Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C#N)cc2)cc1Cl
Temperature: 110 °C
Yield: 74.4 %

Procedure:
5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 145 mg, 0.719 mmol) and potassium carbonate (400 mg, 2.561 mmol) were dissolved in DMSO (3.00 mL). Then 4-fluorobenzonitrile (200 mg, 1.651 mmol) was added and mixture was heated at 110° C. for 18 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to yield the title compound as a clear oil (162 mg, 74%):
Reaction SMILES: OCCCC[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15].C(O)CCCCC[OH:24]>>[OH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: OCCCCCCO
Reactant: C=C(C)C(=O)OCCCCCCCCCCO
Product: C=C(C)C(=O)OCCCCCCO

Procedure:
6-Hydroxyhexylmethacrylate was prepared using the same method as in the preparation of 10-hydroxydecylmethacrylate. 1,6-hexanediol was used instead of 1,10-decanediol. The same molar quantities of reactants were used. 11.5 g of product (62% yield) were collected.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24]Cl)[CH3:21]>C(O)(C)(C)C>[C:14]([O:13][C:3]([CH:4]([CH2:21][CH2:20][O:22][CH2:23][CH3:24])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOCCCl
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A 55% dispersion of sodium hydride in mineral oil (5.46 g) was added by portions to a solution of di-t-butyl malonate (25.8 g) in t-butanol (100 ml) under argon. The reaction mixture was stirred at ambient temperature for 1 hour before sodium iodide (1.53 g) and 2-ethoxyethyl chloride (13.1 ml) were added. The resultant mixture was heated to reflux for 48 hours and then evaporated to dryness. The residue was partitioned between water and ether, the organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The resultant oily residue was purified by flash chromatography on silica by elution with 10% ethyl acetate/hexane to give t-butyl 2-t-butoxycarbonyl-4-ethoxybutyrate (21 g) as a colourless oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.45 (18H, s), 2.07 (2H, m), 3.34 (1H, t), 3.45 (4H, m); Mass Spectrum m/Z 289 (M+H)+.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]1([NH:11][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)C1CCCCC1
Reaction time: 18 h
Yield: 91.5 %

Procedure:
Cyclohexanecarbonyl chloride (14.66 g, 0.1 mol) was added dropwise to a stirred solution of aniline hydrochloride (12.96 g 0.1 mol) and N, N-diisopropylethylamine (15.20 g, 0.2 mol) in dichloromethane (100 ml). The solution was stirred under an atmosphere of argon for 18 h, washed with 0.1 N-HC1 (3×50 ml) and dilute sodium hydrogen carbonate solution (50 ml), dried (MgSO4), and evaporated in vacuo to give the product (18.6 g) as white crystals.
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=2)=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2>C(O)(=O)C>[Br:1][C:6]1[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[S:3][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[N:9]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nccc(-c2sc3ccccc3c2Br)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
Bromine (0.48 g, 3.02 mmol) was slowly added at rt to a mixture of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (0.73 g, 2.52 mmol) in acetic acid (20 mL). The resulting mixture was stirred at rt for 15 h and then heated at 60° C. for 5 h. After cooling to rt, acetic acid was removed in vacuo. 100 mL of saturated sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×100 mL).). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the solid treated with 20 mL of methanol, filtered and dried to give the title compound (0.75 g, 80%). MS (M+H)+ 369/371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:33])[CH2:17][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (44 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was brought to 0° C. Trifluoroacetic acid (0.4 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 15%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([CH:7]2[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[CH2:9][C:8]2=[O:16])=O)[CH2:3][CH2:2]1.Cl.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)#[N:19].CC(O)=O>CCO>[CH:1]1([CH2:4][C:5]2[C:7]3[C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][C:12]=3[N:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:27]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc(C#N)cc3)c2C1
Yield: 51.2 %

