Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1([C:9]2([NH:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18]C)=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:18][O:17][C:15]([CH:14]1[C:4](=[O:5])[C:6]2([CH2:7][CH2:8]2)[C:9]2([CH2:10][CH2:11]2)[NH:12][C:13]1=[O:20])=[O:16]
Reactant: CCOC(=O)CC(=O)NC1(C2(C(=O)OCC)CC2)CC1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)NC2(CC2)C2(CC2)C1=O
Temperature: 85 °C

Procedure:
1′-(2-Ethoxycarbonyl-acetylamino)-bicyclopropyl-1-carboxylic acid ethyl ester (1 g; 3.53 mmol) in toluene (15 ml) is added rapidly to a solution of sodium (81 mg; 3.53 mmol) in methanol (3 ml) under stirring. The reaction mixture is warmed to 85° C. for 40 minutes, cooled to room temperature and the precipitate (sodium salt of title compound) filtered, washed with toluene, then heptane, dissolved in water (0.6 ml) and acidified with 2N HCl (1.75 ml). The resulting resin is decanted from water and crystallized by triturating with TBME (1 ml) to deliver the title compound as colorless crystals (633 mg; 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)c(C)c1
Yield: 99 %

Procedure:
To a suspension of 4-amino-3-methylbenzoic acid (5.00 g, 33.1 mmol) in ethanol (50 ml), concentrated sulfuric acid (5.00 ml) was slowly added. The mixture was heated under reflux for 3 hours. The solvent was distilled off under a reduced pressure. After the volume of the mixture was approximately halved, the mixture was neutralized with a saturated sodium bicarbonate solution. The mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated to give the title compound (5.87 g, 99%) as a light-brown solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH:17][N:18]([CH3:20])C)[C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])[CH3:2].[C:22]([NH:25][CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37]C(N)=[C:35]([F:40])[CH:34]=2)[CH2:28]1)(=[O:24])[CH3:23]>CCO>[C:22]([NH:25][CH2:26][CH:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:20]([NH:18]/[CH:17]=[C:5](/[C:6]([C:7]3[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=3[F:15])=[O:16])\[C:4]([O:3][CH2:1][CH3:2])=[O:21])=[C:35]([F:40])[CH:34]=2)[CH2:28]1)(=[O:24])[CH3:23]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Solvent: CCO
Product: CCOC(=O)/C(=C\Nc1ccc(N2CC(CNC(C)=O)OC2=O)cc1F)C(=O)c1cc(F)c(F)cc1F

Procedure:
Triethylamine (2.09 mL, 15 mmol) was added with stirring to a solution of 2,4,5-trifluorobenzoyl chloride (1.95 g, 10 mmol) and ethyl 3-dimethylaminoacrylate 20 (1.43 g, 10 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at r.t. overnight, and solvent was removed under vacuum. The residue was dissolved in ethyl ether (100 mL) and hexanes (20 mL), and the resulting mixture was washed with water (2×100 mL), 2% aq. citric acid (2×100 mL), brine (100 mL), 2.5% aq. NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried (MgSO4), and the solvents removed under vacuum to provide ethyl-2-(dimethylamino)methylene-2-(2,4,5-trifluorobenzoyl)acetate 21 as a light orange oil (Yield 2.55 g (85%). MS (m/z): 302 [M+H]+. Rt 4.9 min.). A solution of Compound 21 (0.301 g, 1.0 mmol) and 5-(S)-acetamidomethyl-3-(4-amino-3-fluorophenyl)-oxazolidine-2-one (0.267 g, 1.0 mmol) in EtOH (9 mL) was agitated at 40° C. for 16 h. The solvent was removed under vacuum, and the resulting residue dissolved in ethyl ether (75 mL). The ether solution was washed with 3% aq. citric acid (2×40 mL), brine (40 mL), and dried (MgSO4). The solvent was removed under vacuum to afford Compound 22 as a thick light-orange oil. Yield 0.50 g (90%). MS (m/z): 524 [M+H]+. Rt 5.5 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[Na+].[I-:14]>CC#N>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][I:14]
Reactant: Nc1ccc(F)cc1C(=O)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ccc(F)cc1C(=O)CI
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
To a solution of 23.463 g (125.069 mM) of 2'-amino-2-chloro-5'-fluoroacetophenone in 436 ml of CH3CN is added 56.2 g (375.2 mM) of NaI, and the mixture is stirred at room temperature for 45 min. and concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with aqueous Na2S2O3, and brine in order, dried and concentrated to give 29.97 g (Yield: 85.9%) of 2'-amino-5'-fluoro-2-iodoacetophenone as yellow crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7].Cl>O.C1COCC1>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 71.9 %

