Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CC(O)=O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2ccccc2N1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 116.5 %

Procedure:
To a solution of 2-tert-butyl-1H-indole (10 g, 48 mmol) in AcOH (40 mL) was added NaBH4 at 10° C. The mixture was stirred for 20 minutes at 10° C. before being treated dropwise with H2O under ice cooling. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 2-tert-butylindoline (9.8 g), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Br[CH2:40][CH2:41][OH:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][OH:42])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Reactant: OCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol (0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel is sealed and heated at 70° C. for 12 h. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (5×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified using preparative RP LC-MS to give 2-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanol (72) as a yellow powder: ESMS m/z 602.2 (M+H+).
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:28][OH:29])[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:27])[CH2:28][O:29][N+:6]([O-:8])=[O:7])=[O:24])([CH3:20])([CH3:21])[CH3:19]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In 200 ml of dry acetonitrile were suspended 17.9 g of nitronium tetrafluoroboron, and 17.5 ml of 2,4,6-collidine were added dropwise thereto at -5° C. to 0° C. under a nitrogen stream. The reaction mixture was stirred at 0° C. for 30 minutes, 10.7 g of N-t-butoxycarbonyl-L-alaninol were added thereto, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Then, the solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. The insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The thus obtained yellow oil was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (9:1) as an eluent to obtain 7.12 g of the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2×) and dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (mp 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N--H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1ccc(F)cc1Cl
Temperature: 0 °C

Procedure:
A solution of 5.25 g (0.033 mole) of 2-chloro-4-fluorobenzaldehyde in 100 ml of diethyl ether was cooled to -10° C., and 11.2 ml (0.033 mole) of a 2.95M solution of methylmagnesium bromide in diethyl ether was added dropwise with stirring. The reaction mixture was warmed to 0° C. and was stirred for several hours. After warming to room temperature, the reaction mixture was poured into an ice/water mixture. The resulting mixture was extracted with methylene chloride. The solvent was evaporated from the extract under reduced pressure, and the residue was passed through a column of silica gel, eluting first with heptane and then with ethyl acetate/heptane (1/9). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, leaving 1.46 g of 1-(2-chloro-4-fluorophenyl)ethanol as an amber oil. The nmr and ir spectra were consistent with the proposed structure. This reaction was repeated on a larger scale to provide sufficient 1-(2-chloro-4-fluorophenyl)ethanol for Step D.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1ccc(COc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 4-methylbenzyl chloride (4.78 ml), potassium carbonate (6.24 g), methyl iodide (5.41 g) and acetone (50 ml) was heated at reflux for 15 hours. After the reaction mixture was evaporated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(4-methylbenzyloxy)benzoic acid (5.92 g) as colorless crystals.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4]C.Br[Si](C)(C)C>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[S:9]([NH:8][CH2:7][P:3](=[O:2])([OH:4])[OH:6])(=[O:10])=[O:11]
Reactant: COP(=O)(CNS(=O)(=O)c1cccs1)OC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)CNS(=O)(=O)c1cccs1

