Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1.CI.[NH4+].[Cl-]>C1COCC1>[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH:18]([CH3:2])[C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2c(c1)OCO2
Temperature: -15 °C
Yield: 63 %

Procedure:
To a solution of LDA in THF (60 mL) was added methyl 3,4-methylenedioxyphenylacetate (2 g, 10.3 mmol) at -78° C. and the solution was warmed to -15° C. for 45 min. MeI (4.39 g, 30.9 mmol) was added and the reaction was warmed to room temperature for 16 h. The reaction mixture was then poured to a separatory funnel containing NH4Cl (80 mL) and the product was extracted with EtOAc (2×150 mL) and dried over Na2SO4. The crude product obtained by removal of the solvent was purified by flash chromatography to give the product as a colorless solid (1.36 g , 63%). 1H NMR (CDCl3) 6.75 (m, 3H), 5.95 (s 2H), 3.67 (s, 3H), 3.66 (m, 1H), 1.46 (d, J=7.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:17]([O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24](=[O:27])[CH2:25]Cl)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:25][C:24]([C:23]3[CH:28]=[CH:29][CH:30]=[C:21]([O:20][CH:17]([CH3:19])[CH3:18])[CH:22]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: CC(C)Oc1cccc(C(=O)CCl)c1
Product: CC(C)Oc1cccc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3-isopropoxy-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound. Rf =0.44 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [CH3:1][N:2]1[N:6]2[C:7](=[O:18])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=[CH:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([OH:18])[C:4]3[C:5](=[N:6][N:2]([CH3:1])[CH:3]=3)[N:10]=2)=[CH:12][CH:13]=1
Reactant: Cn1ccc2nc(-c3ccc(Cl)cc3)cc(=O)n21
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cc2c(O)cc(-c3ccc(Cl)cc3)nc2n1
Reaction time: 1.5 h

Procedure:
A mixture of 40.5 g. of 1-methyl-5-(p-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7(1H)one (0.156 ml.) and 120 ml. of diphenyl ether is heated with stirring at 250° for 90 minutes and then allowed to stand overnight. The crystallized 6-(4-chlorophenyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ol is filtered off, washed with acetonitrile and dried at 80°, yield: 37.3 g. (90%); m.p. 302°-305°. A sample, recrystallized from ethanol, melts at 305°-307°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:26][CH2:27][CH2:28][CH3:29])=O)(C)(C)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[CH2:26]([C@H:9]1[CH2:10][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:12][CH2:13][NH:8]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Temperature: -40 °C

