Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH:8]=CC2C=CC=CC=2)[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]1=[O:24])=[N+:2]=[N-:3].C([OH:27])C.ClCCl.[BH4-].[Na+].Cl>C(O)C>[N:1]([C@H:4]1[C@@H:7]([CH2:8][OH:27])[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]1=[O:24])=[N+:2]=[N-:3]
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2CO)cc1
Reaction time: 0.08 h

Procedure:
A solution of (cis)-3-azido-1-(4-methoxyphenyl)-4-(2-phenylethenyl)-2-oxoazetidine (6 g, 18.75 mmole) in 1:1 ethanol-dichloromethane (180 ml) was cooled to -78° C. and ozonized until the mixture retained a purple hue. The reaction was purged with nitrogen, and sodium borohydride (2.835 g, 75 mmole) was added as a solid followed by 85 ml of ethanol. The mixture is allowed to stand at -78° C. for five minutes and then stirred at ice-bath temperature for one hour. The reaction was acidified to pH 4 with 3N hydrochloric acid, and the solvents were removed in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate and the organic extracts were washed with saturated potassium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated to a solid which was treated with ether. After standing under ether for three hours at 5° C., the white solid was filtered, washed with fresh ether, hexane, and dried under high vacuum. The yield of the title compound was 3.333 g.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.O[Li].O.[Li].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl.CN(C=O)C.O.C1COCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([Cl:28])=[O:2])=[CH:11][CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Agent: [Li]
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)c1cccnc1-c1ccc(C(F)(F)F)cc1
Reaction time: 3.5 h

Procedure:
To a solution of the title B compound, 2-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (0.626 g, 2.228 mmol) in 1:1 THF:H2O (10 mL) is added LiOH.H2O (0.187 g, 4.456 mmol). After 3.5 h, the reaction mixture is concentrated to dryness under reduced pressure. To a slurry of the crude lithium salt in methylene chloride (10 mL) is added oxalyl chloride (0.78 mL, 8.91 mmol) followed by a few drops DMF. After stirring 16 h, the reaction mixture is concentrated to dryness under reduced pressure and used as is without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].CN(C)C=O>O1CCCC1>[C:27]([O:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)Cl
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(=O)OCC(CCCC)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 50.5 %

Procedure:
To a 100 mL flask stirring under nitrogen was charged 2.88 g (0.0098 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexan-1-ol in 25 mL of tetrahydrofuran. To the mixture was added 2.5 mL of pyridine followed by 1.0 g (0.011 mole) of acryloyl chloride after which a precipitate formed. The reaction was monitored by GLC and was 60% complete after I hour. An additional 1.0 g of acryloyl chloride was added followed by 20 mL of dimethylformamide. The reaction was stirred at 60° C. until the precipitate dissolved and was then stirred overnight at room temperature. The reaction was quenched with 20 mL water and extracted with 10 mL ethyl acetate, washed with 2×10 mL water and 2×20 mL saturated sodium bicarbonate. The solvent was dried and concentrated; the residue was chromatographed on 50 g of silica gel. The product was eluted with a 1 to 1 mixture of hexane and ethyl acetate and gave 1.72 g (50.4% yield) of an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:13]([Cl:27])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:27][C:13]1[CH:12]=[N:11][C:10]2=[N:15][C:14]=1[NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([O:26][CH2:2][C:3]3[CH:4]=[C:5]([NH:9]2)[CH:6]=[CH:7][CH:8]=3)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(CCCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCCCc1cccc(c1)OCc1cccc(c1)N2
Yield: 19.5 %