Procedure:
Lithium hydroxide monohydrate (874 mg, 20.8 mmol) was added to a suspension of the ester 28a (2.00 g, 4.17 mmol), 50 ml water, and 200 ml THF. The mixture was refluxed for 48 hours and then was acidified with concentrated HCl. Water (150 ml) was added and the solution was cooled. The resulting tan precipitate was filtered and washed with water. The tan precipitate was dissolved in 100 ml hot THF and hexanes were added until the solution remained cloudy with stirring. After cooling, crystals were filtered to yield 1.4 g of a light yellow solid, and a second crop of crystals was isolated for a total yield of 1.67 g (86%). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:38][O:39][CH3:40])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:38][O:39][CH3:40])=[N:22][C:23]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(OC(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 149D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:12]3[S:13][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][N:11]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.075 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (THF/hexane) to yielded the title compound as a light brown solid (0.037 g, 18%). MS (ISN) 519.0 [(M−H)−]; mp 264° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2C[C@@H]3C[C@H]2CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg, 0.848 mmol) and DIPEA (271 μL, 1.554 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (1S,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (148 mg, 0.428 mmol, 60.6% yield). LC-MS (M+H)+=346.1. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2H, m), 7.00-7.08 (2H, m), 5.11-5.21 (1H, m), 4.69-4.74 (1H, m), 4.15-4.26 (1H, m), 3.88-3.94 (2H, m), 3.68-3.86 (2H, m), 3.11-3.21 (1H, m), 2.56-2.69 (1H, m), 1.92-2.11 (2H, m), 1.24-1.42 (2H, m).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: O=C(O)C1CCN(c2cccc(Cl)c2)C1=O
Yield: 81.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3-chloroaniline (0.469 mL; 4.36 mmol) in ethanol (3 mL). 1-(3-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.282 g (81%) was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[O:14][CH2:15][CH:17]1[O:19][CH2:18]1
Reactant: Oc1cccc(N2CCCCC2)c1Cl
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1c(OCC2CO2)cccc1N1CCCCC1
Yield: 84.7 %