Procedure:
The dimethyl ester (vii) was treated with bromotrimethylsilane according to the procedure described in Example 1, step 3, to afford the title compound: 1H NMR (300 MHz, CD3OD) δH 7.79 (dd, J=4.8, 1.2 Hz, 1 H), 7.64 (dd, J=3.9, 1.2 Hz, 1 H), 7.17 (dd, J=4.8, 3.9 Hz, 1 H), 3.16 (d, J=13.2 Hz, 2 H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O1[CH2:20][CH2:19][NH:18]C1=O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH2:19][NH2:18])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCO1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Product: NCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
ExxonMobil™ Aromatic 100 solvent (300 mL) was added into a 3-neck round bottom flask containing 4-phenylphenol (50.00 g, 294 mmol) and stirred for 15 minutes at room temperature. Potassium hydroxide pellets (1.9 g, 293 mmol) were added and the mixture heated to reflux temperature for 10 minutes. 2-oxazolidinone (26.5 g, 294 mmol) was added, and the reaction mixture continued to stir at reflux temperature for 4 hours. Additional 2-oxazolidinone (8.05 g, 92.4 mmol) was added and the reaction mixture was allowed to continue stirring at reflux for an additional 4 hours. After indication of complete conversion of 4-phenylphenol by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was filtered and the filtrate was collected. The solvent was evaporated in vacuo to obtain 14.5 g (23%) of the amine as a white solid. 1H NMR (DMSO, 400 MHz) δ 7.63-7.55 (m, 4H), 7.45-7.40 (m, 2H), 7.34-7.28 (m, 1H), 7.05-7.00 (m, 2H), 3.95 (dd, 2H, J=5.8, 5.8 Hz), 2.89 (dd, 2H, J=5.8, 5.8 Hz). 13C NMR (DMSO, 400 MHz) δ 158.3, 139.8, 132.4, 128.8, 127.7, 126.6, 126.1, 1 f4.9, 70.3, 41.0. MS (ESI) for C14H15NO [M+H] calc. 213.28. found 213.96.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].Cl.[CH3:38][N:39]([CH2:41][C:42](Cl)=[O:43])[CH3:40]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:42](=[O:43])[CH2:41][N:39]([CH3:40])[CH3:38])[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Product: CN(C)CC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and dimethylaminoacetyl chloride hydrochloride (Lancaster and Cat. No. L18475). LCMS (M+H)+: m/z=581.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:14][CH:15]([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1>>[F:14][CH:15]([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:9]3[O:10][CH2:11][CH2:12][O:13]3)[CH:6]=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1cccc(C2OCCO2)c1
Reactant: FC(F)Oc1ccc(I)cc1
Product: FC(F)Oc1ccc(C#Cc2cccc(C3OCCO3)c2)cc1
Yield: 85 %

Procedure:
Using essentially the same procedure described in Example 1, step a, and employing 2-(3-ethynylphenyl)-1,3-dioxolane and 1-(difluoromethoxy)-4-iodobenzene, the coupled product was obtained. This product was purified on silica gel (ISCO) using hexanes/EtOAc 5/1 as the eluting solvents to give 2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane as a yellow oil (7.9 g, 85% yield), MS m/e (M+H)+ 317; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7.5-7.6 (m, 4H).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)C.[BrH:10].[CH3:11][C:12]([OH:14])=O>>[BrH:10].[Br:10][CH2:11][C:12]([C:7]1[CH:6]=[N:5][CH:4]=[CH:9][CH:8]=1)=[O:14]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccccn1
Agent: Br
Product: O=C(CBr)c1cccnc1
Temperature: 60 °C

Procedure:
Acetylpyridine (120 g) is added to 33% HBr/AcOH (600 ml) with stirring (If the salt precipitates more AcOH, up to 800 ml may be added). Bromine (176 g) is added and the reaction mixture is heated to 60° C. for 2-3 h. The reaction mixture is cooled and ether (1400 ml) is added. The solid is filtered, washed with ether, and dried to give 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide (Compound 13), in quantitative yield
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:9]1[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]>>[C:6]([C:9]1[CH:10]=[C:11]([C:17]([NH2:18])=[O:2])[C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Product: CC(=O)c1cc(C(N)=O)c(=O)[nH]c1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 100 grams of concentrated sulfuric acid is added 10 g (0.056 mole) of 5-acetyl-1,2-dihydro-6-methyl2-oxo-3-pyridinecarbonitrile. The mixture is stirred at 60° C. for 5 hours, cooled and then poured on 1 kg ice. The resulting solid is collected, washed with water and recrystallized from ethanol to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of 4-fluorobenzenemethanamine, 63 parts of sodium carbonate and 900 parts of N,N-diamethylacetamide was stirred for 1 hour at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 106 parts (75%) of N-[(4-fluorophenyl)methyl]-3-nitro-4-pyridinamine; mp. 136.8° C. (intermediate 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:37](Cl)(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:37](=[O:39])[CH3:38])[CH3:20])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
To a mixture of the compound (540 mg) obtained in Example 446, potassium carbonate (1.96 g) and acetonitrile (30 ml), acetyl chloride(890 mg) was added and heated under reflux for 24 h. Ethyl acetate was added to the reaction mixture, which was washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:ethyl acetate=5:1) to give 330 mg of the titled compound (yield, 55%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.Cl[CH2:21][CH:22]=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:21]=[CH:22][N:12]=[C:7]3[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(N)=Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[C@@H]1c2nccn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 68 °C