Procedure:
To a solution of 3-{3-[(2-{[3-(bromomethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]propyl}phenol (50.0 mg, 0.112 mmol) in tetrahydrofuran (1.09 mL) was added a solution of sodium hydroxide in water (0.893 mL, 0.50 M). The resultant solution was stirred at rt for 16 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give the desired product as a white powder (8 mg, 20%). LCMS for C20H20ClN4O (M+H)+: m/z=367.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.75 (s, 1H), 7.26 (m, 1H), 7.17 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 6.88 (m, 1H), 6.70 (m, 1H), 6.60 (m, 1H), 5.17 (s, 2H), 3.48 (t, J=7.6 Hz, 2H), 2.74 (t, J=6.8 Hz, 2H), 1.91 (m, 2H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][N:7]=1.C(Cl)(Cl)Cl>C(OC(C)C)(C)C>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8]1)=[O:4]
Reactant: Oc1nsc(Cc2ccccc2)n1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CNC(=O)n1sc(Cc2ccccc2)nc1=O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
50 ml of methyl isocyanate were added to a solution of 15 g of 3-hydroxy-5-benzyl-1,2,4-thiadiazole in 400 ml of isopropyl ether and the mixture was stirred at 20° C for 72 hours. 50 ml of chloroform were added thereto and the mixture was vacuum filtered. The recovered crystals were dried to obtain 10 g of 2-(methylcarbamoyl)-5-benzyl-1,2,4-thiadiazole-3-one melting at 146° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1>CCO.C(O)(=O)C>[C:10]([C:18](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (31.7 g, 0.26 mol) and ethyl benzoylacetate (45.5 ml, 0.26 mol) in EtOH (45 ml) under an argon atmosphere was added piperidine (2.6 ml, 0.026 mol) and acetic acid (3 drops). After stirring at room temperature overnight, the resulting solid mixture was treated with hot EtOH (700 ml), and then allowed to cool. The crystals which formed were collected by filtration to afford the title compound (61.0 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](OCC)=[O:12])=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1.[H-].[Na+].O>CS(C)=O>[Br:22][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:11](=[O:12])[CH2:10][N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]=2[CH:6]=1
Reactant: CCOC(=O)CN(Cc1cc(Br)cnc1N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(c2ccccc2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 103 %

Procedure:
Ethyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(phenyl)amino)acetate (3.29 g, 9.0 mmol) was dissolved in anhydrous DMSO (105 mL) under Argon. NaH (361 mg of 60% dispersion in oil, 9.00 mmol) was added and the reaction was stirred for 12 h at room temperature. Water (200 mL) was added and the mixture was extracted with CH2Cl2 (4×100 mL). Combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated to afford 7-bromo-4-phenyl-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (2.95 g, 99%) as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.17-7.12 (m, 2H), 6.82-6.80 (m, 2H), 6.71-6.66 (m, 1H), 4.79 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:25]([CH2:23][CH3:24])[C:26]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: CCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Yield: 77.8 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (380 mg, 9.52 mmol) with ethyl isocyanate (2.0 mL, 25.36 mmol) in DMA afforded 1.725 g of the title compound as a solid, mp 156-157° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:10]=2)[C:5]1=[O:18]>O>[OH:13][CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([F:16])([F:17])[F:15])[CH:10]=2)[C:5](=[O:18])[N:4]1[CH2:3][C:2]([F:19])([F:1])[F:20]
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(=O)N1CC(F)(F)F
Solvent: O
Product: O=C1c2ccc(C(F)(F)F)cc2C(O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
5.5 g of 2-(2,2,2-trifluoro-ethyl)-5-trifluoromethyl-isoindole-1,3-dione were dissolved using 150 ml MeOH(anhydrous) and 1.0 g of KBH4 added at ambient temperature. The mixture was left at ambient temperature for 16 h, cooled to 0° C. and poured into 100 ml of water at 0° C. The methanol was removed in vacuo. The aqueous layer was extracted three times using 100 ml of CH2Cl2 each. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 4.2 g of a viscous oil (Rf(DIP)=0.37, MS (DCI): 300 (M+1)+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 6.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine, 5.51 g of ethyl bromoacetate, 4.5.6 g of potassium carbonate and 20 ml of acetonitrile was refluxed under heating for 2.5 hours. Then, 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 80° C. for 2 hours. To this mixture was added 2-80 g of ethyl bromoacetate. After an hour of stirring at 80° C., 2.28 g of potassium carbonate was added and the mixture was further stirred at 80° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with hexane-ethyl acetate (10:.1). The crystals from the eluate were recrystallized from ethyl acetate-hexane to give 7.4 g of ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4 -benzoxazin-4-yl)acetate. This compound has the following physicochemical properties.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH2:35]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc4ccccc4c3)c3c2CCNCC3)cc1
Yield: 55.4 %

