Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.CN(C)P(N(C)C)(N(C)C)=[O:16].[CH2:24]([O:26][C:27]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25].[O:39]1[CH2:43]CCC1>CCOCC>[CH2:24]([O:26][C:27]1[CH:37]=[C:36]([CH2:38][C:43]([OH:39])=[O:16])[CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]
Reactant: CCOC(=O)c1ccc(C)cc1OCC
Reactant: C1CCOC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Under an atmosphere of nitrogen, n-butyllithium (25 ml, 15% w/w solution in hexane) was added to a solution of diisopropylamine (3.6 g) in tetrahydrofuran (30 ml) at −30° C. The mixture was stirred at −30° C. for 30 minutes, cooled to −75° C., and hexamethylphosphoramide (HMPA, 10 g) was added slowly. A solution of ethyl 2-ethoxy-4-methylbenzoate (5 g) in tetrahydrofuran (10 ml) was then added at −75° C. and the mixture was stirred for two hours. Carbon dioxide gas was then purged into the reaction mixture at −75° C. till complete decolorization. The reaction mixture was then stirred at −75 to −70° C. for 30 minutes and then brought to 10° C., diluted with water (50 ml), and extracted with ether. The aqueous layer was acidified with 10% aqueous sulphuric acid to pH ˜2 and extracted with dichloromethane. The combined dichloromethane layer was washed with water and concentrated in vacuo. The oily product so obtained was re-dissolved in ether (50 ml) and washed with water. The ethereal layer was then concentrated in vacuo to afford a thick oil which solidified on keeping at room temperature to afford 3-ethoxy-4-(ethoxycarbonyl)phenyl acetic acid 4.4 g (72.7%).
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)#[N:9].BrN1C(=[O:31])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:8]([N:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)#[N:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CN1c2ccccc2CCc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 87.5 °C
Yield: 52.2 %

Procedure:
190 ml of chlorobenzene and 25 g of (I) are loaded into a 500 ml pyrex round-bottom flask, under nitrogen. Afterwards, 21.2 g of N-bromosuccinimide and 2.2 g of dibenzoylperoxide are added and the mixture is heated to 85-90° C., keeping this temperature for 1.5 hours. 150 ml of water and 5 g of PEG 6000 are added, heating to 85°-90° C. for 2 hours. After decanting at 60° C., water is removed and the organic phase is washed with further water (2×100 ml). Chlorobenzene is evaporated off under vacuum at 5 mm/Hg and the residue is taken up with 50 ml of ethyl acetate. The mixture is cooled to 0° C. for 2 hours, filtered and dried at 60° C. for 4 hours, to obtain 14 g of (VI), m.p. 111-112° C., with good purity.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=[O:5].[AlH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1>O>[CH3:1][O:2][CH2:3][C:4]([O-:6])=[O:5].[AlH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1
Reactant: COCC(=O)O
Agent: C1CC[AlH]OC1
Solvent: O
Product: COCC(=O)[O-]
Temperature: 1100 °C
Reaction time: 0.83 h

Procedure:
Pseudoboehmite (10.0 g) and methoxyacetic acid (25.6 mL) were refluxed in water (150 mL) for 24 h. which resulted in a white cloudy solution with a trace of insoluble particles. The water was removed in vacuo (10−2 Torr) at 50° C. resulting in a white powder which was washed with diethyl ether (4×150 mL) then dissolved in ethanol (100 mL) while stirring (50 minutes). The alumoxane was precipitated via the addition of ether (300 mL). After drying overnight at 50° C. the solid yield was approximately 20 g. The powder was dissolved in water (100 mL), isolated by filtration, concentrated under vacuum and dried at 50° C. resulting in a white solid material. The alumoxane was heated from 25° C. to 225° C. at the rate of 1° C./min., soaked for 30 mins. at 225° C., followed by a temperature ramp up to 300° C. at the rate of 2° C./min., and soaked for 80 mins., with a final ramp to the maximum temperature of 1100° C. (over 360 minutes) which was then maintained for 400 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CN(C)C1C=CC=CC=1.[C:19]([O:22][CH2:23][CH3:24])(=O)C.[C:25]1([CH3:32])[C:26](C)=[CH:27]C=[CH:29][CH:30]=1>>[CH3:19][O:22][C:23]1[CH:24]=[CH:32][C:25]([C:26]2[NH:9][C:5]3[C:6]([CH:27]=2)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:30][CH:29]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1C
Solvent: CN(C)c1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3[nH]2)cc1
Temperature: 170 °C

