Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.C(O)C.[OH-].[K+].[ClH:34]>O>[ClH:34].[NH:10]1[CH2:11][CH2:12][C:13]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)c1ccccc1Oc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)Oc1ccccc1C21CCNCC1

Procedure:
A mixture of 1'-phenoxycarbonylxanthene-9-spiro-4'-piperidine (370 mg.), ethanol (80 ml.) and a 50% w/v solution of potassium hydroxide in water (20 ml.) is heated under reflux for 22 hours. The mixture is cooled and concentrated hydrochloric acid (20 ml.) is added and the ethanol is evaporated. The residue is washed with ether, water (50 ml.) is added and the resulting solution made alkaline with 3N sodium hydroxide. The alkaline solution is extracted with chloroform and the chloroform extract is washed with water, dried (MgSO4) and evaporated to dryness. The gummy residue is dissolved in ethanol and treated with ethereal hydrochloric acid. The solid is recrystallised from ethanol-ether to give xanthene-9-spiro-4'-piperidine hydrochloride, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: ClCCc1ccncc1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccncc2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 4-(2-chloro-ethyl)-pyridine by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (CD3OD) δ 8.68 (d, J=6.4 Hz, 2H), 8.27 (s, 1H), 7.84 (d, J=6.4 Hz, 2H), 7.06-6.98 (m, 3H), 4.75 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.53 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 409.1.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>CO.O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:43]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=[N+:44]=[N-:45]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(COc2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(COc2cccc(C(N=[N+]=[N-])c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To an ice-cooled suspension of methyl 4-((3-benzoylphenoxy)methyl)benzoate (1.62 g, 4.88 mmol) in methanol (20 mL), was added sodium borohydride (0.27 g, 7.32 mmol). The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford an oil. To a solution of the oil in toluene (25 mL), was added diphenylphosphoryl azide (1.26 mL, 5.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (881 μL, 5.85 mmol). The reaction mixture was stirred at 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water, brine, dried (magnesium sulphate), filtered and concentrated. The crude material was purified by silica gel chromatography eluting with 0-10% ethyl acetate in iso-hexane to afford the title compound (1.62 g, 92% over 2 steps).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[CH:9]([CH:11]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N.[Cl-].[Na+].O>[CH2:12]([C:11]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:18][CH:9]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(C=O)NC(=O)c1ccccn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)Cc1coc(-c2ccccn2)n1
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Hexachloroethane (445 mg, 1.87 mmol) was dissolved in 5 mL CH3CN. A solution of pyridine-2-carboxylic acid (1-formyl-3-methylbutyl)amide (137.5 mg, 0.625 mmol) in 2 mL CH3CN was added followed by triethylamine (375 mg, 3.75 mmol) and triphenylphosphine (491 mg, 1.87 mmol). The resulting mixture was stirred for ½ h, poured into brine, and extracted with 2×25 mL EtOAc. The combined extracts were washed with 1×50 mL brine, dried with Na2SO4 and evaporated to 665 mg of a tan solid which was flash chromatographed through SiO2 (20%-35% hexane/EtOAc) yielding 100 mg (76%) of the title compound as an amber oil, MS (ES) 203 (M+).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][C:23]([OH:25])=[O:24]>C1(C)C=CC=CC=1>[C:23]([O:25][C@@H:11]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]1=[CH:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21])(=[O:24])[CH3:22]
Reactant: CC(=O)O
Reactant: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of androst-5-ene-3,17-dione (2.00 g) in toluene (10 ml) at 15° C., AcOH (10 ml) and LTA (3.40 g) were added. After stirring for 2 h, the mixture was warmed to RT and stirred for 24 h. The reaction was quenched by addition of H2O and extracted three times with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by triturating with a 1:1 mixture of n-hexane:EtOAc (3 ml) to give 4α-acetoxyandrost-5-ene-3,17-dione (600 mg, 25%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH2:21])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH:21][S:30]([CH3:29])(=[O:32])=[O:31])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3]
Reactant: COC(=O)C1(CN)CC(c2ccc(F)c(C#N)c2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(CNS(C)(=O)=O)CC(c2ccc(F)c(C#N)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-cyano-4-fluorophenyl)-5-(aminomethyl)-5-(carbomethoxy)isoxazoline hydrochloride salt (1.15 g) in CH2Cl2 (50 mL) was added triethylamine (1.27 mL) and methanesulfonyl chloride (0.31 mL). The mixture was stirred at RT under N2 for 1 h. The solvent was diluted with CH2Cl2 and washed with water, 1N aqueous HCl, and saturated aqueous NaHCO3. It was dried over MgSO4 and concentrated to a yellow solid (1.13 g). 1H NMR (CDCl3) δ 7.92 (m, 2H), 7.30 (t, 1H), 4.82 (t, 1H), 3.84 (s, 3H), 3.76-3.60 (m, 4H), 3.03 (s, 3H) ppm; ESI mass spectrum z (rel. intensity) 377.9 (M+H, 100).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[C@@H:4]([CH3:6])[OH:5].[CH2:10](O)[CH3:11]>>[CH2:10]([O:8][C:7](=[O:9])[C@H:3]([C@@H:4]([CH3:6])[OH:5])[NH2:2])[CH3:11]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)[C@@H](C)O