Procedure:
2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (111.1 mg, 0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (84.8 mg, 0.5 mmol, 1.0 eq) were suspended in 4 mL of 3:1 EtOH:AcOH and microwaved at 100° C. for 10 minutes. The solvent was removed in vacuo and the resultant residue purified by column chromatography to yield 81.8 mg (51% yield) of 4-(3-Cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile as an off-white powder.
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[N:11]=[C:10]([CH2:12]O)[C:9]([F:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[N:11]=[C:10]([CH2:12][Br:3])[C:9]([F:14])=[CH:8][CH:7]=1
Reactant: OCc1nc(Br)ccc1F
Reactant: O=S(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a stirred solution thionyl bromide (2.44 g, 11.78 mmol, 1.05 eq.) in 50 ml dry DCM, cooled to 5° C., was added dropwise a solution of (6-bromo-3-fluoropyridin-2-yl)methanol (2.54 g, 11.22 mmol, 1 eq.) and pyridine (0.931 g, 11.78 mmol, 1.05 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 150 ml of water and 150 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried of MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 6-bromo-2-(bromomethyl)-3-fluoropyridine (2.89 g, 87% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH2:17][CH:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19]>CC(C)=O>[CH3:19][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)=CCCC(C)CCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCC[C@H](C)CCOc1ccc(C#N)cc1
Yield: 91.4 %

Procedure:
A mixture of 4-cyanophenol (6.0 g, 50.0 mmol), potassium carbonate (27.6 g, 200 mmol) and citronellylbromide (13.15 g, 60.0 mmol) in acetone (200 mL) was heated under reflux for 24 hours. The solvent was evaporated and the residue was taken up with CH2Cl2 (60 mL×2) and the solution filtered. The solvent was evaporated and the resulting oil was purified by flash column chromatography over silica gel (EtOAc/hexanes 1:1) as eluant to give 4-[(3S)-3,7-dimethyl-6-octenyloxy]cyanobenzene (11.76 g, 45.7 mmol, 91.4% yield) as a white oil.
Reaction SMILES: [C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8]C2C3C(=CC=CC=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)[CH2:4]1)#[N:2].[NH4+:48].[Cl-]>CO>[C:1]([C:3]1([NH:28][C:29](=[O:47])[CH:30]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:31][C:32]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:30]2[NH:48][C:42]3[C:41]([CH:40]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:4]1)#[N:2]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCC(C#N)(NC(=O)C(CC(=O)N4CCOCC4)CC4CCCCC4)C3)c3ccccc32)cc1
Agent: [Cl-]
Solvent: CO
Product: N#CC1(NC(=O)C(CC(=O)N2CCOCC2)CC2CCCCC2)CCN(Cc2cc3ccccc3[nH]2)C1
Yield: 76 %