Procedure:
A solution of 33 grams (0.16 mole) of 4-methoxy-bromacetophenone in 230 ml of xylene was dropped into a mixture of 54.5 grams (0.45 mole) of m-anisidine and 76 ml of N,N-dimethyl aniline which was heated to 170° C. bath temperature. After cooling the mixture was treated with ethyl acetate and extracted by shaking with 2N HCl. The aqueous phase was again terated with ethyl acetate and the combined organic phases extracted by shaking several times with 2N HCl. After washing with water and drying the solvent was removed in a vacuum. The crystalline residue was washed colorless with a little ethyl acetate. Yield: 18.8 grams, M.P. 228°-230° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.[OH-:11].[K+].[OH2:13]>CO.C(Cl)Cl>[N+:1]([C:9]1[CH:4]=[CH:5][C:6]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:7][CH:8]=1)([O-:13])=[O:11]
Reactant: O
Reactant: [OH-]
Reactant: Nc1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(-c3ccc([N+](=O)[O-])cc3)c[nH]c2c1
Temperature: 70 °C
Yield: 34 %

Procedure:
To a solution of the protected indol-6-amine (300 mg, 0.76 mmol) in methanol (9.00 mL) was added potassium hydroxide (941 mg, 16.8 mmol). The reaction was warmed to 70° C. for 4 h. After that time, the reaction was diluted with water (10.0 mL) and methylene chloride (15.0 mL) and the organic phase was removed. The aqueous layer was extracted with methylene chloride (3×15.0 mL), and the combined organic phases were concentrated. The crude residue that remained was purified by flash chromatography (10-25-50% ethyl acetate/hexane) to give a burgundy red solid for 3-(4-nitrophenyl)-1H-indol-6-amine (66.3 mg, 0.26 mmol, 34%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11]Cl.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COCCl
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccnc1Br
Temperature: -20 °C

Procedure:
50 g of 2-bromo-3-hydroxypyridine was suspended in 200 ml of tetrahydrofuran, followed by adding 33 ml of chloromethyl methyl ether. While cooling to −20° C. and stirring, 17 g of 60% oily sodium hydride was added thereto little by little. After adding sodium hydride, the cooling medium was removed, followed by stirring at room temperature for 3.5 hours. Under cooling, ice water was added thereto little by little and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10-15% ethyl acetate/hexane as an eluent for separation and purification, to give 35 g of the target compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.Cl.[NH2:28][C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:32]=[CH:31][C:30]=1[OH:48]>CN(C)C=O.ClCCl.N1C=CC=CC=1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][S:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH:32]=[CH:31][C:30]=2[OH:48])=[O:24])=[CH:25][CH:26]=1
Reactant: Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Reactant: O=C(O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
At -78° C., oxalyl chloride (135 mg, 1.06 mmol) was added to a mixture of 4-[2-(2-benzothiazolyl)vinyl]benzoic acid (247 mg, 0.88 mmol), dimethylformamide (one drop) and dichloromethane (10 ml), and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Under ice-cooling, the resulting compound was gradually added to a mixture of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol hydrochloride (320 mg, 0.88 mmol), pyridine (3 ml) and dichloromethane (10 ml), and the resulting mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was heated until reflux and then cooled. Then, the solid material formed was collected by filtration and dried under reduced pressure. Ethanol (10 ml) was added to the resulting solid material, and the mixture was heated until reflux and then cooled. The crystals formed were collected by filtration and dried under reduced pressure to give 4-[2-(2-benzothiazolyl)vinyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzanilide (335 mg, 0.57 mmol, 65%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (242 mg, 1 mmol), 2-methylpropan-2-amine (110 mg, 1.5 mmol), EDCI (382 mg, 2 mmol) and DMAP (244 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature for 3 hours. Then the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude residue was used to the next step without further purification. MS: (M+H)+=297.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:16]([F:27])[CH:15]=2)[N:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=2[O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:16]([F:27])[CH:15]=2)[N:3]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OCC(C)C)c(Cn3nc(C)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)n(Cc2cc(COc3ccc(CCC(=O)O)c(F)c3)ccc2OCC(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a mixed solution of ethyl 3-[4-({3-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-4-isobutoxybenzyl}oxy)-2-fluorophenyl]propanoate (0.37 g, 0.77 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (0.25 g, yield 56%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (1.33 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (1.17 g, yield 93%), which was then recrystallized from tetrahydrofuran-hexane. melting point: 157–158° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1.CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:13][C:14]([C:15]#[N:16])=[C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:18]=1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of imidazole (4.45 g, 65.4 mmol) in tetrahydrofuran (30 mL) and dimethylformamide (10 mL) was added potassium carbonate (9.95 g, 72 mmol) and the mixture was stirred for 30 min at room temp. To this was added 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixture stirred at 90° C. for 3 h then at room temp for 2 days. The mixture was filtered and concentrated and the residue was purified by flash chromatography (SiO2) eluting with 20% to 70% ethyl acetate/hexane to give the title compound as white needles (1.1 g, 9% yield). 1H-NMR (500 MHz, CDCl3) δ ppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H, t, J=8.7, 5.6 Hz), 7.37 (1H, t, J=1.4 Hz), 7.29 (1H, t, J=1.1 Hz), 7.27-7.21 (2H, m). LCMS [M+H]+ calcd for C10H7N3F: 188.058; found: 188.12.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].[CH3:16][C:17]1[NH:18][C:19]([CH3:39])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.P(OC#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH3:16][C:17]1[NH:18][C:19]([CH3:39])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:22]=1[C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Agent: CCOP(=O)(OC#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)N2CCC3(CC2)CC(=O)N(OC)C3=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a solution of of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione.hydrochloride (0.21 g) obtained in Example 9, 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid (0.3 g) and triethylamine (0.26 ml) in dimethylformamide (7 ml) was added dropwise, under ice-cooling, 0.22 ml of diethyl cyano phosphate, and the mixture was stirred for 30 minutes. To the reaction mixture was added water (20 ml), which was stirred at room temperature, followed by extraction with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate. The solvent was then evaporated off under reduced pressure. The residual oily product was subjected to a silica gel column chromatography (eluent, ethyl acetate), and the solvent for the solution containing the desired product was evaporated off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 0.31 g of yellow crystals, m.p. 228° to 230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].CN1CCN(C)C1=O.P(Cl)(Cl)([Cl:26])=O.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>O>[CH2:29]([NH:33][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([Cl:26])[N:8]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCCN
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To 500 mg (2.41 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione were added 2 ml of 1,3-dimethyl-2-imidazolidinone and 8.23 g (53.64 mmol) of phosphorus oxychloride, and the resulting mixture was subjected to heating under reflux for 3 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 5.9 ml (60 mmol) of butylamine and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 430 mg (yield: 63.6%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([CH:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)([CH3:65])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][CH:66]1[CH:63]([CH3:65])[CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)C1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3C(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-isopropyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: Cl.C[C:3]1[C:4](=[CH:9][C:10]2[NH:11][C:12](C)=[CH:13][C:14]=2C)[N:5]=[C:6](C)[CH:7]=1.C(N(CC)CC)C.[B:24](F)([F:26])[F:25].CCOCC>ClCCl>[B-:24]1([F:26])([F:25])[N+:5]2=[CH:6][CH:7]=[CH:3][C:4]2=[CH:9][C:10]2[N:11]1[CH:12]=[CH:13][CH:14]=2
Reactant: FB(F)F
Reactant: CC1=CC(C)=NC1=Cc1[nH]c(C)cc1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: F[B-]1(F)n2cccc2C=C2C=CC=[N+]21
Reaction time: 0.25 h
Yield: 106.1 %