Procedure:
The title compound (0.043 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using naphthalen-2-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C24H22ClN3, 387.15; found, m/z 388.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.74-7.69 (m, 3H), 7.45-7.38 (m, 5H), 7.34-7.32 (m, 1H), 7.18-7.16 (m, 2H), 5.43 (s, 2H), 3.04 (m, 2H), 2.99-2.97 (m, 2H), 2.87-2.85 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.COC(Cl)=O.Cl>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][OH:17])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (obtained according to: EP 0614 911 A1) (34.5 g) and triethylamine (28 ml) in dichloromethane (700 ml) is cooled to −70° C. and treated with methylchloroformate (12.9 ml). The reaction mixture is stirred 0.5 h at −70° C. The temperature is allowed to increase to 0° C. and the solution is stirred another 0.5 h until completion of the reaction. The reaction mixture is taken up in ice-cold dichloromethane, washed with an ice-cold 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water. The organics are dried over sodium sulfate and concentrated to 41.3 g of mixt-anhydride as an oil. This material is taken up in THF and treated at −70° C. with sodium borohydride (5.90 g), followed by absolute methanol (10 ml). The reaction mixture is stirred 15 h at 0° C. and 1 h at ambient temperature to drive the reaction to completion. A 0.5N HCl solution is then carefully added at 0° C., followed by ethyl acetate. The organics are washed with a saturated aqueous sodium carbonate solution, water, dried over sodium sulfate and concentrated. Chromatography on silica gel (A1) yields trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white powder, melting at 88-89° C. Rf (A1) 0.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[S:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:16]=1.C(=O)(O)[O-].[Na+:21]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[S:10][C:9]([C:13]([O-:15])=[O:14])=[CH:8][C:7]=2[CH:16]=1.[Na+:21]
Reactant: COc1ccc2c(=O)sc(C(=O)O)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(=O)sc(C(=O)[O-])cc2c1
Reaction time: 2 h