Procedure:
A suspension of N-{3-cyano-1-[1-(toluene-4-sulfonyl)-1H-indole-3-ylmethyl]-pyrrolidin-3-yl}-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyramide (0.052 g, 0.079 mmol) and Mg (powder) (0.038 g, 1.6 mmol) in MeOH (5 mL) was sonicated at room temperature reaction was monitored by MS. When completed, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated to provide the title compound in 76% yield. The compound was recrystallized from Et2O/hexanes. 1H NMR (CDC13) 8.1 (1H, s), 7.71-7.69 (1H, m), 7.39-7.37(1H, m), 7.25-7.15 (3H, m), 6.9 (1H, s), 4.0-3.8 (2H, m), 3.7-3.3 (1H, m), 3.2-3.1 (1H, m), 3.0-2.5 (3H, m), 2.3-2.15 (2H, m), 1.8-1.4 (5H, m), 1.35-1.03 (5H, m), 0.95-0.78 (3H,m). MS, m/z 506=M+1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:46])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([CH3:45])[CH2:41][CH2:40]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:46][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:39]3[CH2:40][CH2:41][CH:42]([CH3:45])[CH2:43][CH2:44]3)=[CH:38][C:32]=2[N:31]=1)=[O:13]
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCN(c2ccc3[nH]c(-c4n[nH]c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
TFA (0.432 mL, 5.61 mmol) was added to solution of 2,2-difluoro-N-(3-(5-(4-methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropanecarboxamide (30 mg, 0.056 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (20 mg) as an off-white solid. 1H NMR: (400 MHz, CD3OD): δ 8.48 (d, 1H, J=1.2 Hz), 7.43 (dd, 1H, J=1.2 and 8.8 Hz), 7.55 (m, 2H), 7.20 (d, 1H, J=2.0 Hz), 7.06 (dd, 1H, J=2.0 and 9.2 Hz), 3.59 (m, 2H), 2.73 (m, 3H), 2.13 (m, 1H), 1.89-1.77 (m, 3H), 1.53-1.37 (m, 3H), 1.00 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 451.2.
Reaction SMILES: O[C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].FC(F)(F)C(O)=O>ClCCl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11](/[C:2](/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:3]/[C:4]#[N:5])=[CH:12][CH:13]=1
Reactant: CCCCCC(O)(CC#N)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC/C(=C\C#N)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of the above carbinol (107.8 g) in dichloromethane (540 mL) containing trifluoroacetic acid (21.6 mL) was heated at reflux for 7 hours and then was left at room tempertature overnight. The solution was washed in turn with water (250 mL). 1N NaOH solution (500 mL) and with brine (100 mL). After the aqueous layers were backwashed with dichloromethane (2×100 mL). the combined organic phases were dried (MgSO4) and evaporated to yield 99.2 g of crude (E)-3-(4-methoxyphenyl)-2-octenenitrile as an oil. The crude contained <8% of the (Z)-isomer.
Reaction SMILES: [S:1](=[O:24])(=[O:23])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[S:1](=[O:23])(=[O:24])([O:3][C:4]1[CH:21]=[CH:20][C:19]2[C@@H:18]3[C@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C@@H:13]([OH:22])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[NH2:2]
Reactant: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 3.5 °C
Reaction time: 20 h

Procedure:
To a cold (2-5° C.) suspension of moist 17-Oxoestra-1,3,5(10)-trien-3-yl sulfamate (171.7 mmol, from procedure I) in ethanol (450 ml), a solution of sodium borohydride (156.23 mmol) in water (94 ml) was added at 2-5° C. within a period of 20 minutes. The resulting mixture was stirred at 2-5° C. for another 20 hours. A solution of citric acid (495.86 mmol) in water (668 ml) was then added at this temperature within a period of 15 minutes to adjust the pH to 3. Water (668 ml) was added. The resulting crystalline solid was filtered and washed three times with water (500 ml). The wet crystals were suspended in acetone (2010 ml) and the resulting suspension was heated under reflux until complete dissolution. Removal of acetone (1700 ml) by destination resulted in a suspension, which was cooled to ambient temperature and filtered. The crystalline solid was washed with cold acetone (50 ml) and dried in vacuum. Yield: 45.06 g white crystals, purity (HPLC): 99.61%.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=4)=[CH:13][CH:14]=3)[C:9]([CH3:26])=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[S:19][CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[N:22]=4)=[CH:13][CH:14]=3)[C:9]([CH3:26])=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc(C(C)C)cs3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3nc(C(C)C)cs3)cc12