Procedure:
2-[(3,5-Dimethyl-2H-pyrrol-2-ylidene)methyl]-3,5-dimethyl-1H-pyrrole monohydrochloride (4 g, 16.89 mmol) was dissolved into 125 ml of dry dichloromethane to which triethylamine (17.09 g, 168.9 mmol) was added and allowed to stir for 15 minutes. The solution was then cooled with an ice bath to control the temperature during the slow addition of boron trifluoride etherate (2185 g, 168.9 mmol). Once the addition was complete, the ice bath was removed and the reaction was allowed to stir at room temperature for 2 hours. The reaction was then quenched with water and extracted three times with dichloromethane. The organic layer was then washed with saturated sodium carbonate. The organic layer was impregnated onto silica gel and then purified via column chromatography (10% dichloromethane in hexanes) to yield 3.44 g of Bodipy (82% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][OH:11])[CH:2]=[CH2:3].[CH3:12][N:13]=[C:14]=[O:15]>CC(C)=O.C(N(CC)CC)C>[CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][O:11][C:14](=[O:15])[NH:13][CH3:12])[CH:2]=[CH2:3]
Reactant: CN=C=O
Reactant: C=CCN1C(=O)CSC1=NO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CCN1C(=O)CSC1=NOC(=O)NC
Reaction time: 8 h

Procedure:
To a solution of (1.7 g) 3-allyl-2-oximino-4-thiazolidinone in 20 ml of acetone was added 1.0 ml methylisocyanate and 1 drop of triethylamine. The mixture was placed in a pressure bottle and left standing overnight at ambient temperature. The solution was concentrated to a solid residue. Recrystallized from ethyl acetate. Weight 1.7 g. m.p. 108°-110°C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: OC1CCCC1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(OC2CCCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclopentanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, sodium hydride (20 mg) was added and the mixture was stirred an additional 1 h at 90° C. The reaction was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 222 mg of 159.1 as a colorless oil. LCMS (2 min gradient) RT=2.01 min, 242.15 (M+H)+.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCOCC>[C:1]12([NH:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Product: S=C(NC12CC3CC(CC(C3)C1)C2)N1CCOCC1

Procedure:
The thiourea is prepared by reacting 5.0 g. (0.026 mole) of 1-adamantyl isothiocyanate with 2.5 g. (0.029 mole) of morpholine in 250 ml. of ether for ca. 1 hr. at room temperature. The solid which separates is collected and combined with additional compound from concentration of ether filtrate to a small volume: 6.65 g. (91 percent), m.p. 145-147. The analytical sample is recrystallized from ether, m.p. 148.