Procedure:
The product from Step D was dissolved in ethyl acetate, cooled to -40° C. under nitrogen, and the solution saturated with HCl(g). The solution was warmed to 0° C. for 30 min, and then purged with nitrogen. The solvent was removed in vacuo. The product was evaporated from ethyl acetate three times. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH3:8][C:9]([CH3:11])=[O:10].C1OC1C>C[Si](C)(C)N[Si](C)(C)C.Cl.O.C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:9]([OH:10])([CH3:11])[CH3:8])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: CC(C)=O
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(O)P(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml of hexamethyldisilazane is heated to reflux under an inert gas for 20 hours. After this time a clear solution results and the reaction mixture is cooled to room temperature under inert gas and 50 ml of anhydrous acetone is added and an exothermic reaction results. The reaction mixture is allowed to cool to room temperature and the volatile components removed invacuo to afford a clear oil. This oil is dissolved in 50 ml of a 2.0M hydrochloric acid solution in water and washed with 2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer is evaporated to dryness to give a semi-solid residue which is co-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml) yielding3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloride m.p. 159°-161° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid affords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p. 243°-244°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([C:20]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To 250 ml of a suspension of 12.56 g of methyl 2-aminoacetate hydrochloride in dichloromethane, 20.24 g of triethylamine was added, and stirred for 30 minutes at room temperature. After ice-cooling, 20 ml of a solution of 14.66 g of 2-thenoyl chloride in dichloromethane was added dropwise slowly. The ice-bath was removed and the mixture was stirred for 14 hours at room temperature. The precipitated crystals were collected by filtration and washed with dichloromethane. The solvent was removed from the filtrate by distillation under reduced pressure. To the residue was added t-butyl methyl ether to precipitate. The both products were combined to provide 17.20 g of the objective compound as brownish crystals.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.CN(C=O)C>CO.C(O)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:35]([CH3:36])=[CH:34][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-isopropylpiperazin-1-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (36.7 mg, 0.059 mmol), 5M NaOH (236 μL, 1.18 mmol)) in methanol (0.2 mL) and THF (1.0 mL) was stirred at 45° C. for 2 h, then stirred overnight at rt. Acetic acid (1 drop) and DMF (0.3 mL) were added and mixture concentrated to ˜0.3 mL, diluted with DMF/methanol, filtered and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give product after lyophilization. LCMS-ESI+: calc'd for C32H38ClN4O3S: 593.2 (M+H+); Found: 593.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.66 (dd, J=8.5, 1.8 Hz, 1H), 7.61-7.48 (m, 4H), 7.33 (dd, J=5.4, 1.3 Hz, 1H), 5.24 (s, 1H), 4.77-4.40 (m, J=33.2 Hz, 2H), 3.58 (td, J=13.2, 6.6 Hz, 1H), 3.50-3.14 (m, 2H), 2.58 (s, 3H), 1.41 (d, J=6.7 Hz, 6H), 0.95 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:11]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:9]([I:11])=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: II
Reactant: Cc1ccc(C#N)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol, 2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere. N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for one hour. The clear solution became turbid indicating the salt formation. The reaction mixture was cooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 ml) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was re-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03 mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperature below −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a saturated solution of Na2S2O3 (10 ml) and stirred for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over sodium sulphate. The volatiles were evaporated under reduced pressure. The crude product was purified under silica gel (60-120) column chromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg (38%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92 Hz), 7.48-7.50 (t, 1H, J=4.80 Hz).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1>C(O)(=O)C.O>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[NH:23][CH3:24]
Reactant: CNc1c(OC)cc(C(=O)OC)cc1OC
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 44.2 g. of dimethylsulfone and 16 g. of sodium hydride (50% dispersion in oil) in 150 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 4 hours under an atmosphere of nitrogen and the exclusion of moisture. 30.4 g. of 3,5-dimethoxy-4-(methylamino)-benzoic acid methyl ester were added and the mixture was stirred at 80° C. for 10 minutes and at 25° C. for 30 minutes. The mixture was then dissolved in 600 ml. of water and the solution was made neutral by the addition of glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 3',5'-dimethoxy-4'-(methylamino)-2-(methylsulfonyl)-acetophenone having a melting point of 98°-99° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.Cl>C(O)CCC.O1CCOCC1>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: c1ccc(-c2nc(NC3CCNCC3)nc3ccccc23)cc1
Yield: 117.1 %

Procedure:
A solution of 2-chloro-4-phenylquinazoline (1.38 g, 5.75 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (2.81 g, 14.1 mmol) was heated at reflux in n-butanol (20 mL) for 4 h. After removal of the n-butanol on a rotary evaporator, dichloromethane (100 mL) was added and the suspension was sonicated for 30 min and filtered. The solution was then concentrated on a rotary evaporator to give a brown residue. This residue was purified by column chromatography on silica gel (95:5 hexanes/ethyl acetate) to yield a green oil that was treated with 4M HCl in 1,4-dioxane (100 mL) at 100° C. for 1 h. The solvent was removed on a rotary evaporator to give 4-phenyl-N-(piperidine-4-yl)quinazolin-2-amine (2.05 g, 90%) as a dark yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH3:25][C:24]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ncccc4C)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(3-Methyl-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 14.1c from 100 mg (0.24 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1b) and 138 mg (0.97 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[C:8]([CH2:11][CH2:12][CH:13]([OH:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]2[C:26]=1[CH3:27]
Reactant: CCOC(=O)c1cn2c(C)c(C)nc2c(O)c1CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cn2c(C)c(C)nc2c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 96.3 %