Procedure:
(R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydropteridin-6-amine (177 mg, 0.64 mmol) in MeOH (1.5 mL) treated with 50% aqueous chloroacetaldehyde (131 μL, 1.3 Eq.) and the reaction mixture heated to reflux for 6 hours. A further portion of 50% aq. chloroacetaldehyde (400 μL, 3.0 Eq.) was added, and the reaction mixture heated to 68° C. overnight. NaHCO3 (aq. sat.) and EtOAc was added, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Fc1cc(-c2ncccn2)ccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (29AB) (675 mg, 2.61 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine (1.32 mg, 1.82 mL, 13.05 mmol, 5 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (591 mg, 417 uL, 5.23 mmol, 2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][CH2:16][CH:17](O)[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[C:13]=2[CH:12]=1>C(Cl)Cl.O>[Br:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][CH2:16][CH:17]([F:7])[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[C:13]=2[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Solvent: O
Solvent: ClCCl
Product: FC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
DAST (94 mg, 0.583 mmol) was added to a solution of 2-bromo-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (100 mg, 0.29 mmol) in CH2Cl2 (1 mL) under N2 at −78° C. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ether:EA=10:1) to provide 2-bromo-7-fluoro-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indole (40 mg, yield: 40.0%). MS (M+H)+: 346/348.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+]>CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[CH2:30])[OH:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(O)c1ccc(OCCCCl)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C=C(O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Yield: 106.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 0.0195 mol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g, 0.0195 mol), KI (200 mg), NaHCO3 (1.8 g, 0.0215 mol) and CH3CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%) of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzene methanol as a light beige solid, m.p.=142°-144° C.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].CO.[OH-].[Na+].Br[CH2:15][CH2:16][OH:17]>O>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][S:7][CH2:15][CH2:16][OH:17])[CH3:3]
Reactant: OCCBr
Reactant: CCN(CC)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)CCSCCO
Temperature: 25 °C
Yield: 87.5 %

Procedure:
2-(Diethylamino)ethanethiol hydrochloride (5.0 g, 29 mmol) was added to a 250 mL round-bottom flask, 20 mL methanol was added, and the solution cooled in an ice bath with stirring. Sodium hydroxide (2.34 g, 58 mmol), dissolved in water (15 mL), was added, followed by slow addition of 2-bromoethanol (5.9 g, 47 mmol). Stirring was continued while the reaction mixture was allowed to warm to room temperature overnight. The methanol and water were removed under reduced pressure, and the residue dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give 2-[2-(diethylamino)-ethylthio]ethanol as a yellow oil (4.5 g, 87% yield). LC-MS (ES+): m/z=178 [C8H19NOS+H+] for product peak. A 1.0 g aliquot of the crude 2-[2-(diethylamino)ethylthio]ethanol was purified by flash chromatography on silica cartridges, eluting with a gradient of 100% hexane to 100% ethyl acetate over 5 minutes, to give 0.78 g pure 2-[2-(diethylamino)ethylthio]ethanol as a colorless oil after evaporation of the solvents, and the remaining 3.5 g similarly purified, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes, to give an additional 3.11 g pure 2-[2-(diethylamino)ethylthio]ethanol.