Procedure:
A current of dry HCl was passed through a suspension of L-threonine (35.0 g, 0.29 mol) in absolute ethanol (350 ml), with shaking, until a clear solution formed. The solution then refluxed for 30 minutes, and was evaporated to dryness under reduced pressure, and the oily residue was taken up in absolute ethanol (175 mL) and, again, taken to dryness under reduced pressure. The oily residue was then treated with a saturated solution of ammonia in chloroform. The ammonium chloride was filtered off and the filtrate was taken to dryness at 0° C. under reduced pressure. A yellow solid was isolated (36.2 g. 85%); [α]29Na+0.82° (c 5.0, EtOH). Lit.12 [α]29D+0.95° (C 5.0 EtOH); m.p. 51-53° C. (Lit12 52-54° C.); 1H NMR (200 MHz, CDCl3 w/TMS) δ 4.82 (1H.m), 4.40 (1H,d), 4.05 (2H,q), 1.62 (3H,d), 1.21 (3H;t); FABMS 148.2 (M+H); HRFABMS Calcd for C6H14NO3 (M+H) 148-0974, found 148.0972.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>O>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Yield: 89.6 %

Procedure:
To a mixture of ethyl (4-hydroxy-3-methoxyphenyl)acetate (7.00 g), potassium carbonate (5.43 g) and N,N-dimethylformamide (100 mL) was added 4-chloromethyl-5-methyl-2-phenyl-1,3-oxazole (8.16 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetate as white crystals (11.38 g, yield 76%). melting point: 86-87° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:4]1=[O:21])[CH3:2]>CCO.[C].[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[C:4]2=[O:21])=[CH:17][CH:16]=1
Reactant: CCn1c(=O)n(-c2ccc([N+](=O)[O-])cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(N)cc2)c2ncccc21
Reaction time: 3 h
Yield: 41.4 %

Procedure:
The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (10.0 g), 4-nitroaniline (8.0 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2 g) and sodium tert-butoxide (12.5 g) in toluene (160 mL)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) as a light brown solid. A mixture of 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.50 g), sodium hydride (0.400 g) and iodoethane (2.0 mL) in DMF (40 mL) was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a brown solid. A mixture of 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.00 g) as a brown solid.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=1[N:23]=[C:24]=[O:25]>O>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:24]([NH:23][C:16]1[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=1[CH3:14])=[O:25]
Reactant: Cc1cc(C)c(N=C=O)cc1C
Reactant: CC(C)NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C)c(NC(=O)N(O)C(C)C)cc1C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
A solution of N-isopropylhydroxylamine hydrochloride (1.85 g, 16.5 mmol) in water (5 mL) was combined with diethyl ether (50 mL) then cooled in an ice bath. A solution of sodium hydroxide (0.72 g, 18 mmol) in water (10 mL) was added over a 10 minute period. The reaction mixture was stirred for 10 minutes then 2,4,5-trimethylphenyl isocyanate (2.42 g, 15 mmol) was added as a solid. The reaction mixture was stirred at ambient temperature for 18 hours. A white solid was isolated by filtration then recrystallized from hexanes/ethyl acetate to provide 2.4 g of the desired product as a white crystalline solid, m.p. 176.2°-176.8° C. Analysis: Calculated for C13H20N2O2 : %C, 66.07; %H, 8.53; %N, 11.85; Found: %C, 65.85; %H, 8.35; %N, 11.68.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)#[N:21].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(O)cc21
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCCc2ccc(OCc3cccc(C#N)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
tert-Butyl (7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (0.026 g, 0.10 mmol) was combined with m-cyanobenzyl bromide (Aldrich, Cat. #145610) (0.029 g, 0.15 mmol), acetonitrile (2.0 mL) and cesium carbonate (0.065 g, 0.20 mmol) and allowed to stir at r.t. overnight. This was diluted with ethyl acetate, filtered to remove the solids and concentrated under reduced pressure to give crude tert-butyl 7-(3-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.045 g) as a semisolid. Analytical LCMS (M+Na)+: m/z=401.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([N+:11]([O-])=O)[C:4]=1[N+:14]([O-])=O>CCO>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH2:14])[C:5]=1[NH2:11]
Reactant: COc1ccc(OC)c([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CCO
Product: COc1ccc(OC)c(N)c1N