Procedure:
A solution of the ester (70 mg) from Step 1, 2 mL THF, 1 mL MeOH, and 1 mL 2N LiOH was stirred for 24 hours at room temperature. The mixture was poured onto 1N HCl, extracted 2× EtOAc, washed 2× brine, dried (MgSO4), and evaporated. The product was recrystallized from Et2O/hexane to give the title compound as a solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[CH3:24][O:25][C:26](=[O:31])[C:27](OC)=[O:28]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:27]([C:26]([O:25][CH3:24])=[O:31])=[O:28])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(=O)OC
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a solution of N-phenylsulfonyl indole (5.14 g, 20 mmol) in dry THF (100 ml) under argon, and cooled to -65° C., was added t-butyl lithium (13 ml, 22 mmol, 1.7 M in pentane). The solution was allowed to warm to 0° C. and stirred for 1 hr. The above solution was added via canula to a stirred solution of dimethyloxalate (9.5 g, 80 mmol) in THF (250 ml) at 0° C. After 4 hrs at 0° C. the mixture was quenched with saturated aqueous NH4CI and extracted with ethyl acetate (3×100 ml). The dried (MgSO4) extract was evaporated in vacuo, and the residue purified by chromatography over silica gel eluting with hexane/ethyl acetate (b 10:1) to give the α-keto ester 12 (2.3 g, 34%). M.p. 111-112° C. (from ethyl acetate). IR (CHCl3) 3680, 3619, 3415, 3019, 1743, 1692, 1600, 1537 and 1372 cm-1. λmax (ε) (MeOH) 208 (23930), 265 (4460), 275 (4170), 312 (10040) nm. 1H NMR (CDCl3) δ8.06 (1H, d, J=8.5 Hz), 7.78 (2H, d, J=7.5 Hz), 7.58 (1H,d, J=8 Hz), 7.51-7.37 (5H, m), 7.29 (1H, t, J=7.6 Hz), 3.99 (3H, s). 13C NMR (CDCl3) δ177.2, 161.3, 138.5, 136.7, 135.8, 134.1, 129.0, 128.7, 128.5, 127.0, 124.8, 123.4, 122.2, 115.3, 53.3. Anal. calcd for C17H13NO5S C, 59.47; H, 3.82; N, 4.08. Found C, 59.42; H3.84; N, 3.99%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.75 (m, 12H) 1.99 (m, 3H) 2.19 (s, 3H) 2.79 (m, 2H) 3.74 (m, 1H) 4.01 (t, J=14.0 Hz, 2H) 4.68 (m, 1H) 7.67 (d, J=8.6 Hz, 1H) 7.72 (d, J=12.4 Hz, 1H) 7.99 (t, J=8.2 Hz, 1H) 8.20 (d, J=7.3 Hz, 1H) 8.23 (s, 1H) 9.08 (s, 1H). [M+H] calc'd for C26H32F3N7O2, 532. found 532.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: CC(CO)(CCCCBr)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Under N2 atmosphere and cooling with an ice bath, 3,4-dihydro-2H-pyran (33.86 g, 0.40 mol) was added dropwise to a stirred solution of 206d (88.0 g, 0.32 mol) and p-toluenesulfonic acid hydrate (0.05 g, 0.03 mmol) in CH2Cl2 (700 mL). After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was filtered through aluminum oxide (160 g) and the aluminum oxide was washed with CH2Cl2 (800 mL). The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 207d (80.0 g, 70%) as an oil. 1H NMR (CDCl3): δ 7.40-7.14 (m 10H), 4.53 (t, 1H, J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H, J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33 (t, 4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s, 6H), 1.34-1.10 (m, 6H). 13C NMR (CDCl3=77.0 ppm): δ 145.67, 127.91, 127.91, 126.39, 126.37, 125.7, 98.95, 98.81, 76.11, 76.07, 62.78, 61.77, 61.66, 41.88, 41.78, 37.93, 37.75, 33.50, 33.44, 30.59, 30.44, 25.41, 25.37, 22.77, 22.71, 22.62, 19.65, 19.23, 19.15. HRMS (LSIMS, nba): Calcd for C15H28BrO2 (MH+): 355.1272, found: 355.1272.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[OH:23][C:18]1[C:17]([O:24][CH3:25])=[CH:16][C:15]([I:14])=[CH:22][C:19]=1[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(I)cc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: COc1cc(I)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(2-Hydroxy-5-iodo-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-iodo-o-vanillin (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, CDCl3) δ 2.60-2.64 (m, 4H), 3.48-3.52 (m, 4H), 3.69 (s, 2H), 3.85 (s, 3H), 5.39 (s, 1H), 6.94-6.96 (m, 1H), 7.07 (s, 1H), 7.84 (s, 1H), 12.13 (br s, 1H). Mass spectrum (ES) MH+=443.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=1
Reactant: COCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-methoxyethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.