Procedure:
A mixture of 7.47 grams of 2-chloro-3-piperidinophenol, 29.00 grams of epibromohydrin, 28.79 grams of potassium carbonate and 400 ml of acetonitrile is heated to reflux for twenty hours, insoluble matters are removed therefrom by filtration, the filtrate is entirely concentrated to dryness, and the residue is purified by a silica gel chromatography followed by recrystallization from n-hexane to give 8.0 grams (85%) of 1-(2-chloro-3-piperidinophenoxy)-2,3-epoxypropane as colorless crystals of m.p. 55°-57° C. NMR (CDCl3): δ 1.55-1.95 (m, 6H), 2.75-3.19 (m, 7H), 4.10 (dd, 1H, J=11 Hz and 14 Hz), 4.18 (dd, 1H, J=11 Hz and 21 Hz), 6.54-6.77 (m, 2H). Elementary analysis calculated as C14H18ClNO2 : C 62.80, H 6.78, N 5.23, Cl 13.24; Found: C 62.61, H 6.87, N 5.08, Cl 13.15.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].O1CCOCC1.[C:16]1([CH2:22][O:23][CH2:24][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([CH2:22][O:23][CH2:24][CH:25]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Reactant: OCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(COCc1ccccc1)OCCCCCO
Temperature: 80 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
Into another flask, KOH (25.8 g), HO(CH2)5OH (47.9 g) and dioxane (200 ml) were charged and stirred at 90° C. until KOH was dissolved. Then, from a dropping funnel, PhCH2OCH2CH(CH3)OTs (71.2 g) and dioxane (75 ml) were added at 90° C. over a period of 20 minutes. After further stirring at 80° C. for 20 hours, water (350 ml) was added. Extraction with dichloromethane (100 ml) was carried out three times, and the extracted organic phase was washed with water (150 ml), then dried over anhydrous magnesium sulfate, filtered and further concentrated. The concentrated liquid was purified by silica gel column (eluent: hexane/ethyl acetate) to obtain PhCH2OCH2CH(CH3)O(CH2)5OH (20.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][O:16][C:14]([C@@H:9]1[CH2:10][C@@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a solution of methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate (4.68 g, 19.1 mmol) in DCM (47 mL) at RT was added DIPEA (3.66 mL, 21.0 mmol) and 4-dimethylaminopyridine (233 mg, 1.91 mmol) followed by p-toluenesulfonyl chloride (3.82 g, 20.1 mmol). The reaction mixture was stirred at RT overnight, washed with 1N HCl (2 mL), saturated sodium bicarbonate (2 mL), and brine (2 mL), dried over sodium sulfate, filtered and concentrated to give a yellowish oil, which was purified by silica gel chromatography (80 g silica, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate (1.74 g, 23% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[Cl:21].N>>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)[CH:17]=[CH:18][C:13]=1[Cl:12]
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Cl)c(Cl)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.50 (s, 1H), 7.72 (d, J=8.3 Hz 1H), 7.86 (dd, J=8.3, 1.9 Hz 1H), 8.12 (d, J=2.0 Hz, 1H), 8.17 (ddd, J=9.1, 2.8, 1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.97 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 311 (M+H)+, 309 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH2:10])=[N:2]1.N[C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:18]2[CH:19]=[N:20][CH:21]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[N:2]1
Reactant: COC(=O)c1ccncc1N
Reactant: Nc1noc2ccccc12
Product: O=C(O)c1ccncc1Nc1noc2ccccc12
Yield: 2 %