Procedure:
A solution of ethyl 2,3-dimethyl-8-hydroxy-7-(3′-oxo-3′-phenylpropyl)-imidazo[1,2-a]pyridine-6-carboxylate (714 mg, 1.95 mmol) in ethanol (20 ml) is treated with sodium borohydride (74 mg, 1.95 mmol). The reaction mixture is stirred for 2.75 hours at ambient temperature. At 0° C. saturated ammonium chloride solution (20 ml) is added. The solution is evaporated until most of the ethanol has been removed and is extracted with dichloromethane (3×20 ml). The combined organic phases are dried over sodium sulfate and are evaporated to dryness. A brownish foam (692 mg) is obtained which is purified by flash chromatography [silica gel, solvent system: dichloromethane/methanol=15:1 (v/v)]. The title compound (540 mg, 75%) is isolated as an almost colourless foam, 90% purity according to 1H NMR analysis.—1H NMR (CDCl3, 200 MHz): □=1.40 (t, 3 H), 2.13 (mc, 2 H), 2.40 (s, 3 H), 2.52 (s, 3 H), 3.26 (mc, 1 H), 3.50 (mc, 1H), 4.39 (q, 2 H), 4.61 (dd, 1 H), 7.24 (mc, 5 H), 7.95 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:32]1[C@@H:36]([C:37](O)=O)[NH:35][CH2:34][C@@H:33]1O>CS(C)=O.[Cu]I>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:35]5[CH2:34][CH2:33][CH2:32][C@@H:36]5[CH2:37][N:35]5[CH2:36][CH2:32][CH2:33][CH2:34]5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@@H]3CN3CCCC3)cc1OCC2
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 (200 mg, 0.27 mmol), (R)-pyrrolidynlmethylpyrrolidine (412 mg, 1.33 mmol), K3PO4 (228 mg, 0.53 mmol), CuI (20 mg, 0.05 mmol) and L-4-transhydroxyproline (14 mg, 0.11 mmol) in DMSO (1 mL) was heated at 100° C. for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM then C18, gradient 5-45% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 144 (41 mg, 34%) as a white solid. LCMS: RT 4.78 min [M+H]+ 448.4. 1H NMR (DMSO, 400 MHz): δ 8.19 (1H, d, J=8.92 Hz), 7.88 (1H, d, J=0.63 Hz), 7.77 (1H, s), 6.45 (1H, dd, J=9.00, 2.43 Hz), 6.13 (1H, d, J=2.38 Hz), 5.96-5.93 (1H, m), 4.47-4.36 (4H, m), 3.89-3.81 (1H, m), 3.40-3.38 (1H, m), 3.14-3.04 (1H, m), 2.64-2.57 (2H, m), 2.50-2.34 (4H, m), 1.98-1.96 (4H, m), 1.74-1.66 (4H, m), 1.47 (6H, d, J=6.61 Hz)
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[C:11](=[O:20])[C:10]=12)=[O:5])C.Cl.[OH-:23].[Na+]>>[OH:23][C:8]1[N:9]2[C:18]3[C:13]([N:12]([CH3:19])[C:11](=[O:20])[C:10]2=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cn1c(=O)c2c(C(=O)O)nc(O)n2c2ccccc21
Yield: 81 %