Procedure:
3,6-Dimethoxy-benzene-1,2-diamine was synthesized by dissolving 6.0 g of 1,4-dimethoxy-2,3-dinitro-benzene (Eur. J. Org. Chem. 2006, 2786-2794) in 220 mL EtOH, evacuating 3 times with N2 and adding 600 mg of 10wt % Pd/C. The reaction was stirred under a H2 atmosphere (balloon). Another 300 mg of 10wt % Pd/C were added after 2 days and the mixture was stirred for another 24 h. Filtration over a pad of celite and washing with EtOH and EtOAc yielded after concentration in vacuo 4.3 g of the desired compound as black solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:24][C:25]([O:27]C)=[O:26])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:6]1)=[O:4].O1CCCC1.[OH-].[Li+].Cl>O>[C:25]([CH2:24][C:5]1([C:3]([OH:4])=[O:2])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:11]=2)[CH2:6]1)([OH:27])=[O:26]
Reactant: COC(=O)CC1(C(=O)OC)CC(c2ccc(OC)c(OC3CCCC3)c2)=NO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=NOC(CC(=O)O)(C(=O)O)C2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To a solution of the compound obtained from step c in tetrahydrofuran (1.0 eq), was added and lithium hydroxide (5.0 eq) in water (as 5N solution). The mixture was stirred at room temperature over night. The solvent was removed under reduced pressure and the residue thus obtained was diluted with water and acidified with drops of concentrated hydrochloric acid. The organic compound was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and finally concentrated under reduced pressure to afford title organic compound.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][C:6]([NH:10][C:11]([N:4]([O:5][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:3])[CH3:2])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(=O)NO
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(OC(=O)NC(C)(C)C)C(=O)NC(C)(C)C

Procedure:
Acetohydroxamic acid (7.5 grams), tert-butyl isocyanate (22 grams) and a few drops of triethylamine were stirred in 80 ml of methylene chloride for about 48 hours. After stirring, the solvent was removed under vacuum leaving a residue which was recrystallized from a solution containing methylene chloride and hexane. A subsequent recrystallization from methylene chloride left the desired, N-(((1,1-dimethylethyl)amino)carbonyl)-N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide, m.p. 111°-113° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2csc(Cn3cc(N)cn3)n2)OCCO1
Product: CC(=O)c1csc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)n1

Procedure:
Following general procedure B followed by C starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-1,3-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.93 min; [M+H]+=394.01.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:34][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([CH3:23])=[CH:25][CH:26]=[N:27]2)=[CH:32][CH:31]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1ccnc2cc(O)ccc12
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 90 %

Procedure:
Using a procedure analogous to that described for Example 10, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (130 mg, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 4-methyl-7-hydroxyquinoline (80 mg, 0.5 mol), (Chem. Ber. 1967, 100, 2077), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline (160 mg, 90%).
Reaction SMILES: O=O.[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](Cl)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:18]([NH2:22])[CH2:19][CH:20]=[CH2:21]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:22][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:10]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C=CCCN
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCCNc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 60 °C

Procedure:
Under rigorous exclusion of oxygen a mixture of 200 mg (0.88 mmol) 2-chloro-6-methyl-isonicotinic acid tert-butyl ester, 10 mg palladium(II)acetate (0.044 mmol), 27 mg (0.44 mol) BINAP (R(+)-2,2-bis(diphenylphosphino)-1,1-binaphtalene) and 62 mg (0.88 mmol) but-3-enylamine in 10 ml toluene is heated at 60° C. for 4 h. The mixture is diluted with EtOAc, washed with 10% aqueous NaHCO3 and water, dried with sodium sulfate and evaporated. Chromatography of the product on silica gel (hexane/EtOAc 9:1) yields the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OCCC(C)C)=O.[I-:20].[Na+]>C1COCC1.C(OCC)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:20])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1n[nH]c2ncc(F)cc12
Reactant: [I-]
Agent: CC(C)CCON=O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Fc1cnc2[nH]nc(I)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine were initially charged in THF (329 ml), and the mixture was cooled to 0° C. 16.65 ml (131.46 mmol) of boron trifluoride diethyl ether complex were then added slowly. The reaction mixture was cooled further to −10° C. A solution of 10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml) was then added slowly, and the mixture was stirred for a further 30 min. The mixture was diluted with cold diethyl ether (329 ml) and the resulting solid was isolated by filtration. A little at a time, the diazonium salt thus prepared was added to a cold (0° C.) solution of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml), and the mixture was stirred at RT for 30 min. The reaction mixture was poured into ice-water (1.8 l) and extracted twice with ethyl acetate (487 ml each time). The collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. This gave 12.1 g (86% purity, 60% of theory) of the desired compound in the form of a brown solid. The crude product was reacted without further purification.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:27][CH2:26]2)=O)=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:26][CH2:27]2)=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(C(=C2SCCCS2)C2CC2)cc1
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
A solution of 16.0 grams (0.083 mole) of 2-trimethylsilyl-1,3-dithiane in 80 mL of tetrahydrofuran was cooled to 0° C., and 39 mL (0.083 mole) of n-butyllithium (2.1M in hexane) was added. The reaction mixture was stirred for 15 minutes, and 15.0 grams (0.083 mole) of cyclopropyl (4-chlorophenyl) ketone in 40 mL of tetrahydrofuran was added via syringe during a five minute period. Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 minutes and then was allowed to warm for 30 minutes. The reaction mixture was stirred with 100 mL of an aqueous solution saturated with sodium chloride, and then the two phases were separated. The aqueous phase was extracted with one portion of diethyl ether. The ether extract was combined with the organic phase, and this mixture was dried with magnesium sulfate and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure, yielding 24.0 grams of 2-[(4-chlorophenyl)cyclopropylmethylene]-1,3-dithiane as a solid, m.p. 91°-95° C. The nmr spectrum was consistent with the proposed structure.