Procedure:
The title compound was prepared in 2% yield from 1,2-benzoxazol-3-amine and methyl 3-aminoisonicotinate according to the procedure for Preparation 1C, followed by hydrolysis according to Example 1. 1H NMR (400 MHz, DMSO-d6): δ 7.49 (1H, s), 7.73-7.90 (4H, m), 8.38 (1H, s), 9.62 (1H, s), 11.32 (1H, br s). [M+H] calc'd for C13H9N3O3, 256; found 256.
Reaction SMILES: [CH2:1]([C:19]([OH:58])([CH:38]([OH:57])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:59][N:60]([CH3:68])[CH2:61][CH2:62][CH2:63][CH2:64][C:65](O)=[O:66].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:59][N:60]([CH3:68])[CH2:61][CH2:62][CH2:63][CH2:64][C:65]([O:57][CH:38]([C:19]([OH:58])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:66]
Reactant: CN(C)CCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(OC(=O)CCCCN(C)C)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (6Z,9Z,29Z,32Z)-19-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraene-19,20-diol (0.75 g, 0.98 mmol), 5-(dimethylamino)pentanoic acid (285 mg, 2.0 mmol), EDC hydrochloride (378 mg, 2.0 mmol), and 4-(N,N-dimethylamino)pyridine (5 mg) in anhydrous dichloromethane (10 mL) was added DIPEA (0.68 mL, 3.9 mmol). The reaction was stirred for 16 hours at room temperature under nitrogen. TLC (1:1 hexanes/ethyl acetate) indicated that the reaction had stalled, so additional 5-(dimethylamino)pentanoic acid (70 mg, 0.5 mmol) and fresh EDC hydrochloride (300 mg, 1.6 mmol) were added. The reaction was stirred for an additional 24 hours under nitrogen at room temperature. The solution was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL). The combined aqueous layers were back extracted once with dichloromethane (50 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The resulting orange oil was purified by column chromatography on silica gel 60 (eluted with a gradient of 25%→50% ethyl acetate in hexanes) to afford (6Z,9Z,29Z,32Z)-20-hydroxy-20-((9Z,12Z)-octadeca-9,12-dienyl)octatriaconta-6,9,29,32-tetraen-19-yl 5-(dimethylamino)pentanoate as a pale yellow oil (560 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 5.43-5.29 (m, 12H), 4.95 (dd, 1H, J=10.1, 2.7 Hz), 2.78 (t, 6H, J=6.5 Hz), 2.38 (t, 2H, J=7.5 Hz), 2.28 (t, 2H, J=7.5 Hz), 2.22 (s, 6H), 2.09-2.02 (m, 12H), 1.72-1.42 (m, 13H), 1.41-1.19 (m, 56H), 0.90 (t, 9H, J=6.7 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:21]4=[C:22]5[C:17](=[CH:18][CH:19]=3)[CH:16]=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:13]5[CH:12]=[CH:11][C:10]4=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O>CN(C=O)C>[Br:29][C:16]1[CH:15]=[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:13]2[C:22]3=[C:21]4[C:10]([CH:9]=[CH:8][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[C:20]4[CH:19]=[CH:18][C:17]=13)=[CH:11][CH:12]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccc3ccc4c(-c5ccccc5)ccc5ccc2c3c54)cc1
Solvent: CN(C)C=O
Product: Brc1cc(-c2ccccc2)c2ccc3ccc(-c4ccccc4)c4ccc1c2c34

Procedure:
Under a flow of argon, 11.8 g of 1,6-diphenylpyrene, 5.93 g of N-bromosuccinimide and DMF were placed into a flask. The resulting mixture was allowed to react at 60° C. for 2 days. After cooling, the reaction solution was filtered, and solids obtained were washed with clean water, methanol and clean water, and solids obtained were dried under a reduced pressure, whereby white solids of 3-bromo-1,6-diphenylpyrene (8.60 g) were obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]2)[N:7]([CH3:21])[C:6]1=[O:22])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:26])(=O)=O.II>C(O)(=O)C>[Cl:26][C:17]1[CH:16]=[C:15]2[C:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:20]2=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)CN1C(=O)N(C)C2(NC(=O)NC2=O)c2ccccc21
Agent: II
Solvent: CC(=O)O
Product: CC(C)CN1C(=O)N(C)C2(NC(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
1-Isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.76 g) as prepared in Example 37 is suspended in acetic acid (15 ml) and thereto are added sulfuryl chloride (0.3 ml) and a slight amount of iodine, and the mixture is stirred at room temperature for 19 hours. The reaction mixture is poured into ice-water, and the precipitates are taken by filtration and the crystals are dissolved in 10% aqueous sodium hydroxide. The undissolved materials are filtered off, and the filtrate is neutralized with 10% hydrochloric acid, and the precipitates are taken by filtration (this dissolution and precipitation procedure is repeated). The precipitates are taken by filteration and dried to give 6-chloro-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:22][CH2:21][CH2:20][O:19][CH:18]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3=COCCC3)cc2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3CCCOC3)cc2C1

Procedure:
Prepared in analogy to Example A49(b) from 5-(5,6-dihydro-4H-pyran-3-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Light yellow oil. MS (m/e): 248.1 ([M+H-Me2C═CH2]+, 100%).