Procedure:
A mixture of 1-bromo-5-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (1.5 g) and 0.5 N sodium hydroxide solution (40 ml) was heated on steam bath for 18 hours. After cooling and acidification by concentrated hydrochloric acid, the product precipitated out as a cream colored solid (0.9 g, 81% yield), m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:18][CH3:19].O.[Cl-].[NH4+]>O1CCCC1.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: COc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Oc2ccc(N)cn2)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 2-{[4-methyl-3-(methyloxy)phenyl]oxy}-5-nitropyridine (Intermediate 49, 568 mg) in tetrahydrofuran (25 mL)/water (12.50 mL), iron (609 mg, 10.91 mmol) and then ammonium chloride (584 mg, 10.91 mmol) were added and the reaction mixture was stirred for 8 hours at room temperature. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of Na2CO3 (5 mL) and extracted with ethyl acetate (2 times 40 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Biotage system with a 50 g SNAP column) using a as eluent a gradient cyclohexane/ethyl acetate from 8/2 to 1/1. Evaporation afforded the title compound as light yellow oil (465 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:4][Cl:5].[CH2:13](C1OC1)[Cl:14].C(OCC(O)CCl)(=O)C.C(OC(CCl)CO)(=O)C.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC(OC1CCCCO1)CCl)(=O)C.O1CCCCC1OCC(OC(=O)C)CCl.C(=O)([O-])[O-].[K+].[K+]>[Fe](Cl)(Cl)Cl.CO.C(O)(=O)C>[OH:1][CH2:2][CH:3]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:4][Cl:5].[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:3][CH:2]([OH:1])[CH2:13][Cl:14]
Reactant: ClCC1CO1
Agent: Cl[Fe](Cl)Cl
Agent: C1=COCCC1
Agent: CC(=O)OC(CCl)COC1CCCCO1
Solvent: CC(=O)O
Solvent: CO
Product: OC(CCl)COC1CCCCO1
Reaction time: 2 h

Procedure:
1-hydroxy-2-(tetrahydropyran-2-yl)oxy-3-chloropropane can be prepared by the following scheme: epichlorohydrin is reacted with acetic acid in the presence of a catalytic amount of iron trichloride to give a mixture of 1-acetyloxy-3-chloropropan-2-ol and 2-acetyloxy-3-chloropropan-1-ol, the major component. The mixture is treated with dihydropyran in the presence of p-toluenesulfonic acid for five hours at 25° C. to give a mixture of 1-acetyloxy-2-(tetrahydropyran-2-yl)oxy-3-chloropropane and 1-(tetrahydropyranyloxy)-2-acetyloxy-3-chloropropane. The mixture is added to a rapidly stirred mixture of aqueous methanol and potassium carbonate at 25° C. and stirred for two hours. Evaporation of the methanol, extraction and drying yields a mixture 1-hydroxy-2-(tetrahydropyran-2-yl)oxy-3-chloropropane and 1-(tetrahydropyran-2-yl)oxy-2-hydroxy-3-chloropropane. Fractional vacuum distillation yields pure 1-hydroxy-2-(tetrahydropyran-2-yl)-oxy-3-chloro-propane since the minor impurity is converted into the more volatile epoxy compound during the distillation procedure.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc(C(C)=O)cc2)c1
Yield: 77.4 %

Procedure:
Reaction of 4-aminoacetophenone (72 mg, 0.53 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-3-methoxy-benzamide (110 mg, 0.41 mmol, 77% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12]P(=O)(OC)OC)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:43]3[CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41][CH2:42]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C=C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cold (−78° C.) suspension of dimethyl (2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylphosphonate (0.35 g, 0.93 mmol) in THF (8.0 mL) was added a 2.0M solution of LDA in THF (0.49 mL) The resulting solution was allowed to warm to room temperature before the addition of a solution of 1-Boc-4-piperidone (0.19 g, 0.95 mmol) in THF (3 mL). The reaction mixture was then stirred at room temperature for 2 hours, and partitioned between brine and DCM. The organic layer was isolated, washed with brine, dried over MgSO4 and concentrated. The crude residue was then purified by flash chromatrography (0-75% EtOAc in heptane) to give the title compound (0.38 g, 91%). LCMS m/z: 449.2 (MH+).