Procedure:
To a stirred suspension of 1.6345 g. (6.915 mM) of the carboxylic acid of Example 5 in 50 ml. of distilled water is added 0.5809 g. (6.915 mM) of sodium bicarbonate. After stirring at 25° for 2 hours, the solution is filtered and freeze-dried to give sodium 6-methoxy-1-oxo-1H-2-benzothiopyran- 3-carboxylate as a white solid, m.p. >360°.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C)C=O>[C:3]([NH:6][C:7]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCOC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A stirred suspension of 95% sodium hydride (60.8 g, 2.532 mol) in anhydrous dimethylformamide (500 ml) under an atmosphere of argon was cooled to 0° C. (ice bath). A solution of diethyl acetamido-malonate (500 g, 2.302 mol) in anhydrous dimethyl-formamide (1.2 1) was added over a period of 45 minutes while keeping the reaction temperature below 18° C. After the addition was complete, the turbid solution was gradually warmed to room temperature. After stirring for one hour at room temperature, 4-bromobutyl acetate (471.5 g, 2.417 mol) was added. The mixture was then stirred at 59°-60° C. for 18 hours. The resulting slurry was cooled to room temperature, quenched with absolute ethanol (40 ml) and glacial acetic acid (4 ml), stirred for about 15 minutes, poured into a 10% lithium chloride solution and extracted with ethyl acetate (2×3 l). The combined ethyl acetate extracts were washed with 10% lithium chloride (3×3 l), dried (anhydrous sodium sulfate), and evaporated in vacuo to give 750 g of title product as an oil.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([CH:21]=O)[CH:2]=1.[CH3:23][C:24]([NH2:29])([CH2:27][OH:28])[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[ClH:76]>CCO.CCOCC.O.C1(C)C=CC=CC=1>[ClH:76].[CH3:23][C:24]([NH:29][CH2:21][C:3]1[CH:2]=[CH:1][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:9]([C:8]3[C:19]=2[C:4]=1[CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[CH:12]4)([CH2:27][OH:28])[CH2:25][OH:26]
Reactant: O=Cc1ccc2c3cccc4cccc(c5cccc1c52)c43
Reactant: CC(N)(CO)CO
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(CO)(CO)NCc1ccc2c3cccc4cccc(c5cccc1c52)c43
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1 L Erlenmeyer flask was added 3-perylenecarbaldehyde (14.01 g, 50 mmol), 2-methyl-2-amino-1,3-propanediol (Aldrich, 5.52 g, 52.5 mmol), p-toluenesulfonic acid.H2O (Eastman Kodak Co., Rochester, NY, 14650, 0.1 g, 0.5 mmol), and PhCH3 (300 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting orange-brown colored solution was allowed to cool to RT, diluted with absolute EtOH (300 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 1.57 g, 25 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting dark blue solution was added 5 drops of 1M solution of HCl gas in absolute EtOH every 15 minutes. After 3 days the indicator turned dark green then orange and voluminous brown precipitate was present in the flask. To the flask was then added HCl gas (10 mL) in absolute EtOH. The reaction was diluted to 4 L with Et2O and stirred for 1 h. The precipitate was then collected by filtration through a medium porosity glass fritted funnel and pressed dry. The dark brown filter cake was washed thoroughly with 20% HCl (2×250 mL), pressed dry and then washed with CH2Cl2 (2×500 mL), pressed and sucked dry. The solid was recrystallized 3×from CH3OH/Et2O. After filtration, drying at 50°, 6.36 g (31%) of 2-methyl-2-((3-perylenylmethyl)amino)-1,3-propanediol hydrochloride mp 231°-232° (dec), (C,H,Cl,N).
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36](=O)[CH2:37]Cl)=[CH:24][C:23]=2[CH2:40][CH3:41])[C:12]=1[CH2:42][CH2:43][CH3:44].[CH:46]([NH2:48])=[S:47].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1.C(OCC)C.[OH-].[Na+]>[CH2:40]([C:23]1[CH:24]=[C:25]([C:36]2[N:48]=[CH:46][S:47][CH:37]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:42][CH2:43][CH3:44])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:45])[CH3:41]
Reactant: NC=S
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(C(=O)CCl)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-ethylphenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (500 mg, 0.792 mmol), thioformamide (20 mL, 8.0 mmol), and magnesium carbonate in dioxane (10 mL) was heated at reflux for 2 h. The mixture was cooled to room temperature and diluted with diethyl ether and 0.2 M sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 254 mg (50%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.91 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J=8, 1 Hz, 1H), 7.84 (d, J=1 Hz, 1H), 7.40 (m, 6H), 7.08 (m, 2H), 6.80 (d, J=8 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.16 (s, 2H), 4.21 (t, J=6 Hz, 4H), 3.83 (s, 3H), 2.68 (m, 4H), 2.32 (quintet, J=6 Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.21 Ct, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C38H40NO6S (p+1): m/z=638.2576. Found: 638.2579. IR (CHCl3, cm−1) 2964, 1719, 1563, 1461.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[N:6][CH:7]=1.[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>O1CCCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[O:13])=[N:4][CH:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NCCNc1ncc(Br)cn1
Solvent: C1CCOC1
Product: O=C1NCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N1-(5-Bromopyrimidin-2-yl)ethane-1,2-diamine (100 mg) was added to a solution of carbonyl diimidazole (30 mg) in tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred under nitrogen at room temperature for 1 h. The formed solution was concentrated to give an oil, which was purified by preparative TLC to afford the title compound. Yield: 13 mg (12% of theory).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[CH:46][CH:45]=2)=[N:40][N:41]([CH3:43])[CH:42]=1.[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68]O>C1(C)C=CC=CC=1>[CH3:43][N:41]1[CH:42]=[C:37]([O:36][CH2:68][CH2:67][CH2:66][C:58]2[N:57]([CH3:56])[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=3[N:59]=2)[C:38](=[O:55])[C:39]([C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[CH:46][CH:45]=2)=[N:40]1
Reactant: Cn1cc(O)c(=O)c(-c2ccnn2-c2ccccc2)n1
Reactant: Cn1c(CCCO)nc2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(OCCCc2nc3ccccc3n2C)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
Toluene (10 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (173 mg) and triphenylphosphine (229 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-1-methyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (154 mg), 3-(1-methyl-1H-benzimidazol-2-yl)propan-1-ol (143 mg) were further added and the mixture was stirred at room temperature for 22 hr. The crystals precipitated from the reaction mixture were collected by filtration, washed successively with toluene, methanol and diisopropyl ether, and dried to give the title compound (134 mg).