (approximately 2 hrs). The reaction mixture was diluted with 150 mL of hexane then washed with water (3×50 mL). The organic layer was removed, dried over magnesium sulfate, filtered and evaporated under vacuum to give 2.92 g of an oil that was used in the next step without purification. 1H NMR (crude product) (200 MHz,CDCl3): 2.38 (s,3H), 3.66 (s,2H), 7.21 (s,4 H), 7.3-7.6 (m,4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[N:25](C(C)(C)C)[N:26]=[C:27]([CH3:29])[CH:28]=1>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(Br)cc23)n(C(C)(C)C)n1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(Br)cc23)[nH]n1

Procedure:
15 mg of 6-Bromo-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were heated in formic acid for 5 hrs at 90° C., then evaporated and chromatographed on silica (DCM, then DCM/MeOH 40:1). Yield 10 mg. 1H-NMR: (400 MHz, D6-DMSO) 9.33 (1H, br s), 8.86 (1H, br s), 8.26 (1H, d), 8.80 (1H, d) 7.62 (2H, d), 7.51 (2H, d),.6.26 (1H, s), 2.20 (3H, s), 1.35 (9H, s); MS (ESI+)=452.35 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:41]([CH2:40][CH2:39][O:38][CH3:37])(=[O:43])=[O:42])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: COCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 74.9 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.49 mmol), 2-methoxy-1-ethanesulfonyl chloride (J. Org. Chem. 2633, 26, 1961) (77 mg, 0.49 mmol), triethylamine (150 mg, 1.5 mmol) in tetrahydrofuran (23 ml). The crude product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) gave the title compound (225 mg) as an oil. MS: 614 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22])(=[O:4])[CH2:2][CH3:3].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH3:22])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCSCCOc1cccc2c(Cl)c(C(=O)CC)cnc12
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCCSCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Yield: 59.5 %

Procedure:
3-Propanoyl-4-chloro-8-(2-propylthioethoxy)quinoline (2.5 g, 7.40 mmol) and o-toluidine (0.95 g, 8.86 mmol) was refluxed in acetonitrile (10 ml) for 2 h. The solvent was evaporated and the residue was partitioned between methylene chloride and 10% Na2CO3 solution. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (methylene chloride:ethyl acetate 80:20). 1.8 g (60%) of the title compound was obtained.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:47](=[O:62])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](=[O:61])[O:54]CC[Si](C)(C)C)[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1]([NH:4][CH:5]([CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)[C:47]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:61])=[O:54])=[O:62])(=[O:3])[CH3:2]
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)OCC[Si](C)(C)C)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 97.4 %

Procedure:
A solution of benzhydryl 2-{4-[2-(acetylamino)-3-oxo-3-({5-oxo-5-[2-(trimethylsilyl)ethoxy]pentyl}amino)propyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoate (356 mg, 0.41 mmol) and tetrabutylammonium fluoride-1M in THF (4 mL) was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N HCl (3×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (305 mg). MS (APCI(+)) m/e 764 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.31-7.90(m, 2H), 7.73-6.85 (m, 16H), 4.43-4.33 (m, 1H), 3.22-2.48 (m, 6H), 2.22-2.15 (m, 2H), 1.80-1.72 (m, 3H), 1.62-1.25 (m, 4H), 1.05, 1.04, 1.00 (s, s, s, 9H), 1.25-0.78 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH2:31])[CH2:28]1)([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CC(O)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH:31][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 70 °C

Procedure:
To a mixture of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (342 mg, 1.07 mmol), as prepared in Example 2, step 1, and tert-butyl((trans)-3-aminocyclobutyl)carbamate (200 mg, 1.07 mmol) in iPrOH (4 mL) was added DIPEA (0.5 mL). A stir bar was added to the reaction vessel and it was capped and heated in a reaction block at 70° C. for 2 hrs. The solvent was removed and the product was purified via flash chromatography eluting with a gradient of 12%-100% EtOAc in heptanes to afford the title compound (260 mg, 52% yield) as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([OH:17])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:18])[CH:8]([O:17][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CCCC(O)C(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)s1

Procedure:
To a mixture of ethyl 6-(5-chloro-2-thienyl)-5-hydroxy-6-oxohexanoate (21.6 g), pyridine (6.4 g) and tetrahydrofuran (100 ml) was added dropwise phenyl chlorocarbonate (12.7 g) with stirring under ice-cooling. After the resulting mixture was stirred at room temperature for 16 hours, the reaction mixture was concentrated, diluted with ethyl acetate (400 ml) and washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(5-chloro-2-thienyl)-6-oxo-5-phenoxycarbonyloxyhexanoate as a yellow oil (30.5 g, quantitative).